Journal articles on the topic 'MYC, breast cancer, epigenetic reprogramming'
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Laurent, Audrey, Thierry Madigou, Maud Bizot, Marion Turpin, Gaëlle Palierne, Elise Mahé, Sarah Guimard, et al. "TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis." Life Science Alliance 5, no. 7 (March 29, 2022): e202101283. http://dx.doi.org/10.26508/lsa.202101283.
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Methylation and demethylation of cytosines in DNA are believed to act as keystones of cell-specific gene expression by controlling the chromatin structure and accessibility to transcription factors. Cancer cells have their own transcriptional programs, and we sought to alter such a cancer-specific program by enforcing expression of the catalytic domain (CD) of the methylcytosine dioxygenase TET2 in breast cancer cells. The TET2 CD decreased the tumorigenic potential of cancer cells through both activation and repression of a repertoire of genes that, interestingly, differed in part from the one observed upon treatment with the hypomethylating agent decitabine. In addition to promoting the establishment of an antiviral state, TET2 activated 5mC turnover at thousands of MYC-binding motifs and down-regulated a panel of known MYC-repressed genes involved in lysosome biogenesis and function. Thus, an extensive cross-talk between TET2 and the oncogenic transcription factor MYC establishes a lysosomal storage disease–like state that contributes to an exacerbated sensitivity to autophagy inducers.
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Białopiotrowicz, Emilia, Monika Noyszewska-Kania, Neli Kachamakova-Trojanowska, Agnieszka Łoboda, Magdalena Cybulska, Aleksandra Grochowska, Michał Kopczyński, et al. "Serine Biosynthesis Pathway Supports MYC–miR-494–EZH2 Feed-Forward Circuit Necessary to Maintain Metabolic and Epigenetic Reprogramming of Burkitt Lymphoma Cells." Cancers 12, no. 3 (March 3, 2020): 580. http://dx.doi.org/10.3390/cancers12030580.
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Burkitt lymphoma (BL) is a rapidly growing tumor, characterized by high anabolic requirements. The MYC oncogene plays a central role in the pathogenesis of this malignancy, controlling genes involved in apoptosis, proliferation, and cellular metabolism. Serine biosynthesis pathway (SBP) couples glycolysis to folate and methionine cycles, supporting biosynthesis of certain amino acids, nucleotides, glutathione, and a methyl group donor, S-adenosylmethionine (SAM). We report that BLs overexpress SBP enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). Both genes are controlled by the MYC-dependent ATF4 transcription factor. Genetic ablation of PHGDH/PSAT1 or chemical PHGDH inhibition with NCT-503 decreased BL cell lines proliferation and clonogenicity. NCT-503 reduced glutathione level, increased reactive oxygen species abundance, and induced apoptosis. Consistent with the role of SAM as a methyl donor, NCT-503 decreased DNA and histone methylation, and led to the re-expression of ID4, KLF4, CDKN2B and TXNIP tumor suppressors. High H3K27me3 level is known to repress the MYC negative regulator miR-494. NCT-503 decreased H3K27me3 abundance, increased the miR-494 level, and reduced the expression of MYC and MYC-dependent histone methyltransferase, EZH2. Surprisingly, chemical/genetic disruption of SBP did not delay BL and breast cancer xenografts growth, suggesting the existence of mechanisms compensating the PHGDH/PSAT1 absence in vivo.
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Chavdoula, Evangelia, Vollter Anastas, Alessandro La Ferlita, Julian Aldana, Anuvrat Sircar, Michael A. Freitas, Lalit Sehgal, and Philip N. Tsichlis. "Abstract 3019: The epigenetic factor KDM2B alters the serine-glycine synthesis pathway and the one-carbon metabolism (SGOC) in triple-negative breast cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3019. http://dx.doi.org/10.1158/1538-7445.am2022-3019.
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Abstract Epigenetic and metabolic alterations in cancer cells are intertwined. The concentration of metabolites can influence the activity of chromatin modifiers, which in turn can act as metabolic sensors that translate changes in cellular metabolism to transcriptional reprogramming. In the present study, we investigated the role of histone demethylase KDM2B in the metabolic reprogramming of the triple-negative breast cancer (TNBC), in which KDM2B is selectively expressed at high levels. Knockdown of KDM2B in TNBC cell lines reduced their proliferation rate and tumor growth in vivo. Transcriptomic, proteomic, and metabolomic profiling demonstrated that the Serine-Glycine pathway and One Carbon metabolism (SGOC) and other amino acid biosynthetic and catabolic processes are downregulated by the knockdown of KDM2B. Additionally, we see reduction of metabolites produced via these pathways (purines, pyrimidines, formate, glutathione and NADPH). Importantly, the expression of the enzymes involved in the SGOC metabolic pathway (e.g. PHGDH, PSAT1, PSPH, SHMT2, MTHFD1L, MTHFD2 and DHFR) depends on c-MYC, NRF2, and ATF4 which our data show that they are under the positive regulatory control of KDM2B. The epistatic relationship between these factors, with the expression of the enzymes of the SGOC pathway and the effects of the KDM2B knockdown on chromatin occupancy and accessibility of the promoters of these factors is in progress and will be presented. Analysis of TCGA data showed positive and statistically significant correlations between KDM2B and the SGOC gene signature in TNBC patients. In addition, the metabolic pathway signature that distinguishes control and shKDM2B-transduced cells corresponds to the metabolic signature of a subset of TNBCs, which have been reported to carry poor prognosis. The present study highlights the role of the epigenetic factor KDM2B as an upstream regulator of the metabolic reprogramming of TNBC. Citation Format: Evangelia Chavdoula, Vollter Anastas, Alessandro La Ferlita, Julian Aldana, Anuvrat Sircar, Michael A. Freitas, Lalit Sehgal, Philip N. Tsichlis. The epigenetic factor KDM2B alters the serine-glycine synthesis pathway and the one-carbon metabolism (SGOC) in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3019.
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Ferreira, Alexandra G., Olga Zimmermannova, Ervin Ascic, Ilia Kurochkin, Diego Soto-Cabrera, Ariane Eceiza, Hreinn Benonisson, et al. "Abstract A40: Restoring tumor immunogenicity with dendritic cell reprogramming." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A40. http://dx.doi.org/10.1158/2326-6074.tumimm22-a40.
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Abstract Immunotherapy is revolutionizing cancer treatment, but success is limited to a fraction of patients. Tumor immunosurveillance and immunotherapy relies on presentation of tumor-associated antigens by conventional dendritic cells type 1 (cDC1). However, tumors develop mechanisms to avoid immune recognition such as downregulation of antigen presentation and exclusion of cDC1. We have previously demonstrated that enforced expression of the transcription factors PU.1, IRF8 and BATF3 (PIB) imposes the lineage conversion of fibroblasts to cDC1 by direct cell reprogramming. Here, we hypothesize that PIB reprograms cancer cells directly into functional tumor-antigen presenting cells (tumor-APCs) with enhanced immunogenicity. First, we show that enforced expression of PIB in a wide range of murine and human cancer cells from different origins is sufficient to induce surface expression of hematopoietic and DC-lineage specific markers (CD45 and Clec9a). Moreover, reprogramming restored the expression of antigen presentation complexes (MHC-I and MHC-II) and activated the expression of the co-stimulatory molecules CD40, CD80 and CD86, required for productive T cell activation. Transcriptomic analysis using mRNA-sequencing showed that PIB imposes a global cDC1 gene signature and an antigen presentation program in tumor cells as early as day 3 of reprogramming, overriding the original cancer cell program. Furthermore, Assay for Transposase-Accessible Chromatin (ATAC) sequencing analysis revealed that PIB-mediated cDC1 reprogramming elicited rapid epigenetic remodeling followed by gradual rewiring of transcriptional program and stabilization of cDC1 identity. Functionally, tumor-APCs present endogenous antigens on MHC-I, prime naïve CD8+ T and become prone to CD8+ T cell mediated killing. Tumor-APCs secrete pro-inflammatory cytokines (IL-12) and chemoattractants (CXCL10), uptake and process exogenous antigens, phagocyte dead cells, and cross-present exogenous antigens to activate naïve T-cells. In addition, reprogrammed tumor cells harboring TP53, KRAS and PTEN mutations downregulated proliferation and showed impaired tumorigenicity in vitro and in vivo. Importantly, we show that intra-tumoral injection of reprogrammed tumor-APCs elicited tumour growth control in vivo alongside increasing infiltration of CD8+ T and NK cells in B16-OVA tumors. Finally, we showed that our approach can be employed to convert primary cancer cells derived from melanoma, lung, breast, pancreatic, urothelial, and head and neck carcinomas as well as cancer associated fibroblasts. In summary, we provide evidence for the direct reprogramming of tumor cells into immunogenic cDC1-like cells, with restored antigen presentation capacity and the ability to reinstate anti-tumor immunity. Our approach elicits the immune system against cancer and counteract major tumor evasion mechanisms including tumor heterogeneity and impaired antigen presentation, laying the foundation for developing immunotherapeutic strategies based on the cellular reprogramming of human cancer cells. Citation Format: Alexandra G. Ferreira, Olga Zimmermannova, Ervin Ascic, Ilia Kurochkin, Diego Soto-Cabrera, Ariane Eceiza, Hreinn Benonisson, Inês Caiado, Rita Silvério-Alves, Fábio F. Rosa, Cristiana F. Pires, David Gomez-Jimenez, Carina Bernardo, Monika Bauden, Roland Anderson, Mattias Höglund, Kenichi Miharada, Yukio Nakamura, Lennart Greiff, Malin Lindstedt, Carlos-Filipe Pereira. Restoring tumor immunogenicity with dendritic cell reprogramming [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A40.
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Lacouture, Aurélie, Cynthia Jobin, Alisson Clemenceau, Cindy Weidmann, Line Berthiaume, Dominic Bastien, Isabelle Laverdière, et al. "Abstract P5-02-01: A FACS-free purification method to study estrogen signaling, organoid formation, and metabolic reprogramming in mammary epithelial cells." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–02–01—P5–02–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-02-01.
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Abstract Mammary epithelial cells (MECs) are known to have their metabolism reprogrammed following pregnancy to allow the increased energy requirements for lactation. The estrogen receptor α (ERα) is mainly associated with the regulation of biological pathways linked to mammary gland development but its influence on MECs metabolism is still unknown. Our hypothesis is that ERα reprograms cell metabolism in normal MECs, a phenomenon that would be reprogrammed during breast carcinogenesis. Few in vitro models are used to study MECs, and most of them do not express ERα. Primary MECs can be used to overcome this issue, but methods to purify these cells generally require flow cytometry and fluorescence-activated cell sorting (FACS), which require specialized instruments and expertise. Herein, we present in detail a FACS-free protocol for purification and primary culture of mouse MECs to study ERα metabolic functions using mass spectrometry (MS). Purified MECs from nulliparous mice remain differentiated for up to six days with >85% luminal epithelial cells in two-dimensional culture. When seeded in Matrigel, they form organoids that recapitulate the mammary gland morphology in vivo by developing lumens, contractile cells, and lobular structures. MECs express a functional ERα signaling pathway in both two- and three-dimensional cell culture, as shown at the mRNA and protein levels and by the phenotypic characterization. Extracellular metabolic flux analysis showed that estrogens induce a metabolic switch favouring aerobic glycolysis over mitochondrial respiration in MECs grown in two-dimensions, a phenomenon known as the Warburg effect. We also performed (MS)-based metabolomics in organoids. Estrogens altered the levels of metabolites from various pathways, including aerobic glycolysis, citric acid cycle, urea cycle, and amino acid metabolism, demonstrating that ERα reprograms cell metabolism in mammary organoids. To further understand this reprogramming, stable isotope tracer analysis in primary culture organoids are currently performed. In addition, pregnancy and breast-feeding are known to be protective against breast carcinogenesis. Consequently, we also performed MEC purification and organoid culture using mammary glands from multiparous mice. Intriguingly, organoid phenotypic characterization indicated a difference in organoid structures between MECs from nulliparous and multiparous mice. Furthermore, we observe significant differences in estrogenic response between both conditions, suggesting that pregnancy and/or lactation promotes the establishment of specific epigenetic marks that are preserved even ex vivo. Chromatin immunoprecipitation of specific histone marks and MS-based metabolic studies are ongoing to better understand the different responses of mammary organoids to estrogens between nulliparous and multiparous mice. Overall, we have optimized mouse MEC isolation and purification for two- and three-dimensional cultures and for MS-based metabolomics. We demonstrated that these organoids retain a functional ERα pathway over time and that ERα significantly reprograms multiple metabolic pathways. This model represents a valuable tool to study how estrogens modulate mammary gland biology, and particularly how these hormones reprogram metabolism during lactation and breast carcinogenesis. Citation Format: Aurélie Lacouture, Cynthia Jobin, Alisson Clemenceau, Cindy Weidmann, Line Berthiaume, Dominic Bastien, Isabelle Laverdière, Martin Pelletier, Caroline Diorio, Francine Durocher, Étienne Audet-Walsh. A FACS-free purification method to study estrogen signaling, organoid formation, and metabolic reprogramming in mammary epithelial cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-02-01.
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LaFlamme, Brooke. "Epigenetic reprogramming in treatment-resistant breast cancer." Nature Genetics 46, no. 5 (April 28, 2014): 423. http://dx.doi.org/10.1038/ng.2977.
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Berger, Adeline, Nicholas J. Brady, Rohan Bareja, Brian Robinson, Vincenza Conteduca, Michael A. Augello, Loredana Puca, et al. "N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer." Journal of Clinical Investigation 129, no. 9 (August 19, 2019): 3924–40. http://dx.doi.org/10.1172/jci127961.
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Suriyamurthy, Sudha, David Baker, Peter ten Dijke, and Prasanna Vasudevan Iyengar. "Epigenetic Reprogramming of TGF-β Signaling in Breast Cancer." Cancers 11, no. 5 (May 24, 2019): 726. http://dx.doi.org/10.3390/cancers11050726.
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The Transforming Growth Factor-β (TGF-β) signaling pathway has a well-documented, context-dependent role in breast cancer development. In normal and premalignant cells, it acts as a tumor suppressor. By contrast, during the malignant phases of breast cancer progression, the TGF-β signaling pathway elicits tumor promoting effects particularly by driving the epithelial to mesenchymal transition (EMT), which enhances tumor cell migration, invasion and ultimately metastasis to distant organs. The molecular and cellular mechanisms that govern this dual capacity are being uncovered at multiple molecular levels. This review will focus on recent advances relating to how epigenetic changes such as acetylation and methylation control the outcome of TGF-β signaling and alter the fate of breast cancer cells. In addition, we will highlight how this knowledge can be further exploited to curb tumorigenesis by selective targeting of the TGF-β signaling pathway.
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Pathiraja, T. N., S. R. Nayak, Y. Xi, S. Jiang, J. P. Garee, D. P. Edwards, A. V. Lee, et al. "Epigenetic Reprogramming of HOXC10 in Endocrine-Resistant Breast Cancer." Science Translational Medicine 6, no. 229 (March 26, 2014): 229ra41. http://dx.doi.org/10.1126/scitranslmed.3008326.
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Sharma, D., B. B. Knight, R. Yacoub, T. Liu, L. Taliaferro-Smith, A. Nagalingam, and R. M. O'Regan. "Using epigenetic reprogramming to target triple-negative breast cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e14565-e14565. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14565.
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e14565 Background: The outcome for patients with breast cancer has been significantly improved by the use of targeted agents. The prognosis of triple negative (TN) breast cancers, which do not express hormone receptors (ER, PR) or Her2, is poor, because of an aggressive clinical course and lack of targeted therapeutic agents. Epigenetic silencing of specific genes has been observed in breast cancer and some of these genes are more important due to available targeted therapies such as ER. Since all endocrine therapies are designed to block ER function in some way, the identification of new therapies or strategies that could sensitize TN breast cancers to existing endocrine therapy could provide a revolutionary means of treating this aggressive subtype of cancer Methods: We examined the efficacy of combined treatment of HDAC inhibitor LBH589 and DNMT inhibitor decitabine to regenerate ER and PR in TN breast cancer cells using RT-PCR and immunoblotting. Changes in growth and proliferation of TN breast cancer cells in response to LBH589 and decitabine treatment were determined by XTT, BrdU incorporation and colony formation assay. Changes in apoptotic proteins were determined by western blotting. Athymic nude mice were used to establish pre-clinical models for TN breast cancer cells and effectiveness of combined treatment of LBH589 and decitabine was determined. Tumors biopsies were analyzed for ER and PR re-expression by western blot analysis and immunohistochemistry at the end of the treatment. Results: Combined treatment of LBH589 and decitabine resulted in re-expression of ER and PR in TN breast cancers in vitro and in vivo. Although re-expression of ER and PR were noted following LBH589 treatment alone, re-expression was more robust with the combination. TN breast cancer cells showing re-expressed ER can be targeted with tamoxifen. Tamoxifen inhibits growth of TN breast cancer cells re- expressing ER by triggering apoptosis. Conclusions: The importance of epigenetic events such as DNA methylation and HDAC inhibition in tumor progression is becoming increasingly evident. A trial evaluating the ability of LBH589 and decitabine to re- express ER, which can then be targeted by tamoxifen, is planned in patients with metastatic TN breast cancer. No significant financial relationships to disclose.
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Shen, Liangliang, John M. O’Shea, Mohan R. Kaadige, Stéphanie Cunha, Blake R. Wilde, Adam L. Cohen, Alana L. Welm, and Donald E. Ayer. "Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP." Proceedings of the National Academy of Sciences 112, no. 17 (April 13, 2015): 5425–30. http://dx.doi.org/10.1073/pnas.1501555112.
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Triple-negative breast cancers (TNBCs) are aggressive and lack targeted therapies. Understanding how nutrients are used in TNBCs may provide new targets for therapeutic intervention. We demonstrate that the transcription factor c-Myc drives glucose metabolism in TNBC cells but does so by a previously unappreciated mechanism that involves direct repression of thioredoxin-interacting protein (TXNIP). TXNIP is a potent negative regulator of glucose uptake, aerobic glycolysis, and glycolytic gene expression; thus its repression by c-Myc provides an alternate route to c-Myc–driven glucose metabolism. c-Myc reduces TXNIP gene expression by binding to an E-box–containing region in the TXNIP promoter, possibly competing with the related transcription factor MondoA. TXNIP suppression increases glucose uptake and drives a dependence on glycolysis. Ectopic TXNIP expression decreases glucose uptake, reduces cell proliferation, and increases apoptosis. Supporting the biological significance of the reciprocal relationship between c-Myc and TXNIP, a Mychigh/TXNIPlow gene signature correlates with decreased overall survival and decreased metastasis-free survival in breast cancer. The correlation between the Mychigh/TXNIPlow gene signature and poor clinical outcome is evident only in TNBC, not in other breast cancer subclasses. Mutation of TP53, which is a defining molecular feature of TNBC, enhances the correlation between the Mychigh/TXNIPlow gene signature and death from breast cancer. Because Myc drives nutrient utilization and TXNIP restricts glucose availability, we propose that the Mychigh/TXNIPlow gene signature coordinates nutrient utilization with nutrient availability. Further, our data suggest that loss of the p53 tumor suppressor cooperates with Mychigh/TXNIPlow-driven metabolic dysregulation to drive the aggressive clinical behavior of TNBC.
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Maali, Amirhosein, Faezeh Maroufi, Farzin Sadeghi, Amir Atashi, Reza Kouchaki, Mona Moghadami, and Mehdi Azad. "Induced pluripotent stem cell technology: trends in molecular biology, from genetics to epigenetics." Epigenomics 13, no. 8 (April 2021): 631–47. http://dx.doi.org/10.2217/epi-2020-0409.
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Induced pluripotent stem cell (iPSC) technology, based on autologous cells’ reprogramming to the embryonic state, is a new approach in regenerative medicine. Current advances in iPSC technology have opened up new avenues for multiple applications, from basic research to clinical therapy. Thus, conducting iPSC trials have attracted increasing attention and requires an extensive understanding of the molecular basis of iPSCs. Since iPSC reprogramming is based on the methods inducing the expression of specific genes involved in pluripotency states, it can be concluded that iPSC reprogramming is strongly influenced by epigenetics. In this study, we reviewed the molecular basis of reprogramming, including the reprogramming factors (OCT4, SOX2, KLF4, c-MYC, NANOG, ESRRB, LIN28 as well as their regulatory networks), applied vectors (retroviral vectors, adenoviral vectors, Sendaiviral vectors, episomal plasmids, piggyBac, simple vectors, etc.) and epigenetic modifications (miRNAs, histones and DNA methylation states) to provide a comprehensive guide for reprogramming studies.
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Rahman, Mohammad Mijanur, Andrew C. Brane, and Trygve O. Tollefsbol. "MicroRNAs and Epigenetics Strategies to Reverse Breast Cancer." Cells 8, no. 10 (October 8, 2019): 1214. http://dx.doi.org/10.3390/cells8101214.
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Breast cancer is a sporadic disease with genetic and epigenetic components. Genomic instability in breast cancer leads to mutations, copy number variations, and genetic rearrangements, while epigenetic remodeling involves alteration by DNA methylation, histone modification and microRNAs (miRNAs) of gene expression profiles. The accrued scientific findings strongly suggest epigenetic dysregulation in breast cancer pathogenesis though genomic instability is central to breast cancer hallmarks. Being reversible and plastic, epigenetic processes appear more amenable toward therapeutic intervention than the more unidirectional genetic alterations. In this review, we discuss the epigenetic reprogramming associated with breast cancer such as shuffling of DNA methylation, histone acetylation, histone methylation, and miRNAs expression profiles. As part of this, we illustrate how epigenetic instability orchestrates the attainment of cancer hallmarks which stimulate the neoplastic transformation-tumorigenesis-malignancy cascades. As reversibility of epigenetic controls is a promising feature to optimize for devising novel therapeutic approaches, we also focus on the strategies for restoring the epistate that favor improved disease outcome and therapeutic intervention.
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Marengo, Barbara, Ombretta Garbarino, Andrea Speciale, Lorenzo Monteleone, Nicola Traverso, and Cinzia Domenicotti. "MYC Expression and Metabolic Redox Changes in Cancer Cells: A Synergy Able to Induce Chemoresistance." Oxidative Medicine and Cellular Longevity 2019 (June 25, 2019): 1–9. http://dx.doi.org/10.1155/2019/7346492.
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Chemoresistance is due to multiple factors including the induction of a metabolic adaptation of tumor cells. In fact, in these cells, stress conditions induced by therapies stimulate a metabolic reprogramming which involves the strengthening of various pathways such as glycolysis, glutaminolysis and the pentose phosphate pathway. This metabolic reprogramming is the result of a complex network of mechanisms that, through the activation of oncogenes (i.e., MYC, HIF1, and PI3K) or the downregulation of tumor suppressors (i.e., TP53), induces an increased expression of glucose and/or glutamine transporters and of glycolytic enzymes. Therefore, in order to overcome chemoresistance, it is necessary to develop combined therapies which are able to selectively and simultaneously act on the multiple molecular targets responsible for this adaptation. This review is focused on highlighting the role of MYC in modulating the epigenetic redox changes which are crucial in the acquisition of therapy resistance.
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Moyer, Sydney M., Nina Ilic, Sydney Gang, Taylor E. Arnoff, and William C. Hahn. "Abstract 2361: MYC-driven breast cancer tumorigenesis is dependent on normal mitochondrial function." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2361. http://dx.doi.org/10.1158/1538-7445.am2022-2361.
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Abstract While the transcription factor MYC is amplified in all breast cancer subtypes, nearly 60% of patients with triple-negative tumors have elevated MYC copy number and expression. Patients with triple-negative breast cancer (TNBC) typically have increased metastasis, decreased response to therapies, and poor outcomes, highlighting MYC’s causal association with disease aggressiveness and low survival rates. Unfortunately, MYC is not considered directly pharmacologically tractable. Therefore, we sought to identify collateral “genetic dependencies,” downstream of oncogenic MYC. Using comparative genome-scale CRISPR/Cas9 screening in isogenic human mammary epithelial cells (HMECs), we have identified two mitochondrial membrane transporter genes, TIMM17A and MTCH2, specifically required for MYC-dependent proliferation and survival. Since MYC is suspected to drive metabolic reprogramming in cancers, we assessed how MYC affected mitochondrial protein content by quantitative mass spectrometry. This revealed an increase in N-acetylaspartate (NAA) in HMECs with MYC amplification compared to other genetic backgrounds. Interestingly, increased NAA levels are dependent on TIMM17A and MTCH2 presence. Loss of either of these genes results in cell death coupled with decreased NAA. NAA supplementation in the media of MYC-HMECs following loss of TIMM17A or MTCH2 can rescue the cell death. Importantly, NAA supplementation in cells with guides targeting GFP (negative control) or general essential gene RPL11 did not show increased cell growth/viability - showing that the NAA supplementation is specifically compensating for loss of mitochondrial transport function in MYC-HMECs. Based on these data, it appears that MYC-amplified TNBCs are uniquely dependent on TIMM17A and MTCH2 mitochondrial transporter function because they drive metabolic reprogramming resulting in addiction to N-acetylaspartate production. To conclude these studies, we are evaluating the dependence on mitochondrial transport and NAA synthesis in MYC-amplified TNBCs by assessing the function of TIMM17A and MTCH2 as MYC-specific genetic dependencies in patient derived xenografts of TNBC and determining if TNBCs are addicted to increased NAA synthesis by overexpressing aspartoacylase to breakdown NAA. Successful completion of this work will provide novel drug targets required for survival of aggressive MYC-amplified breast cancers. Citation Format: Sydney M. Moyer, Nina Ilic, Sydney Gang, Taylor E. Arnoff, William C. Hahn. MYC-driven breast cancer tumorigenesis is dependent on normal mitochondrial function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2361.
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Ayad, Nagi, Robert Suter, David Robbins, and Martine Roussel. "MBRS-02. BET BROMODOMAIN PROTEIN-KINASE INHIBITOR COMBINATIONS FOR THE TREATMENT OF MEDULLOBLASTOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii399. http://dx.doi.org/10.1093/neuonc/noaa222.523.
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Abstract Recent sequencing studies have implicated many epigenetic regulators in medulloblastoma. The epigenetic reader protein Brd4 has been implicated in various cancers including medulloblastoma. Brd4 controls expression of the medulloblastoma essential genes MYC in G3 medulloblastomas, which have poor prognosis as well as GLI1 and GLI2 levels in Sonic hedgehog (SHH) driven medulloblastomas, which have intermediate prognosis. Highly selective Brd4 inhibitors have been developed that reduce MYC, GLI1 and GLI2 levels. These inhibitors have gone into clinical trials for multiple cancer indications including medulloblastoma. However, resistance is common for Brd4 inhibitors warranting combination therapies for improved clinical outcome. We have developed a computational pipeline termed SynergySeq that predicts patient specific combinations of Brd4 inhibitors along with kinase inhibitors. We demonstrate that Brd4-kinase inhibitors robustly reduce proliferation of Shh and MYC driven medulloblastoma cells. Improved efficacy is related to dampening the adaptive kinome reprogramming response that occurs after Brd4 inhibition. Our findings suggest that SynergySeq can be utilized to inform patient selection for clinical trials utilizing Brd4 inhibitors in medulloblastoma and other brain tumors.
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Dimitrakopoulos, Foteinos-Ioannis, Anastasia Kottorou, and Aspasia Tzezou. "Endocrine resistance and epigenetic reprogramming in estrogen receptor positive breast cancer." Cancer Letters 517 (October 2021): 55–65. http://dx.doi.org/10.1016/j.canlet.2021.05.030.
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Katz, Tiffany A., Yi Huang, Nancy E. Davidson, and Rachel C. Jankowitz. "Epigenetic reprogramming in breast cancer: From new targets to new therapies." Annals of Medicine 46, no. 6 (July 24, 2014): 397–408. http://dx.doi.org/10.3109/07853890.2014.923740.
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Chu, Pei-Yi, Ming-Feng Hou, Ji-Ching Lai, Long-Fong Chen, and Chang-Shen Lin. "Cell Reprogramming in Tumorigenesis and Its Therapeutic Implications for Breast Cancer." International Journal of Molecular Sciences 20, no. 8 (April 12, 2019): 1827. http://dx.doi.org/10.3390/ijms20081827.
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Breast cancer is the most common malignancy in women worldwide and can be categorized into several subtypes according to histopathological parameters or genomic signatures. Such heterogeneity of breast cancer can arise from the reactivation of mammary stem cells in situ during tumorigenesis. Moreover, different breast cancer subtypes exhibit varieties of cancer incidence, therapeutic response, and patient prognosis, suggesting that a specific therapeutic protocol is required for each breast cancer subtype. Recent studies using molecular and cellular assays identified a link between specific genetic/epigenetic alterations and distinct cells of origin of breast cancer subtypes. These alterations include oncogenes, tumor suppressor genes, and cell-lineage determinants, which can induce cell reprogramming (dedifferentiation and transdifferentiation) among two lineage-committed mammary epithelial cells, namely basal and luminal cells. The interconversion of cell states through cell reprogramming into the intermediates of mammary stem cells can give rise to heterogeneous breast cancers that complicate effective therapies of breast cancer. A better understanding of mechanisms underlying cell reprogramming in breast cancer can help in not only elucidating tumorigenesis but also developing therapeutics for breast cancer. This review introduces recent findings on cancer gene-mediated cell reprogramming in breast cancer and discusses the therapeutic potential of targeting cell reprogramming.
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Bettuzzi, Saverio. "N-Myc-mediated epigenetic reprogramming in advanced prostate cancer: personalized medicine and quality of biological samples." Translational Cancer Research 8, Suppl 6 (December 2019): S639—S641. http://dx.doi.org/10.21037/tcr.2019.10.07.
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Dittharot, Kanthanadon, Sumana Dakeng, Parichat Suebsakwong, Apichart Suksamrarn, Pimpicha Patmasiriwat, and Moltira Promkan. "Cucurbitacin B Induces Hypermethylation of Oncogenes in Breast Cancer Cells." Planta Medica 85, no. 05 (November 21, 2018): 370–78. http://dx.doi.org/10.1055/a-0791-1591.
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AbstractBreast cancer is a complex disease driven by multiple factors including both genetic and epigenetic alterations. Recent studies revealed that abnormal gene expression induced by epigenetic changes including aberrant promoter methylation plays a critical role in human breast carcinogenesis. Cucurbitacin B has antiproliferative activity against various human breast cancer cells, but the molecular mechanism is not completely understood. In this study, we explore the influence of cucurbitacin B from Trichosanthes cucumerina on the methylation status at the promoter of oncogenes c-Myc, cyclin D1, and survivin in breast cancer cell lines. Growth inhibitory effect of cucurbitacin B on breast cancer cells was assessed by MTT assay and colony formation assay. Methylation status of genomic DNA was determined by methylation-specific PCR. Gene and protein expression levels of all genes studied were analyzed by real-time RT-PCR and western blot. The results indicated that cucurbitacin B could inhibit cell growth in breast cancer cells. The oncogene promoters are usually hypomethylated in cancer cells. Upon cucurbitacin B treatment, upregulation of DNMT1 and obvious heavy methylation in the promoters of c-Myc, cyclin D1, and survivin, which consequently downregulated the expression of all these oncogenes, were observed. Hence, cucurbitacin B proved to be a potential cancer therapeutic agent, in part by inducing hypermethylation and silences the oncogenic activation.
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Farias, E. F., K. Petrie, B. Leibovitch, J. Murtagh, M. B. Chornet, T. Schenk, A. Zelent, and S. Waxman. "Interference with Sin3 function induces epigenetic reprogramming and differentiation in breast cancer cells." Proceedings of the National Academy of Sciences 107, no. 26 (June 14, 2010): 11811–16. http://dx.doi.org/10.1073/pnas.1006737107.
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Becker, Lisa M., Joyce T. O’Connell, Annie P. Vo, Margo P. Cain, Desiree Tampe, Lauren Bizarro, Hikaru Sugimoto, et al. "Epigenetic Reprogramming of Cancer-Associated Fibroblasts Deregulates Glucose Metabolism and Facilitates Progression of Breast Cancer." Cell Reports 31, no. 9 (June 2020): 107701. http://dx.doi.org/10.1016/j.celrep.2020.107701.
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García-Chico, Celia, Susana López-Ortiz, Saúl Peñín-Grandes, José Pinto-Fraga, Pedro L. Valenzuela, Enzo Emanuele, Claudia Ceci, et al. "Physical Exercise and the Hallmarks of Breast Cancer: A Narrative Review." Cancers 15, no. 1 (January 3, 2023): 324. http://dx.doi.org/10.3390/cancers15010324.
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Growing evidence suggests that, among the different molecular/cellular pathophysiological mechanisms associated with cancer, there are 14 hallmarks that play a major role, including: (i) sustaining proliferative signaling, (ii) evading growth suppressors, (iii) activating invasion and metastasis, (iv) enabling replicative immortality, (v) inducing angiogenesis, (vi) resisting cell death, (vii) reprogramming energy metabolism, (viii) evading immune destruction, (ix) genome instability and mutations, (x) tumor-promoting inflammation, (xi) unlocking phenotypic plasticity, (xii) nonmutational epigenetic reprogramming, (xiii) polymorphic microbiomes, and (xiv) senescent cells. These hallmarks are also associated with the development of breast cancer, which represents the most prevalent tumor type in the world. The present narrative review aims to describe, for the first time, the effects of physical activity/exercise on these hallmarks. In summary, an active lifestyle, and particularly regular physical exercise, provides beneficial effects on all major hallmarks associated with breast cancer, and might therefore help to counteract the progression of the disease or its associated burden.
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Ganapathi, Shireen S., Nicolas M. Garcia, Veerin R. Sirihorachai, and Elizabeth R. Lawlor. "Abstract A011: Emergence of persister cells following bromodomain inhibition in Ewing sarcoma." Clinical Cancer Research 28, no. 18_Supplement (September 15, 2022): A011. http://dx.doi.org/10.1158/1557-3265.sarcomas22-a011.
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Abstract Ewing sarcoma (ES) is driven by the tumor initiating fusion EWS::FLI1 that causes widespread transcriptional dysregulation via epigenetic reprogramming. ES cells are highly plastic and heterogenous and have features of both neural crest and mesenchymal lineages. Epigenetic plasticity is well established as a mediator of disease progression and drug resistance, leading to the creation of heterogeneous tumor cell subpopulations that can initiate metastasis and relapse. Successful therapeutic strategies for metastatic or relapsed ES patients are limited and unchanged in the last three decades. Identification of new therapeutic strategies, and defining the effect of new agents on ES biology, is critical to improving patient outcomes. Given the epigenetic dependencies of ES, epigenetic modifying agents are an important class of drugs to investigate. The class of bromodomain and extra-terminal domain protein inhibitors (BETi) have shown preclinical efficacy in ES models but drug combinations will be needed. We are testing the hypothesis that transcriptional rewiring downstream of BETi will create new dependencies in ES cells that could be therapeutically exploited with biologically-defined combinations. Our studies show that the BETi, BMS-986158, the first BETi to be tested in pediatric patients, has profound cytostatic effects in preclinical ES models in vitro and in vivo. Our data further reveal that long term exposure to BMS-986158 creates a persister population of cells that reacquires proliferative capacity. We performed RNA-seq studies on parent, acutely treated (72 hours), and persister populations from three ES cell lines to define the effects of short and long term BET inhibition. Exposure to BMS-986158 led to strong inhibition of the EWS::FLI1-activated gene signature that was evident both acutely and in persister cells. Thus, despite continued inhibition of EWS::FLI1 activity, persister cells restored their ability to survive and proliferate. Gene Set Enrichment Analysis of transcripts that were significantly altered in persister cells identified gene programs involved in development and lineage commitment, including polycomb targets, suggesting that persister cells may have been rewired to more stem-like states. In addition, in two of the three cell lines, persister cells demonstrated upregulation of MYC target genes and cell cycle programs that were initially repressed by BET inhibition. Ongoing studies are investigating the molecular mechanisms by which MYC programs are reactivated in persister cells. We anticipate that epigenetic reprogramming mediates the transcriptional rewiring of MYC programs in persister cells, thereby escaping the cytostatic effects of continued BET inihbition. By defining these mechanisms we aim to identify new vulnerabilities that can be exploited in the context of BETi combination trials in the future. Citation Format: Shireen S. Ganapathi, Nicolas M. Garcia, Veerin R. Sirihorachai, Elizabeth R. Lawlor. Emergence of persister cells following bromodomain inhibition in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A011.
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Luo, Weibo, and Maowu Luo. "Abstract A009: ZMYND8 is an epigenetic regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): A009. http://dx.doi.org/10.1158/1538-7445.cancepi22-a009.
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Abstract 27-hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming. Citation Format: Weibo Luo, Maowu Luo. ZMYND8 is an epigenetic regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A009.
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Treviño, Lindsey S., Quan Wang, and Cheryl L. Walker. "Hypothesis: Activation of rapid signaling by environmental estrogens and epigenetic reprogramming in breast cancer." Reproductive Toxicology 54 (July 2015): 136–40. http://dx.doi.org/10.1016/j.reprotox.2014.12.014.
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Qattan, Amal. "Metabolic Reprogramming of Triple-Negative Breast Cancer: The Role of miRNAs." microRNA Diagnostics and Therapeutics 3, no. 1 (December 20, 2017): 1–8. http://dx.doi.org/10.1515/micrnat-2017-0001.
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AbstractMicroRNAs (miRNAs) are well known to influence the expression of the genes that regulate critical cellular functions. Various reports have suggested that they play critical roles in breast cancer metabolism through the regulation of various metabolic pathways, including the metabolism of glucose, lipids, glycolysis and the mitochondrial tricarboxylic acid cycle (TCA). miRNAs regulate the metabolic process by targeting key molecules (enzymes, kinases transporters) or by modifying the expression of key transcription molecules. In addition, miRNAs can indirectly regulate mRNA translation by targeting chromatin-remodeling enzymes. Furthermore, miRNAs influence the expression of both oncogenes and tumor suppressors and have a major impact on PI3K/AKT, HIF, and MYC signal transduction, which contributes to the metabolic phenotype in human cancer. Although human epidermal growth factor and endocrine therapies have been effective in treating breast cancer, for locally advanced and distant metastases mortality remains high. Drug resistance and recurrence remain major hurdles for advanced breast cancer therapy. Given the critical influence of metabolic reprogramming in the progression of neoplasm, tumorigenesis and metastasis, research should focus on novel targets of metabolic enzymes to reverse drug resistance and improve overall survival rates. Blocking the miRNAs that contribute to metabolic reprogramming or the use of exogenous miRNAs as antisense oligonucleotides, may be an effective way to treat aggressive, chemo-resistant cancers. This review summarizes current knowledge on the mechanism of action of miRNAs in altering the metabolism of cancer cells and presents possible therapeutic approaches to treating breast cancers that are resistant to current drugs.
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Yuan, Xueying, Michael Soth, Philip Jones, and Jeffrey Rosen. "Abstract B020: Reprogramming epithelial-mesenchymal transition and the immune microenvironment in triple-negative breast cancer with epigenetic drugs." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): B020. http://dx.doi.org/10.1158/1538-7445.cancepi22-b020.
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Abstract Triple-negative breast cancer (TNBC) is a biologically heterogeneous and clinically important breast cancer subtype because if considered a distinct disease, TNBC would rank as the 5th leading cause of cancer deaths in women. Patients resistant to standard-of-care chemotherapies have poor survival. EMT is a reversible process in which epithelial cells lose polarity and cell-cell junctions to gain mesenchymal traits. A hybrid EMT state that displays plasticity is correlated with chemotherapy resistance. Besides tumor intrinsic factors, tumor-associated immune cells such as neutrophils and macrophages can display a pro-tumoral phenotype and contribute to chemotherapy resistance. Epigenetic enzymes can reprogram both the tumor cell EMT and tumor-associated immune cells. Thus, targeting epigenetic enzymes is a potential strategy to improve the response of TNBC to chemotherapy. Our overall goal, therefore, is to identify novel epigenetic drug(s) that can potentially be used in the clinic in combination with chemotherapy to improve the survival of TNBC patients. Previously, we performed a morphology-based epigenetic drug screen using organoid cultures of two independent mesenchymal TNBC cell models. We identified ten epigenetic drugs able to reprogram EMT, specifically several histone deacetylase (HDAC) and bromodomain (BRD) inhibitors. We selected Quisinostat, an HDAC inhibitor, and IACS-70654, an inhibitor of p300/CBP BRD, as representative of these two classes of drugs for further study. First, we determined the effects of both inhibitors in our unique syngeneic TNBC mouse models. In a claudin-low mesenchymal model T12, IACS-70654 induced the expression of epithelial marker ZO-1, reduced tumor proliferation, and reduced the infiltration of neutrophils. Accordingly, we then treated a neutrophil-enriched luminal-like TNBC model 2208L with IACS-70654. We discovered that IACS-70654 prevented tumor growth and drastically decreased neutrophil infiltration. Quisinostat also reduced tumor proliferation, improved the response to Carboplatin, and strongly induced the expression of epithelial marker E-cadherin in the T12 model. Moreover, it reduced neutrophil and regulatory T cell infiltration significantly and increased anti-tumoral macrophage infiltration. To complement these in vivo studies, we also isolated tumor-associated macrophages from T12 and studied their response in vitro to assess the direct effects of the inhibitors. Both epigenetic drugs reduced the expression of the pro-tumoral phenotype markers Arginase 1 and CD206 and induced the expression of the anti-tumoral phenotypic markers CD86 and MHCII. In summary, we showed that both Quisinostat and IACS-70654 reduced tumor proliferation and reprogramed both tumor cell EMT and tumor-associated immune cells. Future studies will characterize the effects of both compounds in additional TNBC models and employ single-cell ATAC-seq and RNA-seq to elucidate potential mechanisms and pathways employed by these two different classes of epigenetic drugs in both tumor cells and tumor-associated immune cells. Citation Format: Xueying Yuan, Michael Soth, Philip Jones, Jeffrey Rosen. Reprogramming epithelial-mesenchymal transition and the immune microenvironment in triple-negative breast cancer with epigenetic drugs. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B020.
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Wu, Si-Yu, Yi Xiao, Jin-Li Wei, Xiao-En Xu, Xi Jin, Xin Hu, Da-Qiang Li, Yi-Zhou Jiang, and Zhi-Ming Shao. "MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer." Journal for ImmunoTherapy of Cancer 9, no. 7 (July 2021): e002528. http://dx.doi.org/10.1136/jitc-2021-002528.
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BackgroundTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks definite treatment targets. Tumor immune microenvironment (TIME) heterogeneity has a profound impact on the immunotherapy response. Tumors with non-inflamed TIME derive limited benefit from immunotherapy. However, what drives the formation of the non-inflamed TIME in TNBC remains unclear.MethodsUsing our multiomics database of TNBC, we conducted an analysis to explore the key genomic events driving the formation of the non-inflamed TIME in TNBC. In vitro and in vivo studies further revealed potential mechanisms and the efficacy of combination treatment with immunotherapy.ResultsWith transcriptomic and genomic data, we systematically analyzed the TIME of TNBC and revealed that the classical basal-like subtype of TNBC consisted of two distinct microenvironment phenotypes, defined as the ‘inflamed’ and ‘non-inflamed’ subtypes. We performed further screening and demonstrated that MYC amplification and overexpression led to low immune infiltration and cytolytic activity in TIME. Mechanistically, MYC bound to DNMT1 promoter and activated DNMT1 transcription in TNBC cells, thus suppressing the Cyclic GMP-AMP synthase (cGAS)-STING pathway via an epigenetic regulatory way. In MYC-overexpressing TNBC, decitabine, an Food and Drug Administration (FDA)-approved DNA methyltransferase inhibitor, converted tumors from non-inflamed to inflamed tumors by enhancing T cell infiltration. Furthermore, the combination of decitabine with programmed cell death protein 1 (PD-1) inhibitor reversed T cell exhaustion and improved T cell function in mouse models, which elicited potent antitumor activity in MYC-overexpressing TNBC.ConclusionsOur work elucidates that the classic oncogene MYC induces immune evasion by repressing innate immunity. Furthermore, we provide a rationale for combining DNA methyltransferase inhibition with immunotherapy for the treatment of MYC-overexpressing TNBC.
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Miftakhova, Regina R., Aigul R. Rakhmatullina, Rimma N. Mingaleeva, Ekaterina E. Garanina, Svetlana F. Khaiboullina, and Albert A. Rizvanov. "The expression of pluripotency genes regulates properties of cancer stem cells in MCF-7 breast cancer model." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23018-e23018. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23018.
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e23018 Background: More than 1.6 million cases of breast cancer (BC) are diagnosed annually worldwide. Despite advances in diagnoses and treatment, BC remains the third leading cause of death in women. Metastases and chemotherapy resistance are the main factors contributing to BC mortality. The ability of tumor cells to overcome the drug-induced growth inhibition is now linked to a unique population of cancer initiating tumor cells, often referred as cancer stem cells (CSC). CSC represent a small fraction of tumor cells, therefore, currently used isolation protocols have a low yield and are poorly reproducible, hampering research on the role of these cells in cancer chemoresistance. We propose a novel approach to generate large quantities of CSC-like cells by genetic reprogramming of non-stem cancer cells. Methods: We postulate that CSC-enriched cell line can be developed in vitro by upregulating of proteins controlling cancer cell pluripotency including Oct4, Sox2, NANOG, KLF4 and c-Myc. Increased transcriptional and translational activity of these genes in MCF-7 cells was demonstrated by real time-PCR and Western blot. Proliferation and migration of cells overexpressing Oct4, Sox2, NANOG, KLF4 and c-Myc were analyzed as well. Also, changes in CSC population counts and their sensitivity to chemotherapy were investigated using sphere formation assay. Results: We found that cell proliferation rate was correlated with the expression level of c-Myc and Oct4. Increased CSC counts were found in cells with overexpressed Oct4 (62.7%), KLF4 (97%) and NANOG (121.3%) proteins as compared to the parental cells. Overexpression of SOX2, NANOG and KLF4 significantly increased CSC resistance to docetaxel (83,3±6,8; 93,3±4,5 and 80,3±5,0 spheres respectively) when compared to the original cells (48,3±3,0 spheres). Conclusions: We conclude that overexpression of pluripotency proteins Oct4, Sox2, NANOG, KLF4 and c-Myc changes the CSC counts and proliferation capacity of BC cells. Acknowledgements: The study was funded by RFBR, according to the research project No. 16-34-60210 mol_а_dk, and by Russian Government Program of Competitive Growth of Kazan Federal University.
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Arreal, Leire, Marco Piva, Sonia Fernández, Ajinkya Revandkar, Ariane Schaub- Clerigué, Josep Villanueva, Amaia Zabala-Letona, et al. "Targeting PML in triple negative breast cancer elicits growth suppression and senescence." Cell Death & Differentiation 27, no. 4 (October 1, 2019): 1186–99. http://dx.doi.org/10.1038/s41418-019-0407-5.
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Abstract Oncogene addiction postulates that the survival and growth of certain tumor cells is dependent upon the activity of one oncogene, despite their multiple genetic and epigenetic abnormalities. This phenomenon provides a foundation for molecular targeted therapy and a rationale for oncogene-based stratification. We have previously reported that the Promyelocytic Leukemia protein (PML) is upregulated in triple negative breast cancer (TNBC) and it regulates cancer-initiating cell function, thus suggesting that this protein can be therapeutically targeted in combination with PML-based stratification. However, the effects of PML perturbation on the bulk of tumor cells remained poorly understood. Here we demonstrate that TNBC cells are addicted to the expression of this nuclear protein. PML inhibition led to a remarkable growth arrest combined with features of senescence in vitro and in vivo. Mechanistically, the growth arrest and senescence were associated to a decrease in MYC and PIM1 kinase levels, with the subsequent accumulation of CDKN1B (p27), a trigger of senescence. In line with this notion, we found that PML is associated to the promoter regions of MYC and PIM1, consistent with their direct correlation in breast cancer specimens. Altogether, our results provide a feasible explanation for the functional similarities of MYC, PIM1, and PML in TNBC and encourage further study of PML targeting strategies for the treatment of this breast cancer subtype.
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Zhang, Yang, Bingwei Xu, Junfeng Shi, Jieming Li, Xinlan Lu, Li Xu, Helen Yang, et al. "BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways." Cellular Oncology 43, no. 6 (October 2, 2020): 1049–66. http://dx.doi.org/10.1007/s13402-020-00537-1.
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Abstract Purpose Stemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a transcriptional and epigenetic mediator, for TNBC. Methods Two independent patient cohorts were subjected to bioinformatic and IHC examination for clinical association of candidate cancer drivers. The efficacy and biological bases for co-targeting these drivers were interrogated using cancer cell lines, a protein kinase array, chemical inhibitors, RNAi/CRISPR/Cas9 approaches, and a 4 T1-Balb/c xenograft model. Results We found that amplification of the chromosome 8q24 region occurred in nearly 20% of TNBC tumors, and that it coincided with co-upregulation or amplification of c-Myc and FAK, a key effector of integrin-dependent signaling. This co-upregulation at the mRNA or protein level correlated with a poor patient survival (p < 0.0109 or p < 0.0402, respectively). Furthermore, we found that 14 TNBC cell lines exhibited high vulnerabilities to the combination of JQ1 and VS-6063, potent pharmacological antagonists of the BRD4/c-Myc and integrin/FAK-dependent pathways, respectively. We also observed a cooperative inhibitory effect of JQ1 and VS-6063 on tumor growth and infiltration of Ly6G+ myeloid-derived suppressor cells in vivo. Finally, we found that JQ1 and VS-6063 cooperatively induced apoptotic cell death by altering XIAP, Bcl2/Bcl-xl and Bim levels, impairing c-Src/p130Cas-, PI3K/Akt- and RelA-associated signaling, and were linked to EMT-inducing transcription factor Snail- and Slug-dependent regulation. Conclusion Based on our results, we conclude that the BRD4/c-Myc- and integrin/FAK-dependent pathways act in concert to promote breast cancer cell survival and poor clinical outcomes. As such, they represent promising targets for a synthetic lethal-type of therapy against TNBC.
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Travaglini, Lorena, Laura Vian, Monia Billi, Francesco Grignani, and Clara Nervi. "Epigenetic reprogramming of breast cancer cells by valproic acid occurs regardless of estrogen receptor status." International Journal of Biochemistry & Cell Biology 41, no. 1 (January 2009): 225–34. http://dx.doi.org/10.1016/j.biocel.2008.08.019.
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Khaled and Bidet. "New Insights into the Implication of Epigenetic Alterations in the EMT of Triple Negative Breast Cancer." Cancers 11, no. 4 (April 18, 2019): 559. http://dx.doi.org/10.3390/cancers11040559.
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Breast cancer is the most common cancer and leading cause of cancer death among women worldwide, encompassing a wide heterogeneity of subtypes with different clinical features. During the last two decades, the use of targeted therapies has emerged in clinical research in order to increase treatment efficiency, improve prognosis and reduce recurrence. However, the triple negative breast cancer (TNBC) subtype remains a clinical challenge, with poor prognosis since no therapeutic targets have been identified. This aggressive breast cancer entity lacks expression of oestrogen receptor (ER) and progesterone receptor (PR), and it does not overexpress human epidermal growth factor receptor 2 (HER2). The major reason for TNBC poor prognosis is early therapeutic escape from conventional treatments, leading to aggressive metastatic relapse. Metastases occur after an epithelial-mesenchymal transition EMT of epithelial cells, allowing them to break free from the primary tumour site and to colonize distant organs. Cancer-associated EMT consists not only of acquired migration and invasion ability, but involves complex and comprehensive reprogramming, including changes in metabolism, expression levels and epigenetic. Recently, many studies have considered epigenetic alterations as the primary initiator of cancer development and metastasis. This review builds a picture of the epigenetic modifications implicated in the EMT of breast cancer. It focuses on TNBC and allows comparisons with other subtypes. It emphasizes the role of the main epigenetic modifications lncRNAs, miRNAs, histone and DNA- modifications in tumour invasion and appearance of metastases. These epigenetic alterations can be considered biomarkers representing potential diagnostic and prognostic factors in order to define a global metastatic signature for TNBC.
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Tauro, Marilena, Tao Li, and Conor C. Lynch. "Abstract PD3-10: Dual epigenetic/autophagy inhibition as a novel strategy to tackle triple negative breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD3–10—PD3–10. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd3-10.
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Abstract Clinical Significance: Despite initial response to therapies, patients with triple negative breast cancer (TNBC) have the highest risk of metastatic relapse within 5 years of diagnosis. There is an urgent need for better treatments for this deadly disease. To this end, understanding the molecular drivers can reveal novel therapeutic targets. Background: The TNBC oncogenic program is known to be driven by MYC. MYC expression is regulated by bromodomain proteins and several bromodomain inhibitors such as JQ1 have proven effective at inhibiting MYC expression. However, resistance can occur rapidly upon activation of alternative cell survival mechanisms, such as autophagy. TNBC is noted for its elevated basal autophagy. Interestingly, publicly available datasets show that ULK3, an initial effector of the autophagy program, is upregulated in TNBC patients while the opposite is observed for the classical autophagy initiator ULK1. Moreover, TNBC patients with low ULK3 expression levels tend to achieve longer relapse free survival (RFS) than higher expression cohort, in opposition to ULK1. Importantly, ULK3 has not been investigated to date in regulating TNBC cell intrinsic autophagy and no drugs exist that can inhibit ULK3. Methods and Results: Given the importance of MYC and ULK3 in TNBC progression, our team developed a novel class of small molecules, namely dual BRD4/ULK3 inhibitors, that are superior to JQ1 alone in limiting TNBC viability. In vitro data demonstrate that TNBC cells are more sensitive to the cytotoxic activity of the dual inhibitors compared to other breast cancer subtypes. Further investigation through western blot analysis confirms the effectiveness of these novel dual inhibitors in abrogating MYC expression overtime, and completely blocking the autophagy program (measured by downstream ULK3, ULK1, LC3B, p62 protein levels), resulting in cell death. Interestingly, the human cell line SUM159R, that is resistant to BRD4 inhibitor JQ1 and cross-resistant to standard chemotherapeutics (doxorubicin) is also highly sensitive to our dual inhibitors, implying their potential use for the treatment of refractory TNBC disease. Excitingly, and for the first time, using a genetic silencing approach (shULK3 in SUM159), we demonstrated that ULK3 is critical for TNBC autophagy and cell survival. As a proof of concept, we reproduced the same genetic silencing experiment in a different cell line, namely WM1366-LC3BmCherry-GFP, an LC3B conveniently engineered system used to visualize proper autophagosome formation and material degradation through autophagy. We verified that both genetic ablation and pharmacologic inhibition of ULK3 are strategies that lead to cancer cell death. Conclusions: In conclusion, we 1) characterized a novel class of dual BRD4/kinase compounds, capable of inhibiting BRD4 activity and autophagy, and superior to the BRD4 inhibitor, JQ1. 2) showed that ULK3 is over-expressed in TNBC. 3) demonstrated that silencing ULK3 blocks autophagy in TNBC cell lines and results in significantly lower cell viability. 4) found that our dual inhibitors present a double bind for TNBC cells that results in increased cytotoxicity and potentially will be useful for the treatment of resistant TNBC. Clinically, we also posit that our dual inhibitors could be easily administered as a single agent, avoiding the potential complication of pharmacokinetics/pharmacodynamics associated with administering multiple therapies. Citation Format: Marilena Tauro, Tao Li, Conor C Lynch. Dual epigenetic/autophagy inhibition as a novel strategy to tackle triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD3-10.
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Lubecka, Katarzyna, Agnieszka Kaufman-Szymczyk, Barbara Cebula-Obrzut, Piotr Smolewski, Janusz Szemraj, and Krystyna Fabianowska-Majewska. "Novel Clofarabine-Based Combinations with Polyphenols Epigenetically Reactivate Retinoic Acid Receptor Beta, Inhibit Cell Growth, and Induce Apoptosis of Breast Cancer Cells." International Journal of Molecular Sciences 19, no. 12 (December 10, 2018): 3970. http://dx.doi.org/10.3390/ijms19123970.
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An epigenetic component, especially aberrant DNA methylation pattern, has been shown to be frequently involved in sporadic breast cancer development. A growing body of literature demonstrates that combination of agents, i.e. nucleoside analogues with dietary phytochemicals, may provide enhanced therapeutic effects in epigenetic reprogramming of cancer cells. Clofarabine (2-chloro-2′-fluoro-2′-deoxyarabinosyladenine, ClF), a second-generation 2′-deoxyadenosine analogue, has numerous anti-cancer effects, including potential capacity to regulate epigenetic processes. Our present study is the first to investigate the combinatorial effects of ClF (used at IC50 concentration) with epigallocatechin-3-gallate (EGCG, tea catechin) or genistein (soy phytoestrogen), at physiological concentrations, on breast cancer cell growth, apoptosis, and epigenetic regulation of retinoic acid receptor beta (RARB) transcriptional activity. In MCF7 and MDA-MB-231 cells, RARB promoter methylation and expression of RARB, modifiers of DNA methylation reaction (DNMT1, CDKN1A, TP53), and potential regulator of RARB transcription, PTEN, were estimated using methylation-sensitive restriction analysis (MSRA) and quantitative real-time polymerase chain reaction (qPCR), respectively. The combinatorial exposures synergistically or additively inhibited the growth and induced apoptosis of breast cancer cells, followed by RARB hypomethylation with concomitant multiple increase in RARB, PTEN, and CDKN1A transcript levels. Taken together, our results demonstrate the ability of ClF-based combinations with polyphenols to promote cancer cell death and reactivate DNA methylation-silenced tumor suppressor genes in breast cancer cells with different invasive potential.
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Perone, Ylenia, and Luca Magnani. "Going off the grid: ERα breast cancer beyond estradiol." Journal of Molecular Endocrinology 57, no. 1 (July 2016): F1—F5. http://dx.doi.org/10.1530/jme-16-0062.
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Novel studies have linked cholesterol biosynthesis to drug resistance in luminal breast cancer. Structural data suggest that cholesterol metabolites, including 27-hydroxycholesterol (27HC), can act as ERα ligands in these cells. Additionally, hypercholesterolemia has now been linked to breast cancer progression. The focus of this review is to briefly summarize these recent findings and discuss how epigenetic reprogramming is definitively connected to endogenous cholesterol biosynthesis. We elaborate on how these data support a working model in which cholesterol biosynthesis promotes autocrine, pro-invasive signaling via activation of a series of closely related transcription factors. Importantly, we discuss how this mechanism of resistance is specifically associated with aromatase inhibitors. Finally, we examine how the field is now considering the development of anticholesterol therapeutics and companion biomarkers to stratify and treat ERα breast cancer patients. In particular, we review recent progress in pharmaceutical strategies targeting the cholesterol molecular machinery in primary and secondary breast cancers.
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Mishra, Prachi, Wei Tang, and Stefan Ambs. "ADHFE1 is a MYC-linked oncogene that induces metabolic reprogramming and cellular de-differentiation in breast cancer." Molecular & Cellular Oncology 5, no. 3 (April 19, 2018): e1432260. http://dx.doi.org/10.1080/23723556.2018.1432260.
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Bonanomi, Marcella, Noemi Salmistraro, Giulia Fiscon, Federica Conte, Paola Paci, Valentina Bravatà, Giusi Irma Forte, et al. "Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells." Cancers 13, no. 20 (October 9, 2021): 5058. http://dx.doi.org/10.3390/cancers13205058.
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Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epigenetic transcriptional reprogramming. By integrating metabolomics and transcriptomics in a triple-negative human breast cancer cell line, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, ROS generation, and scavenging. Our data highlight the critical role of NADH in controlling the oncogene-dependent crosstalk between metabolism and the epigenetically mediated transcriptional program that sustains energetic and anabolic demands in cancer cells.
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Yang, Li, Jae Young So, Nicolas Skrypek, Anand Merchant, George Nelson, Howard Yang, and Maxwell Lee. "Abstract P1-05-08: Targeting tumor heterogeneity and breast cancer metastasis through the metastatic microenvironment mediated epigenetic reprogramming." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–05–08—P1–05–08. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-05-08.
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Abstract Targeting tumor heterogeneity and breast cancer metastasis through the metastaticmicroenvironment mediated epigenetic reprogrammingLi Yang and Jae Young So, Nicolas Skrypek, Anand Merchant, George Nelson, Howard H.Yang, Maxwell P. LeeNational Cancer Institute, National Institutes of Health, Bethesda, MD 20892Current cancer treatments are largely based on the genetic characterization of primarytumors and are ineffective for metastatic disease. There is lack of mechanistic understanding ashow cancer cells are selected and evolved to establish distant metastatic colonies. In addition,tumor heterogeneity and biomarker identification remain to be some of the most difficultchallenges in cancer treatment. In the current study, we discovered an increased DNAmethyltransferase 3B (DNMT3B) in metastatic nodules and in tumor cells with epithelia tomesenchymal (EMT) phenotype. Of great interest, high levels of DNMT3B were correlated withpoor clinical outcomes in multiple human breast cancer datasets. Mechanistically, DNMT3Balters multiple pathways including STAT3, NFkappaB, PI3K/Akt, beta-catenin, Notch signalingas well as EMT, which are critical for cancer cell survival, apoptosis, proliferation, invasion, andcolonization. We further identified PGE2 and IL6 as critical inflammatory mediators inDNMT3B induction. Importantly, targeting IL6 or PGE2 production reduced DNMT3Bexpression and improved chemo treatment or PD1 immune therapy. Furthermore, perioperative(surgical removal of primary tumors) targeting DNMT3B in combination with chemotherapymarkedly suppressed tumor recurrence and metastasis in preclinical mouse models for triplenegative breast cancer. Our studies identify DNMT3B as an important mechanism fortranscription regulation in tumor heterogeneity that is critical for tumor invasion and metastasis,thus suggesting a validated target for treating metastatic disease. Citation Format: Li Yang, Jae Young So, Nicolas Skrypek, Anand Merchant, George Nelson, Howard Yang, Maxwell Lee. Targeting tumor heterogeneity and breast cancer metastasis through the metastatic microenvironment mediated epigenetic reprogramming [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-05-08.
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Li, Yihao, Xintao Qiu, Xiaoqing Wang, Hui Liu, Renee Geck Geck, Alok Tewari, Kin-Hoe Chow, et al. "Abstract P4-01-04: FGFR inhibitor mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces therapeutic resistance in triple negative breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P4–01–04—P4–01–04. http://dx.doi.org/10.1158/1538-7445.sabcs21-p4-01-04.
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Abstract How cancer cells adapt to evade the therapeutic effects of drugs targeting oncogenic drivers is poorly understood. Here we report an epigenetic mechanism leading to the adaptive resistance of triple-negative breast cancer (TNBC) to fibroblast growth factor receptor (FGFR) inhibitors. Prolonged FGFR inhibition suppresses the function of BRG1-dependent chromatin remodeling leading to an epigenetic state that derepresses YAP-associated enhancers. These chromatin changes induce the expression of several amino acid transporters resulting in increased intracellular levels of specific amino acids that reactivate mTORC1. Consistent with this mechanism, addition of mTORC1 or YAP inhibitors to FGFR blockade synergistically attenuated the growth of TNBC patient-derived xenografts (PDX) models. Collectively, these findings reveal a novel feedback loop involving an epigenetic state transition and metabolic reprogramming that leads to adaptive therapeutic resistance and provide new therapeutic strategies to overcome this mechanism of resistance. Citation Format: Yihao Li, Xintao Qiu, Xiaoqing Wang, Hui Liu, Renee Geck Geck, Alok Tewari, Kin-Hoe Chow, Tengfei Xiao, Paloma Cejas, Quang-Dé Nguyen, Henry Long, Shirley X Liu, Alex Toker, Myles Brown. FGFR inhibitor mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces therapeutic resistance in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-04.
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Padayachee, Jananee, and Moganavelli Singh. "Therapeutic applications of CRISPR/Cas9 in breast cancer and delivery potential of gold nanomaterials." Nanobiomedicine 7 (January 1, 2020): 184954352098319. http://dx.doi.org/10.1177/1849543520983196.
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Globally, approximately 1 in 4 cancers in women are diagnosed as breast cancer (BC). Despite significant advances in the diagnosis and therapy BCs, many patients develop metastases or relapses. Hence, novel therapeutic strategies are required, that can selectively and efficiently kill malignant cells. Direct targeting of the genetic and epigenetic aberrations that occur in BC development is a promising strategy to overcome the limitations of current therapies, which target the tumour phenotype. The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system, composed of only an easily modifiable single guide RNA (sgRNA) sequence bound to a Cas9 nuclease, has revolutionised genome editing due to its simplicity and efficiency compared to earlier systems. CRISPR/Cas9 and its associated catalytically inactivated dCas9 variants facilitate the knockout of overexpressed genes, correction of mutations in inactivated genes, and reprogramming of the epigenetic landscape to impair BC growth. To achieve efficient genome editing in vivo, a vector is required to deliver the components to target cells. Gold nanomaterials, including gold nanoparticles and nanoclusters, display many advantageous characteristics that have facilitated their widespread use in theranostics, as delivery vehicles, and imaging and photothermal agents. This review highlights the therapeutic applications of CRISPR/Cas9 in treating BCs, and briefly describes gold nanomaterials and their potential in CRISPR/Cas9 delivery.
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Ward, Ashley V., Shawna B. Matthews, Lynsey M. Fettig, Duncan Riley, Jessica Finlay-Schultz, Kiran V. Paul, Matthew Jackman, Peter Kabos, Paul S. MacLean, and Carol A. Sartorius. "Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism." Cancers 14, no. 7 (March 31, 2022): 1776. http://dx.doi.org/10.3390/cancers14071776.
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Metabolic reprogramming remains largely understudied in relation to hormones in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer. In this study, we investigated how estrogens, progestins, or the combination, impact metabolism in three ER and PR positive breast cancer cell lines. We measured metabolites in the treated cells using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Top metabolic processes upregulated with each treatment involved glucose metabolism, including Warburg effect/glycolysis, gluconeogenesis, and the pentose phosphate pathway. RNA-sequencing and pathway analysis on two of the cell lines treated with the same hormones, found estrogens target oncogenes, such as MYC and PI3K/AKT/mTOR that control tumor metabolism, while progestins increased genes associated with fatty acid metabolism, and the estrogen/progestin combination additionally increased glycolysis. Phenotypic analysis of cell energy metabolism found that glycolysis was the primary hormonal target, particularly for the progestin and estrogen-progestin combination. Transmission electron microscopy found that, compared to vehicle, estrogens elongated mitochondria, which was reversed by co-treatment with progestins. Progestins promoted lipid storage both alone and in combination with estrogen. These findings highlight the shift in breast cancer cell metabolism to a more glycolytic and lipogenic phenotype in response to combination hormone treatment, which may contribute to a more metabolically adaptive state for cell survival.
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Eduardo, Mariana Bustamante, Gannon Cottone, Seema Khan, and Susan Clare. "Abstract P6-11-03: Lipid-rich environment induces epigenetic reprogramming in non-transformed breast epithelial cells enhancing a mammary cell plasticity." Cancer Research 83, no. 5_Supplement (March 1, 2023): P6–11–03—P6–11–03. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-11-03.
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Abstract Introduction. The identification of women specifically at risk for estrogen receptor negative breast cancer (ER- BC) and the targeted treatment of this disease are significantly unmet clinical needs. We analyzed the gene expression profiles of epithelial cells from the contralateral unaffected breasts (CUBs) of BC patients and identified a lipid metabolism gene signature enriched in the CUBs of women with ER- BC (PMID: 28263391). Subsequently, we observed that exposure of non-transformed breast epithelial cells to lipids results in significant changes in gene expression and histone posttranslational modifications; and increased flux through multiple metabolic reactions, including those of serine and methionine (PMID: 35508495). Interestingly, the upregulated genes are involved in neural development, axon guidance, neural crest pathways and stemness. Neural genes are highly expressed in Triple Negative Breast Cancers (TNBCs) especially in the C2 cluster. Given that mammary stem/progenitor cells have distinct metabolic properties compared to other mammary cell subsets, we hypothesized that upon lipid exposure, stem-like cells have a survival advantage, and that lipid induces epigenetic reprogramming into neural-like cells which may foster a malignant transformation. Methods. To interrogate potential mechanisms linking lipids and epigenetic reprogramming, we performed CUT&RUN for H3K4me3 and H3K27me3 in non-transformed, estrogen and progesterone receptor negative MCF-10A cells cells exposed to vehicle or octanoic acid (OA) for 24 hrs. Peaks were called using MACS2 and differential peaks identified with DiffBind. Differentially expressed genes affected by OA (PMID: 28263391) were compared with target genes from the CUT&RUN. To determine the contribution in OA exposed cells of serine and methionine metabolism to S-adenosyl methionine (SAM), 13C-glucose tracing was performed. The Aldefluour assay was used to identify stem-like (ALDH+) cells in lipid-exposed MCF-10A cells. To determine if lipid-exposed cells adopt a neural-like phenotype, MCF-10A cells were grown on Poly-D-Lysine/Laminin (PDL/LM) coated plates. Results. A total of 661 differential peaks were identified for H3K4me3 (FDR < 0.05) encompassing TNBC C2 markers (NRTN, CHRM3) and genes involved in neuron differentiation, axonogenesis (NGFR, NGF, FOXA2), neural crest migration (NTRK2, MMP2) and EMT (DLL4, MMP15). Approximately 73% of H3K4me3 OA-associated peaks encompass regulatory regions of genes that experienced a significant increase in gene expression with OA exposure (FDR < 0.01), including NGFR (log2 FC = 11.7), FOXA2 (log2 FC = 11.6), NGF (log2 FC = 8). Twelve H3K27me3 peaks were significantly enriched in vehicle (FDR < 0.05) and associated with increased gene expression in OA, among them were the stem cell markers LGR6 (log2 FC = 1.9) and PLAG1 (log2 FC = 2.8). 13C stable isotope tracing revealed that in presence of OA, glucose contributes to increased fractional abundance of the SAM M+1 isotopologue (adj p = 0.003) indicating that carbons derived from the serine synthesis pathway are used for re-methylation of homocysteine to methionine. Vehicle treated cells growing on PDL/LM plates assumed an epithelial phenotype while OA-treated cells adopted a neurite-like phenotype. Upon OA treatment the percentage of ALDH+ cells increased by a minimum of 10%. Conclusions. The increase of fractional abundance of SAM and the upregulation of neural genes regulated by H3K4me3 as well as the enrichment of ALDH+ cells and the development of a neural-like phenotype in a rich lipid environment, suggests that lipid exposure affects the production of SAM, which results in epigenetic fostered plasticity, leading to reprogramming/selecting cells with a multi-potential embryonic or stem-like state and/or differentiation to a neural/neural crest-like state. Citation Format: Mariana Bustamante Eduardo, Gannon Cottone, Seema Khan, Susan Clare. Lipid-rich environment induces epigenetic reprogramming in non-transformed breast epithelial cells enhancing a mammary cell plasticity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-03.
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Matkar, Smita, Paras Sharma, Shubin Gao, Buddha Gurung, Bryson W. Katona, Jennifer Liao, Abdul Bari Muhammad, et al. "An Epigenetic Pathway Regulates Sensitivity of Breast Cancer Cells to HER2 Inhibition via FOXO/c-Myc Axis." Cancer Cell 28, no. 4 (October 2015): 472–85. http://dx.doi.org/10.1016/j.ccell.2015.09.005.
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Bowers, Laura W., Steven S. Doerstling, Meghana G. Shamsunder, Claire G. Lineberger, Emily L. Rossi, Stephanie A. Montgomery, Michael F. Coleman, et al. "Reversing the Genomic, Epigenetic, and Triple-Negative Breast Cancer–Enhancing Effects of Obesity." Cancer Prevention Research 15, no. 9 (June 13, 2022): 581–94. http://dx.doi.org/10.1158/1940-6207.capr-22-0113.
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Abstract The reversibility of the procancer effects of obesity was interrogated in formerly obese C57BL/6 mice that lost weight via a nonrestricted low-fat diet (LFD) or 3 distinct calorie-restricted (CR) regimens (low-fat CR, Mediterranean-style CR, or intermittent CR). These mice, along with continuously obese mice and lean control mice, were orthotopically injected with E0771 cells, a mouse model of triple-negative breast cancer. Tumor weight, systemic cytokines, and incidence of lung metastases were elevated in the continuously obese and nonrestricted LFD mice relative to the 3 CR groups. Gene expression differed between the obese and all CR groups, but not the nonrestricted LFD group, for numerous tumoral genes associated with epithelial-to-mesenchymal transition as well as several genes in the normal mammary tissue associated with hypoxia, reactive oxygen species production, and p53 signaling. A high degree of concordance existed between differentially expressed mammary tissue genes from obese versus all CR mice and a microarray dataset from overweight/obese women randomized to either no intervention or a CR diet. Assessment of differentially methylated regions in mouse mammary tissues revealed that obesity, relative to the 4 weight loss groups, was associated with significant DNA hypermethylation. However, the anticancer effects of the CR interventions were independent of their ability to reverse obesity-associated mammary epigenetic reprogramming. Taken together, these preclinical data showing that the procancer effects of obesity are reversible by various forms of CR diets strongly support translational exploration of restricted dietary patterns for reducing the burden of obesity-associated cancers. Prevention Relevance: Obesity is an established risk and progression factor for triple-negative breast cancer (TNBC). Given rising global rates of obesity and TNBC, strategies to reduce the burden of obesity-driven TNBC are urgently needed. We report the genomic, epigenetic, and procancer effects of obesity are reversible by various calorie restriction regimens.
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Zimmermannova, Olga, Ilia Kurochkin, Diego S. Cabrera, Ariane E. Tenreiro, Hreinn Benonisson, Alexandra G. Ferreira, Inês Caiado, et al. "Reprogramming Human Cancer Cells into Antigen Presentation." Blood 138, Supplement 1 (November 5, 2021): 1709. http://dx.doi.org/10.1182/blood-2021-152322.
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Abstract Cancer progression entails close crosstalk between tumor cells and immune system. Recent advances in understanding mutual tumor-immune interactions translated into the development of cancer immunotherapy, changing the cancer treatment paradigm. Nevertheless, despite achieving long-term effect even in advanced malignancies, only a minor subset of patients responds to immunotherapy. The activation of the immune system, as well as good response to the immunotherapy strongly depends on tumor immunogenicity and effective presentation of tumor-associated antigens by conventional dendritic cells type 1 (cDC1). However, downregulation of antigen-presentation machinery and cDC1 exclusion represent major mechanisms of cancer immune evasion, leading to immunotherapy failure. Previously, we identified a combination of 3 transcription factors, PU.1, IRF8, and BATF3 (PIB) that instructed direct reprogramming of fibroblasts into cDC1-like cells endowed with the ability to present and cross-present antigens. Here, we hypothesize that cDC1-direct reprogramming employing PIB transcription factors can impose antigen-presentation directly in human tumor cells, generating functional tumor-antigen presenting cells (tumor-APCs) able to prime antigen-specific T cell responses. Here, we used a large panel of human cell lines (>30) derived from leukemia and multiple solid tumors including glioblastoma, melanoma, breast, pancreatic, ovarian, prostate, head and neck, and lung adenocarcinoma and evaluated dendritic cell reprogramming efficiency. Enforced expression of PIB induced a cDC1-phenotype in tumor cells, as demonstrated by an emerging CD45+HLA-DR+ population and the activation of the cDC1-markers CD11c, CD141, and CLEC9A. Induced cells showed global transcriptional reprogramming towards cDC1 fate imposing a tumor-APC signature in cancer cells at varying efficiencies ranging between 0.2±0.1% to 94.5±7.6% according to the tumor cell of origin. PIB induces rapid transcriptomic and epigenetic rewiring of cancer cells towards cDC1-fate, activating antigen presentation and processing machinery. This reprogramming process is asynchronous and leads to the generation of intermediate populations with active tumor-APC gene expression signatures. Furthermore, tumor-APCs upregulated expression of HLA-ABC and the co-stimulatory molecules CD40, CD80, and CD86, suggesting the acquired ability to prime immune-effectors. Functionally, tumor-APCs secrete pro-inflammatory cytokines including IL12p70, TNFα, CXCL10, and IL-29 upon TLR3/4 stimulation with Poly:IC and LPS, are competent in phagocytosis of dead cells and proteins, and can activate antigen-specific CD8+ T-cells. Importantly, cDC1-cell fate adoption was accompanied by downregulation of proliferation and diminished tumorigenicity, as evidenced by the loss of anchorage-independent growth. Importantly, cDC1-reprogramming was efficient in primary tissues obtained from head and neck, breast, urothelial and pancreatic carcinoma, as well as melanoma patients. Notably, PIB-mediated cDC1 reprogramming of tumor cells is substantially augmented when combined with a histone deacetylase inhibitor, valproic acid. In summary, PIB expression imposes cDC1 fate and function in a broad range of human cancer cells suggesting a capacity to elicit anti-tumor responses by orchestrating innate and adaptive immunity. Our strategy combines cDC1 antigen-processing and presenting abilities with the endogenous generation of tumor-antigens. This approach merges cell fate reprogramming with cancer immunotherapy, paving the way for the development of novel gene therapy for cancer. Disclosures No relevant conflicts of interest to declare.
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Lim, S. M. L., I. Aksoy, K. G. C. Lim, J. Karuppasamy, U. Divakar, F. J. Ma, F. L. Lam, S. J. N. Remulla, and L. W. Stanton. "Re-establishing pluripotency in adult cells derived from breast stromal tissue." Journal of Clinical Oncology 29, no. 27_suppl (September 20, 2011): 227. http://dx.doi.org/10.1200/jco.2011.29.27_suppl.227.
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227 Background: Recent advances in pluripotent stem cell biology offer patient-specific disease models to investigate in vitro mechanisms of tumorigenesis. Induced pluripotent stem (iPS) cells were originally derived by reprogramming of human dermal fibroblasts through ectopic expression of pluripotency–associated transcription factors. A limitation to the use of dermal fibroblasts as the starting cell type for reprogramming is that it usually takes weeks to expand cells from a single biopsy, and the efficiency of the process is very low. In contrast, a large number of adipose-derived mesenchymal stromal cells (Ad-MSCs) can be easily obtained from the stroma of human breast tissue, without the time-consuming steps of cell expansion. Here we investigated the ability to induce pluripotency in committed, Ad-MSCs derived from the stroma of breast tissue. Methods: The aim of this study is to investigate the potential of using Ad-MSCs derived from surgically discarded breast stromal tissue to generate human iPS. Discarded tissue during surgical procedures was processed in vitro and Ad-MSCs were derived. These Ad-MSCs were then used to generate iPS cells by ectopic expression of “Yamanaka’s cocktail” containing OCT4, SOX2, KLF4 and c-MYC. Results: The success rate in generating iPS cells from human Ad-MSCs derived from breast stromal tissue is very high compared to the use of dermal fibroblasts. In our study, almost all human Ad-MSC cell lines can be reprogrammed into iPS cells, which share the same characteristics as skin fibroblast-derived iPS cells and human embryonic stem cells in their morphology, gene expression profile and differentiation capacities. Conclusions: We are now optimizing this approach and making it more clinically relevant by adopting an integration-free method to deliver the reprogramming factors. The successful reprogramming of breast stromal-derived Ad-MSCs into iPS cells may provide a valuable source of patient-specific iPS cells to study the mechanism of tumorigenesis in patients with breast cancer.
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Sivanandhan, Dhanalakshmi, Sridharan Rajagopal, Chandru Gajendran, Naveen Sadhu, Mohd Zainuddin, Ramachandraiah Gosu, and Luca Rastelli. "Abstract B029: LSD1-HDAC6 dual inhibitor JBI-802 is an epigenetic modulating agent with a novel mechanism of action that target MYC amplification in multiple neuroendocrine tumor types." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): B029. http://dx.doi.org/10.1158/1538-7445.cancepi22-b029.
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Abstract MYC is considered a master regulator of human cancers by modulating the transcription of numerous cancer-related genes. MYC amplification is reported in about 15% of all human cancers and is generally associated with poor prognosis and resistance to treatments. Focal amplification of MYC together with mutation in RB1 and p53 is an important event in the metastatic process of neuroendocrine tumor development. While limited options are available for direct targeting, transcriptional modulation via epigenetic modulating agent could be an attractive and viable option to target neuroendocrine cancers. JBI-802 inhibits the transcriptional regulator coREST via its component LSD1/HDAC6 therefore blocking neuroendocrine transdifferentiation and inducing cell death resulting in activity against neuroendocrine tumors. At the same time, this molecule has shown a good safety profile in toxicological studies. We have now identified a novel aspect of JBI-802 mechanism of action, the ability to induce downregulation of MYC RNA and degradation of MYC protein both in vitro and in animal models of two neuroendocrine tumors, small cell lung cancer and neuroendocrine prostate cancer JBI-802 showed significant anti-proliferative activity (0.2 to 1 µM) against several cancer cell lines as shown by Alamar blue or CTG assays. Sensitive ones included small cell lung cancer (SCLC), gastric cancer, breast cancer cell lines with RB1 mutation. Interestingly, dual inhibitor JBI-802 was also active in cell lines with MYC over-expression, while LSD1 selective inhibitors have been reported to be inactive in these cell lines. JBI-802 also inhibited MYC at RNA as well as protein level in hematological and solid tumors as assessed by RT-qPCR at RNA level and by Western blotting at protein level, while single agent LSD1 and HDAC6 inhibitors did not show significant modulation. JBI-802 also showed strong tumor growth inhibition of these tumors in mouse xenograft models. MYC levels showed a dose dependent inhibition in these tumors when tested at the end of the study. Only dual inhibition of both LSD1/HDAC6 with JBI-802 as opposed to single target inhibition is able to effectively downregulate MYC level and achieve efficacy in MYC amplified models in vivo and in vitro. This novel mechanism increases the potential population of neuroendocrine patients that could be sensitive to this compound, going beyond the proof of principle already established preclinically and clinically by single target LSD1 inhibitors. Therefore, by targeting 2 major pathways in neuroendocrine tumor development, JBI-802 novel mechanism of action is uniquely suited for the treatment of high unmet neuroendocrine tumors like small cell lung cancer, neuroendocrine prostate cancer and advanced, MYC amplified tumors. Based on this rationale, JBI-802 is being tested in phase 1/2 clinical trial focus on this type of tumors. Citation Format: Dhanalakshmi Sivanandhan, Sridharan Rajagopal, Chandru Gajendran, Naveen Sadhu, Mohd Zainuddin, Ramachandraiah Gosu, Luca Rastelli. LSD1-HDAC6 dual inhibitor JBI-802 is an epigenetic modulating agent with a novel mechanism of action that target MYC amplification in multiple neuroendocrine tumor types. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B029.