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1
Børresen-Dale, A. L. "Tumour suppressor genes in breast cancer." European Journal of Cancer 34 (September 1998): S37. http://dx.doi.org/10.1016/s0959-8049(98)80137-8.
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S Patil, Priya, Jaydeep N Pol, and Ashalata D Patil. "ROLE OF TUMOUR SUPPRESSOR GENE P53 IN TRIPLE NEGATIVE BREAST CANCER." International Journal of Anatomy and Research 5, no. 4.2 (November 1, 2017): 4585–89. http://dx.doi.org/10.16965/ijar.2017.402.
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Lai, Dulcie, Stacy Visser-Grieve, and Xiaolong Yang. "Tumour suppressor genes in chemotherapeutic drug response." Bioscience Reports 32, no. 4 (April 23, 2012): 361–74. http://dx.doi.org/10.1042/bsr20110125.
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Since cancer is one of the leading causes of death worldwide, there is an urgent need to find better treatments. Currently, the use of chemotherapeutics remains the predominant option for cancer therapy. However, one of the major obstacles for successful cancer therapy using these chemotherapeutics is that patients often do not respond or eventually develop resistance after initial treatment. Therefore identification of genes involved in chemotherapeutic response is critical for predicting tumour response and treating drug-resistant cancer patients. A group of genes commonly lost or inactivated are tumour suppressor genes, which can promote the initiation and progression of cancer through regulation of various biological processes such as cell proliferation, cell death and cell migration/invasion. Recently, mounting evidence suggests that these tumour suppressor genes also play a very important role in the response of cancers to a variety of chemotherapeutic drugs. In the present review, we will provide a comprehensive overview on how major tumour suppressor genes [Rb (retinoblastoma), p53 family, cyclin-dependent kinase inhibitors, BRCA1 (breast-cancer susceptibility gene 1), PTEN (phosphatase and tensin homologue deleted on chromosome 10), Hippo pathway, etc.] are involved in chemotherapeutic drug response and discuss their applications in predicting the clinical outcome of chemotherapy for cancer patients. We also propose that tumour suppressor genes are critical chemotherapeutic targets for the successful treatment of drug-resistant cancer patients in future applications.
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Försti, Asta, Qianren Jin, Lena Sundqvist, Magnus Söderberg, and Kari Hemminki. "Use of Monozygotic Twins in Search for Breast Cancer Susceptibility Loci." Twin Research 4, no. 4 (August 1, 2001): 251–59. http://dx.doi.org/10.1375/twin.4.4.251.
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AbstractWe have used Swedish monozygotic twins concordant for breast cancer to study genetic changes associated with the development of breast cancer. Because loss of heterozygosity (LOH) at a specific genomic region may reflect the presence of a tumour suppressor gene, loss of the same allele in both of the twins concordant for breast cancer may pinpoint a tumour suppressor gene that confers a strong predisposition to breast cancer. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a set of microsatellite markers on chromosomes 1, 13, 16 and 17, containing loci with known tumour suppressor genes. The two main regions, where more twin pairs than expected had lost the same allele, were located at 16qtel, including markers D16S393, D16S305 and D16S413, and at 17p13, distal to the p53 locus. Our results show that the monozygotic twin model can be used to suggest candidate regions of potential tumour suppressor genes, even with a limited number of twin pairs.
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Buchholz, Thomas A., Michael M. Weil, Michael D. Story, Eric A. Strom, William A. Brock, and Marsha D. McNeese. "Tumor suppressor genes and breast cancer." Radiation Oncology Investigations 7, no. 2 (1999): 55–65. http://dx.doi.org/10.1002/(sici)1520-6823(1999)7:2<55::aid-roi1>3.0.co;2-#.
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Oliveira, Andre M., Jeffrey S. Ross, and Jonathan A. Fletcher. "Tumor Suppressor Genes in Breast Cancer." Pathology Patterns Reviews 124, suppl_1 (December 1, 2005): S16—S28. http://dx.doi.org/10.1309/5xw3l8lu445qwgqr.
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Wijshake, Tobias, Zhongju Zou, Beibei Chen, Lin Zhong, Guanghua Xiao, Yang Xie, John G. Doench, Lynda Bennett, and Beth Levine. "Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin." Proceedings of the National Academy of Sciences 118, no. 5 (January 25, 2021): e2020478118. http://dx.doi.org/10.1073/pnas.2020478118.
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Beclin 1, an autophagy and haploinsufficient tumor-suppressor protein, is frequently monoallelically deleted in breast and ovarian cancers. However, the precise mechanisms by which Beclin 1 inhibits tumor growth remain largely unknown. To address this question, we performed a genome-wide CRISPR/Cas9 screen in MCF7 breast cancer cells to identify genes whose loss of function reverse Beclin 1-dependent inhibition of cellular proliferation. Small guide RNAs targeting CDH1 and CTNNA1, tumor-suppressor genes that encode cadherin/catenin complex members E-cadherin and alpha-catenin, respectively, were highly enriched in the screen. CRISPR/Cas9-mediated knockout of CDH1 or CTNNA1 reversed Beclin 1-dependent suppression of breast cancer cell proliferation and anchorage-independent growth. Moreover, deletion of CDH1 or CTNNA1 inhibited the tumor-suppressor effects of Beclin 1 in breast cancer xenografts. Enforced Beclin 1 expression in MCF7 cells and tumor xenografts increased cell surface localization of E-cadherin and decreased expression of mesenchymal markers and beta-catenin/Wnt target genes. Furthermore, CRISPR/Cas9-mediated knockout of BECN1 and the autophagy class III phosphatidylinositol kinase complex 2 (PI3KC3-C2) gene, UVRAG, but not PI3KC3-C1–specific ATG14 or other autophagy genes ATG13, ATG5, or ATG7, resulted in decreased E-cadherin plasma membrane and increased cytoplasmic E-cadherin localization. Taken together, these data reveal previously unrecognized cooperation between Beclin 1 and E-cadherin–mediated tumor suppression in breast cancer cells.
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Tan, D. S. P., C. Marchiò, and J. S. Reis-Filho. "Hereditary breast cancer: from molecular pathology to tailored therapies." Journal of Clinical Pathology 61, no. 10 (August 4, 2008): 1073–82. http://dx.doi.org/10.1136/jcp.2008.057950.
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Hereditary breast cancer accounts for up to 5–10% of all breast carcinomas. Recent studies have demonstrated that mutations in two high-penetrance genes, namely BRCA1 and BRCA2, are responsible for about 16% of the familial risk of breast cancer. Even though subsequent studies have failed to find another high-penetrance breast cancer susceptibility gene, several genes that confer a moderate to low risk of breast cancer development have been identified; moreover, hereditary breast cancer can be part of multiple cancer syndromes. In this review we will focus on the hereditary breast carcinomas caused by mutations in BRCA1, BRCA2, Fanconi anaemia (FANC) genes, CHK2 and ATM tumour suppressor genes. We describe the hallmark histological features of these carcinomas compared with non-hereditary breast cancers and show how an accurate histopathological diagnosis may help improve the identification of patients to be screened for mutations. Finally, novel therapeutic approaches to treat patients with BRCA1 and BRCA2 germ line mutations, including cross-linking agents and PARP inhibitors, are discussed.
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Moerland, E., MH Breuning, CJ Cornelisse, and AM Cleton-Jansen. "Exclusion of BBC1 and CMAR as candidate breast tumour-suppressor genes." British Journal of Cancer 76, no. 12 (December 1997): 1550–53. http://dx.doi.org/10.1038/bjc.1997.594.
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Liang, Ying, Qi Lu, Wei Li, Dapeng Zhang, Fanglin Zhang, Qingping Zou, Lu Chen, et al. "Reactivation of tumour suppressor in breast cancer by enhancer switching through NamiRNA network." Nucleic Acids Research 49, no. 15 (July 30, 2021): 8556–72. http://dx.doi.org/10.1093/nar/gkab626.
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Abstract Dysfunction of Tumour Suppressor Genes (TSGs) is a common feature in carcinogenesis. Epigenetic abnormalities including DNA hypermethylation or aberrant histone modifications in promoter regions have been described for interpreting TSG inactivation. However, in many instances, how TSGs are silenced in tumours are largely unknown. Given that miRNA with low expression in tumours is another recognized signature, we hypothesize that low expression of miRNA may reduce the activity of TSG related enhancers and further lead to inactivation of TSG during cancer development. Here, we reported that low expression of miRNA in cancer as a recognized signature leads to loss of function of TSGs in breast cancer. In 157 paired breast cancer and adjacent normal samples, tumour suppressor gene GPER1 and miR-339 are both downregulated in Luminal A/B and Triple Negative Breast Cancer subtypes. Mechanistic investigations revealed that miR-339 upregulates GPER1 expression in breast cancer cells by switching on the GPER1 enhancer, which can be blocked by enhancer deletion through the CRISPR/Cas9 system. Collectively, our findings reveal novel mechanistic insights into TSG dysfunction in cancer development, and provide evidence that reactivation of TSG by enhancer switching may be a promising alternative strategy for clinical breast cancer treatment.
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Chimonidou, Maria, Areti Strati, Alexandra Tzitzira, Georgia Sotiropoulou, Nikos Malamos, Vasilis Georgoulias, and Evi S. Lianidou. "DNA Methylation of Tumor Suppressor and Metastasis Suppressor Genes in Circulating Tumor Cells." Clinical Chemistry 57, no. 8 (August 1, 2011): 1169–77. http://dx.doi.org/10.1373/clinchem.2011.165902.
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BACKGROUND Circulating tumor cells (CTCs) are associated with prognosis in a variety of human cancers and have been proposed as a liquid biopsy for follow-up examinations. We show that tumor suppressor and metastasis suppressor genes are epigenetically silenced in CTCs isolated from peripheral blood of breast cancer patients. METHODS We obtained peripheral blood from 56 patients with operable breast cancer, 27 patients with verified metastasis, and 23 healthy individuals. We tested DNA extracted from the EpCAM-positive immunomagnetically selected CTC fraction for the presence of methylated and unmethylated CST6, BRMS1, and SOX17 promoter sequences by methylation-specific PCR (MSP). All samples were checked for KRT19 (keratin 19, formerly CK-19) expression by reverse-transcription quantitative PCR. RESULTS In CTCs of patients with operable breast cancer, promoter methylation of CST6 was observed in 17.9%, BRMS1 in 32.1%, and SOX17 in 53.6% of patients. In CTCs of patients with verified metastasis, promoter methylation of CST6 was observed in 37.0%, BRMS1 in 44.4%, and SOX17 in 74.1%. In healthy individuals, promoter methylation of CST6 was observed in 4.3%, BRMS1 in 8.7%, and SOX17 in 4.3%. DNA methylation of these genes for both operable and metastatic breast cancer was significantly different from that of the control population. CONCLUSIONS DNA methylation of tumor suppressor and metastasis suppressor genes is a hallmark of CTCs and confirms their heterogeneity. Our findings add a new dimension to the molecular characterization of CTCs and may underlie the acquisition of malignant properties, including their stem-like phenotype.
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Dhillon, Kiranjit K., Ilirjana Bajrami, Toshiyasu Taniguchi, and Christopher J. Lord. "Synthetic lethality: the road to novel therapies for breast cancer." Endocrine-Related Cancer 23, no. 10 (October 2016): T39—T55. http://dx.doi.org/10.1530/erc-16-0228.
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When theBRCA1andBRCA2tumour suppressor genes were identified in the early 1990s, the immediate implications of mapping, cloning and delineating the sequence of these genes were that individuals in families with aBRCAgene mutation could be tested for the presence of a mutation and their risk of developing cancer could be predicted. Over time though, the discovery ofBRCA1andBRCA2has had a much greater influence than many might have imagined. In this review, we discuss how the discovery ofBRCA1andBRCA2has not only provided an understanding of the molecular processes that drive tumourigenesis but also reignited an interest in therapeutically exploiting loss-of-function alterations in tumour suppressor genes.
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Yu, Jia, Jacqueline Zayas, Bo Qin, and Liewei Wang. "Targeting DNA methylation for treating triple-negative breast cancer." Pharmacogenomics 20, no. 16 (November 2019): 1151–57. http://dx.doi.org/10.2217/pgs-2019-0078.
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Triple-negative breast cancer (TNBC) accounts for 15–20% of all invasive breast cancers and tends to have aggressive histological features and poor clinical outcomes. Unlike, estrogen receptor- or HER2-positive diseases, TNBC patients currently lack the US FDA-approved targeted therapies. DNA methylation is a critical mechanism of epigenetic modification. It is well known that aberrant DNA methylation contributes to the malignant transformation of cells by silencing critical tumor suppressor genes. DNA methyltransferase inhibitors reactivate silenced tumor suppressor genes and result in tumor growth arrest, with therapeutic effects observed in patients with hematologic malignancies. The antitumor effect of these DNA methyltransferase inhibitors has also been explored in solid tumors, especially in TNBC that currently lacks targeted therapies.
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Hwang-Verslues, Wendy W., King-Jen Chang, Eva Y. H. P. Lee, and Wen-Hwa Lee. "Breast Cancer Stem Cells and Tumor Suppressor Genes." Journal of the Formosan Medical Association 107, no. 10 (October 2008): 751–66. http://dx.doi.org/10.1016/s0929-6646(08)60188-6.
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Rakha, Emad A., Andrew R. Green, Des G. Powe, Rebecca Roylance, and Ian O. Ellis. "Chromosome 16 tumor-suppressor genes in breast cancer." Genes, Chromosomes and Cancer 45, no. 6 (2006): 527–35. http://dx.doi.org/10.1002/gcc.20318.
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Karray-Chouayekh, Sondes, Fatma Trifa, Abdelmajid Khabir, Nouredine Boujelbane, Tahia Sellami-Boudawara, Jamel Daoud, Mounir Frikha, Ali Gargouri, and Raja Mokdad-Gargouri. "Clinical Significance of Epigenetic Inactivation of hMLH1 and BRCA1 in Tunisian Patients with Invasive Breast Carcinoma." Journal of Biomedicine and Biotechnology 2009 (2009): 1–7. http://dx.doi.org/10.1155/2009/369129.
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Aberrant hypermethylation of gene promoter regions is one of the mechanisms for inactivation of tumour suppressor genes in many human cancers including breast carcinoma. In the current study, we aimed to assess by MSP, the methylation pattern of two cancer-related genes involved in DNA repair: hMLH1 (mutL homolog 1,colon cancer,nonpolyposis type 2(E. coli) and BRCA1 (breast cancer 1,early onset) in 78 primary breast cancers from Tunisian patients. The methylation frequencies were 24.36% for hMLH1 and 46% for BRCA1. BRCA1 methylation correlated with age at diagnosis (P=.015) and 5-years disease free survival (P=.016) while hMLH1 methylation was more frequent in larger tumors (P=.002) and in presence of distant metastasis (P=.004). Furthermore, methylation of hMLH1 significantly correlated with high level of P53 expression (P=.006) and with overall survival (P=.015) suggesting that silencing of hMLH1 through aberrant promoter methylation could be used as a poor prognosis indicator in breast cancer.
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Sharma, Gayatri, Sameer Mirza, Yi-Hsin Yang, Rajinder Parshad, Priya Hazrah, Siddartha Datta Gupta, and Ranju Ralhan. "Prognostic Relevance of Promoter Hypermethylation of Multiple Genes in Breast Cancer Patients." Analytical Cellular Pathology 31, no. 6 (January 1, 2009): 487–500. http://dx.doi.org/10.1155/2009/416923.
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Background: Methylation-mediated suppression of detoxification, DNA repair and tumor suppressor genes has been implicated in cancer development. This study was designed to investigate the impact of concurrent methylation of multiple genes in breast tumors on disease prognosis.Methods: Methylation specific PCR was carried out to analyze the methylation status of seven genes in archived breast tissues and determine the effect of aberrant methylation of multiple genes on disease prognosis and patients’ survival.Results: Promoter hypermethylation was observed in PRB 67%, ERα 64%, RASSF1A 63%, p16INK4A 51%, PRBβ2 22%, GSTP1 25% and BRCA1 27% of the breast cancers, respectively. Concurrent methylation of BRCA1, ERα, GSTP1 and RARβ2, was observed in a large proportion of breast cancers analyzed, suggesting that these genes do not appear to be methylated alone. Patients with high methylation indices had poor prognosis (p < 0.001, Hazards ratio = 14.58). Cox regression analysis showed RARβ2 promoter methylation to be an independent important determinant of breast cancer prognosis.Conclusions: Our results suggest that methylation of multiple genes plays an important role in prognosis of breast cancer. Our study not only describes the association of methylation mediated silencing of multiple genes with the severity of disease, but also drives to speculate the molecular crosstalk between genes or genetic pathways regulated by them individually.
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Tegally, Houriiyah, Kevin H. Kensler, Zahra Mungloo-Dilmohamud, Anisah W. Ghoorah, Timothy R. Rebbeck, and Shakuntala Baichoo. "Discovering novel driver mutations from pan-cancer analysis of mutational and gene expression profiles." PLOS ONE 15, no. 11 (November 24, 2020): e0242780. http://dx.doi.org/10.1371/journal.pone.0242780.
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As the genomic profile across cancers varies from person to person, patient prognosis and treatment may differ based on the mutational signature of each tumour. Thus, it is critical to understand genomic drivers of cancer and identify potential mutational commonalities across tumors originating at diverse anatomical sites. Large-scale cancer genomics initiatives, such as TCGA, ICGC and GENIE have enabled the analysis of thousands of tumour genomes. Our goal was to identify new cancer-causing mutations that may be common across tumour sites using mutational and gene expression profiles. Genomic and transcriptomic data from breast, ovarian, and prostate cancers were aggregated and analysed using differential gene expression methods to identify the effect of specific mutations on the expression of multiple genes. Mutated genes associated with the most differentially expressed genes were considered to be novel candidates for driver mutations, and were validated through literature mining, pathway analysis and clinical data investigation. Our driver selection method successfully identified 116 probable novel cancer-causing genes, with 4 discovered in patients having no alterations in any known driver genes: MXRA5, OBSCN, RYR1, and TG. The candidate genes previously not officially classified as cancer-causing showed enrichment in cancer pathways and in cancer diseases. They also matched expectations pertaining to properties of cancer genes, for instance, showing larger gene and protein lengths, and having mutation patterns suggesting oncogenic or tumor suppressor properties. Our approach allows for the identification of novel putative driver genes that are common across cancer sites using an unbiased approach without any a priori knowledge on pathways or gene interactions and is therefore an agnostic approach to the identification of putative common driver genes acting at multiple cancer sites.
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Moggs, J. G., T. C. Murphy, F. L. Lim, D. J. Moore, R. Stuckey, K. Antrobus, I. Kimber, and G. Orphanides. "Anti-proliferative effect of estrogen in breast cancer cells that re-express ERα is mediated by aberrant regulation of cell cycle genes." Journal of Molecular Endocrinology 34, no. 2 (April 2005): 535–51. http://dx.doi.org/10.1677/jme.1.01677.
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Estrogen receptor (ER)-negative breast carcinomas do not respond to hormone therapy, making their effective treatment very difficult. The re-expression of ERα in ER-negative MDA-MB-231 breast cancer cells has been used as a model system, in which hormone-dependent responses can be restored. Paradoxically, in contrast to the mitogenic activity of 17β-estradiol (E2) in ER-positive breast cancer cells, E2 suppresses proliferation in ER-negative breast cancer cells in which ERα has been re-expressed. We have used global gene expression profiling to investigate the mechanism by which E2 suppresses proliferation in MDA-MB-231 cells that express ERα through adenoviral infection. We show that a number of genes known to promote cell proliferation and survival are repressed by E2 in these cells. These include genes encoding the anti-apoptosis factor SURVIVIN, positive cell cycle regulators (CDC2, CYCLIN B1, CYCLIN B2, CYCLIN G1, CHK1, BUB3, STK6, SKB1, CSE1 L) and chromosome replication proteins (MCM2, MCM3, FEN1, RRM2, TOP2A, RFC1). In parallel, E2-induced the expression of the negative cell cycle regulators KIP2 and QUIESCIN Q6, and the tumour-suppressor genes E-CADHERIN and NBL1. Strikingly, the expression of several of these genes is regulated in the opposite direction by E2 compared with their regulation in ER-positive MCF-7 cells. Together, these data suggest a mechanism for the E2-dependent suppression of proliferation in ER-negative breast cancer cells into which ERα has been reintroduced.
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Porta, Giuseppe Della, Paolo Radice, and Marco A. Pierotti. "Onco-Suppressor Genes in Human Cancer." Tumori Journal 75, no. 4 (August 1989): 329–36. http://dx.doi.org/10.1177/030089168907500406.
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The analysis of the molecular mechanisms governing multistep carcinogenesis became experimentally approachable since the identification and characterization in tumor cells of altered or activated versions of cellular genes (oncogenes) that normally control cell growth and differentiation. The activating mutations confer new properties to the oncogene products and should therefore be considered as gain of function mutations. In addition, the oncogenes appear to act as dominant genetic traits since they act also in the presence of the homologous wild-type allele. However, the concept of a dominance of the transformed phenotype has been challenged by early experiments with somatic cell hybrids which showed that the fusion of normal and malignant cells may suppress the tumorigenic phenotype. The suppression or reversion of the malignant phenotype by the introduction of a normal chromosome into a tumor cell line has lent support to the idea that a family of cellular genes are coding for factors capable to interact with the cell-growth control machinery. These genes seem to reconstitute the normal control of cell growth even in the presence of an activated oncogene. In addition, a two-mutation model has been proposed to explain the epidemiological and clinical features of childhood cancers. According to the model, the development of these malignancies can be caused by the loss or inactivation of both alleles of cellular genes, as suggested by the somatic cell hybrid experiments where the function of the inactivated genes is restored by the contribution of those derived from the normal parental cells. This family of genes is designated as onco-suppressor genes since their product is necessary for the normal regulated cell growth and is lacking or inactivated in malignant cells. At gene level they should be considered as recessive genetic traits, since the tumor phenotype appears when both alleles of an oncosuppressor gene are inactivated. The mutations affecting their normal functions belong to the type « loss of function ». The molecular analysis of retinoblastoma has led to the cloning and sequencing of the related onco-suppressor gene (RB gene) whose product displays the features of a gene-regulatory protein. In addition, a binding between the RB product and various viral onco-proteins (E1A, large T, E7) has been demonstrated, thus suggesting a mechanism of RB inactivation by which some DNA viruses can transform the host cell. Finally, the increasing availability of DNA markers, defining restriction fragment length polymorphisms, has led to the mapping of the loci of inherited predisposition for familial cancer syndromes such as MEN-1, VHL and NF-2 and to the extension to common cancers of the allele losses analysis that can reveal onco-suppressor gene inactivation. This indirect approach has suggested the occurrence of different onco-suppressor genes for sporadic breast, colonic and lung cancers, bladder carcinoma, germinal tumors of the testis and malignant melanoma. In particular, colonic cancer provides a significant example of a possible multistep scenario for carcinogenesis in humans in which activated oncogenes (e.g. ras) and inactivated putative onco-suppressor genes (on chromosome 17 and 18) coexist in the same cell.
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Menghi, Francesca, Koichiro Inaki, XingYi Woo, Pooja A. Kumar, Krzysztof R. Grzeda, Ankit Malhotra, Vinod Yadav, et al. "The tandem duplicator phenotype as a distinct genomic configuration in cancer." Proceedings of the National Academy of Sciences 113, no. 17 (April 7, 2016): E2373—E2382. http://dx.doi.org/10.1073/pnas.1520010113.
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Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, endometrial, and liver cancers, TDP tumors conjointly exhibit tumor protein p53 (TP53) mutations, disruption of breast cancer 1 (BRCA1), and increased expression of DNA replication genes pointing at rereplication in a defective checkpoint environment as a plausible causal mechanism. The resultant TDs in TDP augment global oncogene expression and disrupt tumor suppressor genes. Importantly, the TDP strongly correlates with cisplatin sensitivity in both TNBC cell lines and primary patient-derived xenografts. We conclude that the TDP is a common cancer chromotype that coordinately alters oncogene/tumor suppressor expression with potential as a marker for chemotherapeutic response.
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Pushkarev, A. V., M. G. Galeev, V. A. Pushkarev, and A. V. Sultanbaev. "Genetic Predictors of Malignancy: a Literature Review." Creative surgery and oncology 11, no. 2 (May 22, 2021): 157–65. http://dx.doi.org/10.24060/2076-3093-2021-11-2-157-165.
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The review covers recent research on cancer as a genetic disease manifesting both sporadically and in germline through variant genomic mutations or DNA rearrangements. This change can be point mutations, chromosomal aberrations or hypermethylation leading to DNA repair failures. Defects in tumour suppressor genes (BRCA1, BRCA2, CHEK2, PTCH1, etc.) underly hereditary predisposition to breast cancer (BC) and ovarian cancer (OC) due to genome instability. Studying somatic mutations is key to the understanding of carcinogenesis mechanisms and finding apt therapies. Heterogeneity of cancers renders the tumour mutation profiling uneasy. The treatment choice and efficacy in BC and OC depends on homologous recombination defects in tumour cells usually imposed by damaged BRCA1/2 genes. CHEK2- associated neoplasms account for most hereditary BCs linked to flaws in the DNA repair machinery. Overexpression of the PTCH1 protein is the target in breast, lung, ovarian, colonic cancers, etc.Genetic research has fundamentally altered our understanding of the aetiology and pathogenesis of human malignancy. The molecular cancer phenotype is of paramount importance in the disease prognosis and treatment personalisation.
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Boulton, S. J. "Cellular functions of the BRCA tumour-suppressor proteins." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 633–45. http://dx.doi.org/10.1042/bst0340633.
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Inherited germline mutations in either BRCA1 or BRCA2 confer a significant lifetime risk of developing breast or ovarian cancer. Defining how these two genes function at the cellular level is essential for understanding their role in tumour suppression. Although BRCA1 and BRCA2 were independently cloned over 10 years ago, it is only in the last few years that significant progress has been made towards understanding their function in cells. It is now widely accepted that both genes play critical roles in the maintenance of genome stability. Evidence implicates BRCA2 as an integral component of the homologous recombination machinery, whereas BRCA1 is an E3 ubiquitin ligase that has an impact on DNA repair, transcriptional regulation, cell-cycle progression and meiotic sex chromosome inactivation. In this article, I will review the most recent advances and provide a perspective of potential future directions in this field.
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LIN, Fang, and Munankarmy AMIK. "ROLES OF LARGE TUMOR SUPPRESSOR GENES IN BREAST CANCER." International Journal of Advanced Research 5, no. 11 (November 30, 2017): 954–58. http://dx.doi.org/10.21474/ijar01/5854.
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Cox, Laura A., Gang Chen, and Eva Y. H. P. Lee. "Tumor suppressor genes and their roles in breast cancer." Breast Cancer Research and Treatment 32, no. 1 (1994): 19–38. http://dx.doi.org/10.1007/bf00666203.
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Lee, Eva Y. H. P. "Tumor suppressor genes and their alterations in breast cancer." Seminars in Cancer Biology 6, no. 3 (June 1995): 119–25. http://dx.doi.org/10.1006/scbi.1995.0019.
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Euhus, D., R. Ashfaq, D. Bu, A. M. Leitch, and C. Lewis. "Assessment of tumor suppressor gene methylation for breast cancer risk screening." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 1004. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.1004.
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1004 Background: Tumor suppressor gene (TSG) methylation is frequently detected in benign proliferative breast tissue suggesting that it occurs early in breast carcinogenesis. If it can be screen-detected and is associated with breast cancer risk it could be exploited for breast cancer prevention. Methods: Nipple duct lavage (NDL) samples, obtained from 150 women selected to represent a wide range of breast cancer risk, were evaluated by quantitative methylation-specific real time PCR. High risk breasts were defined as those contralateral to a breast cancer (N = 63) and those of women with a 5-year Gail risk ≥ twice the age- and race-matched general population risk (N = 64). The prevelence of TSG methylation and marked atypia was compared for high risk and lower risk breasts using Chi-square. Data for breasts ipsilateral to a breast cancer are shown for comparison, but not included in the calculations for the high risk category. Results: Samples with adequate cellularity were obtained for 219 breasts (76%). The proportion of healthy breasts with ≥ 1% of the gene copies methylated was 13% for Cyclin D2, 19% for APC, 19% for HIN-1, 16% for RASSF1A, and 9% for RAR-beta. RAR-beta provided the best risk discrimination as 15% of high risk breasts were methylated at a level that exceeded the 95th percentile of the lower risk breasts (0.9% of gene copies methylated, P = 0.05). For the table , methylation fractions for all five genes were summed and the threshold for classifying a breast as positive was set to the 95th percentile of the lower risk breasts (methylation sum = 25.0%). Both methylation and marked atypia provide some discrimination between high and lower risk breasts; the combination, however, provides the best discrimination (24% marker positive for high risk versus 9% for lower risk, P = 0.02). Conclusions: TSG methylation in NDL samples is a marker of breast cancer risk that is complementary to cytology. [Table: see text] [Table: see text]
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Hui, Li, Vanessa Rodrik, Rafal M. Pielak, Stefan Knirr, Yang Zheng, and David A. Foster. "mTOR-dependent Suppression of Protein Phosphatase 2A Is Critical for Phospholipase D Survival Signals in Human Breast Cancer Cells." Journal of Biological Chemistry 280, no. 43 (August 18, 2005): 35829–35. http://dx.doi.org/10.1074/jbc.m504192200.
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A critical aspect of tumor progression is the generation of survival signals that overcome default apoptotic programs. Recent studies have revealed that elevated phospholipase D activity generates survival signals in breast and perhaps other human cancers. We report here that the elevated phospholipase D activity in the human breast cancer cell line MDA-MB-231 suppresses the activity of the putative tumor suppressor protein phosphatase 2A in a mammalian target of rapamycin (mTOR)-dependent manner. Increasing the phospholipase D activity in MCF7 cells also suppressed protein phosphatase 2A activity. Elevated phospholipase D activity suppressed association of protein phosphatase 2A with both ribosomal subunit S6-kinase and eukaryotic initiation factor 4E-binding protein 1. Suppression of protein phosphatase 2A by SV40 small t-antigen has been reported to be critical for the transformation of human cells with SV40 early region genes. Consistent with a critical role for protein phosphatase 2A in phospholipase D survival signals, either SV40 small t-antigen or pharmacological suppression of protein phosphatase 2A restored survival signals lost by the suppression of either phospholipase D or mTOR. Blocking phospholipase D signals also led to reduced phosphorylation of the pro-apoptotic protein BAD at the protein phosphatase 2A dephosphorylation site at Ser-112. The ability of phospholipase D to suppress protein phosphatase 2A identifies a critical target of an emerging phospholipase D/mTOR survival pathway in the transformation of human cells.
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JOSEPH JERRY, D., NICHOLAS B. GRINER, and LUWEI TAO. "TUMOR SUPPRESSOR PATHWAYS AND CELLULAR ORIGINS OF BREAST CANCER: NEW COMPLEXITIES AND NEW HOPES." Nano LIFE 01, no. 01n02 (March 2010): 1–16. http://dx.doi.org/10.1142/s179398441000002x.
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Heritable breast cancer syndromes have identified the recognition and processing of DNA double strand breaks as a fundamental vulnerability in the breast epithelium. The role of homology-directed DNA repair is particularly prominent, indicating that this repair pathway is rate-limiting. Although the activities of the tumor suppressor genes underlying heritable breast cancer act in a common pathway of DNA double strand break repair, the specific lesions result in surprisingly different patterns of biomarkers in the breast cancers, suggesting that they arise from different cell types that include the luminal, basal and progenitor cells within the breast epithelium. Therefore, each cell type appears to have distinct underlying vulnerabilities in repair of DNA double strand breaks. While the heterogeneity of targets poses a challenge to develop specific therapies, these pathways also render tumor cells sensitive to drugs targeting double strand break repair pathways offering new options for therapies. As double strand break repair is a common pathway underlying breast cancer risk, therapies that enhance the proficiency of this pathway offer a strategy for chemoprevention.
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Guerra, E., G. Vacca, B. Palombo, and S. Alberti. "Prognostic Value of Mutations in TP53 and RAS Genes in Breast Cancer." International Journal of Biological Markers 18, no. 1 (January 2003): 49–53. http://dx.doi.org/10.1177/172460080301800108.
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The identification of molecular indicators of higher risk for specific subgroups of cancer patients may allow to develop more aggressive therapeutic strategies aimed at cases with the highest likelihood of response. This would avoid unnecessary toxicity to patients and alleviate the burden of cancer care for healthcare systems. Activated oncogenes and mutated tumor suppressor genes are causal determinants of the appearance and progression of tumors in man. They therefore represent potential indicators of prognosis and/or response to therapy. However, even in cases of well-studied oncogenes and tumor suppressor genes such as TP53 and RAS, their attributed prognostic and predictive value is often based on studies of insufficient statistical power that often lead to conflicting conclusions. Findings in favor or against the use of TP53 and RAS as prognostic and predictive indicators in breast cancer are reviewed and discussed here.
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Cheng, Yuen Yee, Ellie Mok, Sarah Tan, Catherine Leygo, Chris McLaughlin, A. M. George, and Glen Reid. "SFRP Tumour Suppressor Genes Are Potential Plasma-Based Epigenetic Biomarkers for Malignant Pleural Mesothelioma." Disease Markers 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/2536187.
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Malignant pleural mesothelioma (MPM) is associated with asbestos exposure. Asbestos can induce chronic inflammation which in turn can lead to silencing of tumour suppressor genes. Wnt signaling pathway can be affected by chronic inflammation and is aberrantly activated in many cancers including colon and MPM. SFRP genes are antagonists of Wnt pathway, and SFRPs are potential tumour suppressors in colon, gastric, breast, ovarian, and lung cancers and mesothelioma. This study investigated the expression and DNA methylation of SFRP genes in MPM cells lines with and without demethylation treatment. Sixty-six patient FFPE samples were analysed and have showed methylation of SFRP2 (56%) and SFRP5 (70%) in MPM. SFRP2 and SFRP5 tumour-suppressive activity in eleven MPM lines was confirmed, and long-term asbestos exposure led to reduced expression of the SFRP1 and SFRP2 genes in the mesothelium (MeT-5A) via epigenetic alterations. Finally, DNA methylation of SFRPs is detectable in MPM patient plasma samples, with methylated SFRP2 and SFRP5 showing a tendency towards greater abundance in patients. These data suggested that SFRP genes have tumour-suppresive activity in MPM and that methylated DNA from SFRP gene promoters has the potential to serve as a biomarker for MPM patient plasma.
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Chagay, Natalia B., and Ashot M. Mkrtumyan. "Estrogen metabolism, lifetime methylation disorders, and breast cancer." Problems of Endocrinology 65, no. 3 (September 12, 2019): 161–73. http://dx.doi.org/10.14341/probl10070.
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Oncogenesis can be caused by an increase in the activity of genes responsible for initiating tumor growth in stem or progenitor cells, as well as a reduction in the functioning of suppressor genes. Endogenous estrogen exposure is associated with an increased risk of breast cancer in both pre- and postmenopausal women.
The most important step in the understanding of the pathogenesis of breast cancer was the development of the theory of the switching of estrogen’s effect from hormonal to genotoxic, in which the main culprits of carcinogenesis are not chemical metabolites of estrogens, but their derivatives, corresponding to chemical procarcinogens according to their damaging characteristics. The origin of these substances and the formation of estrogen genotoxicity lies in the disruption of the inactivation process of catechol estrogens in methylation reactions.
The main epigenetic modification of the human genome is the methylation of cell DNA molecules. DNA methylation does not alter the primary sequence of nucleotides, but is necessary for the functional suppression of certain genes. The phenomenon of hypomethylation-hypermethylation underlies the long-term silencing of various genes, including tumor suppressor genes.
Nutrition and a lifestyle associated with smoking and the consumption of excessive quantities of alcohol determine estrogen metabolism and the availability of methyl groups in the body, as well as epigenetic changes in the DNA of the genome. The assessment of individual risk of breast cancer on the basis of an assay for the expression and methylation of the COMT gene responsible for estrogen metabolism seems relevant.
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Kumar, Umesh, Ujjawal Sharma, and Garima Rathi. "Reversal of hypermethylation and reactivation of glutathione S-transferase pi 1 gene by curcumin in breast cancer cell line." Tumor Biology 39, no. 2 (February 2017): 101042831769225. http://dx.doi.org/10.1177/1010428317692258.
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One of the mechanisms for epigenetic silencing of tumor suppressor genes is hypermethylation of cytosine residue at CpG islands at their promoter region that contributes to malignant progression of tumor. Therefore, activation of tumor suppressor genes that have been silenced by promoter methylation is considered to be very attractive molecular target for cancer therapy. Epigenetic silencing of glutathione S-transferase pi 1, a tumor suppressor gene, is involved in various types of cancers including breast cancer. Epigenetic silencing of tumor suppressor genes can be reversed by several molecules including natural compounds such as polyphenols that can act as a hypomethylating agent. Curcumin has been found to specifically target various tumor suppressor genes and alter their expression. To check the effect of curcumin on the methylation pattern of glutathione S-transferase pi 1 gene in MCF-7 breast cancer cell line in dose-dependent manner. To check the reversal of methylation pattern of hypermethylated glutathione S-transferase pi 1, MCF-7 breast cancer cell line was treated with different concentrations of curcumin for different time periods. DNA and proteins of treated and untreated cell lines were isolated, and methylation status of the promoter region of glutathione S-transferase pi 1 was analyzed using methylation-specific polymerase chain reaction assay, and expression of this gene was analyzed by immunoblotting using specific antibodies against glutathione S-transferase pi 1. A very low and a nontoxic concentration (10 µM) of curcumin treatment was able to reverse the hypermethylation and led to reactivation of glutathione S-transferase pi 1 protein expression in MCF-7 cells after 72 h of treatment, although the IC50 value of curcumin was found to be at 20 µM. However, curcumin less than 3 µM of curcumin could not alter the promoter methylation pattern of glutathione S-transferase pi 1. Treatment of breast cancer MCF-7 cells with curcumin causes complete reversal of glutathione S-transferase pi 1 promoter hypermethylation and leads to re-expression of glutathione S-transferase pi 1, suggesting it to be an excellent nontoxic hypomethylating agent.
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Neiger, Hannah E., Emily L. Siegler, and Yihui Shi. "Breast Cancer Predisposition Genes and Synthetic Lethality." International Journal of Molecular Sciences 22, no. 11 (May 25, 2021): 5614. http://dx.doi.org/10.3390/ijms22115614.
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BRCA1 and BRCA2 are tumor suppressor genes with pivotal roles in the development of breast and ovarian cancers. These genes are essential for DNA double-strand break repair via homologous recombination (HR), which is a virtually error-free DNA repair mechanism. Following BRCA1 or BRCA2 mutations, HR is compromised, forcing cells to adopt alternative error-prone repair pathways that often result in tumorigenesis. Synthetic lethality refers to cell death caused by simultaneous perturbations of two genes while change of any one of them alone is nonlethal. Therefore, synthetic lethality can be instrumental in identifying new therapeutic targets for BRCA1/2 mutations. PARP is an established synthetic lethal partner of the BRCA genes. Its role is imperative in the single-strand break DNA repair system. Recently, Olaparib (a PARP inhibitor) was approved for treatment of BRCA1/2 breast and ovarian cancer as the first successful synthetic lethality-based therapy, showing considerable success in the development of effective targeted cancer therapeutics. Nevertheless, the possibility of drug resistance to targeted cancer therapy based on synthetic lethality necessitates the development of additional therapeutic options. This literature review addresses cancer predisposition genes, including BRCA1, BRCA2, and PALB2, synthetic lethality in the context of DNA repair machinery, as well as available treatment options.
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Tian, Sunny, Karina Bertelsmann, Linda Yu, and Shuying Sun. "DNA Methylation Heterogeneity Patterns in Breast Cancer Cell Lines." Cancer Informatics 15s4 (January 2016): CIN.S40300. http://dx.doi.org/10.4137/cin.s40300.
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Heterogeneous DNA methylation patterns are linked to tumor growth. In order to study DNA methylation heterogeneity patterns for breast cancer cell lines, we comparatively study four metrics: variance, I2 statistic, entropy, and methylation state. Using the categorical metric methylation state, we select the two most heterogeneous states to identify genes that directly affect tumor suppressor genes and high- or moderate-risk breast cancer genes. Utilizing the Gene Set Enrichment Analysis software and the ConsensusPath Database visualization tool, we generate integrated gene networks to study biological relations of heterogeneous genes. This analysis has allowed us to contribute 19 potential breast cancer biomarker genes to cancer databases by locating “hub genes” – heterogeneous genes of significant biological interactions, selected from numerous cancer modules. We have discovered a considerable relationship between these hub genes and heterogeneously methylated oncogenes. Our results have many implications for further heterogeneity analyses of methylation patterns and early detection of breast cancer susceptibility.
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Sano, Tomohiko, Xun Sun, Yan Feng, Shengzhi Liu, Misato Hase, Yao Fan, Rongrong Zha, et al. "Inhibition of the Growth of Breast Cancer-Associated Brain Tumors by the Osteocyte-Derived Conditioned Medium." Cancers 13, no. 5 (March 3, 2021): 1061. http://dx.doi.org/10.3390/cancers13051061.
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The brain is a common site of metastasis from advanced breast cancer but few effective treatments are available. We examined a therapeutic option with a conditioned medium (CM), focusing on the role of Lrp5 and β-catenin in Wnt signaling, and IL1ra in osteocytes. Osteocytes presented the innate anti-tumor effect and the overexpression of the above genes strengthened their action. In a mouse model, the injection of their CM inhibited mammary tumors and tumor-driven osteolysis. Importantly, Lrp5- and/or IL1ra-overexpressing osteocytes or the local administration of β-catenin-overexpressing CM markedly inhibited brain tumors. In the transport analysis, tumor-suppressing factors in CM were shown to diffuse through the skull. Mechanistically, the CM with overexpression of the above genes downregulated oncogenic genes such as MMP9, Runx2, TGFβ, and Snail in breast cancer cells. Also, the CM with β-catenin overexpression downregulated CXCL1 and CXCL5 and upregulated tumor suppressors such as LIMA1, DSP, p53, and TRAIL in breast cancer cells. Notably, whole-genome proteomics revealed that histone H4 was enriched in CM and acted as an atypical tumor suppressor. Lrp5-overexpressing MSCs were also shown to act as anti-tumor agents. Collectively, this study demonstrated the therapeutic role of engineered CM in brain tumors and the tumor-suppressing action of extracellular histone H4. The result sheds light on the potential CM-based therapy for breast cancer-associated brain metastases in a minimally invasive manner.
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Kurose, Sonomi, Kentaro Nakayama, Sultana Razia, Masako Ishikawa, Tomoka Ishibashi, Hitomi Yamashita, Seiya Sato, et al. "Whole-Exome Sequencing of Rare Site Endometriosis-Associated Cancer." Diseases 9, no. 1 (February 4, 2021): 14. http://dx.doi.org/10.3390/diseases9010014.
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Malignant transformation of extraovarian endometriosis is rare, with the carcinogenesis mechanism unclear. To clarify the actionable variants of rare-site endometriosis-associated cancer (RSEAC), we performed whole-exome sequencing for the tumor, in two patients. The intestine was affected in both cases, although the histology was that of clear cell carcinoma and undifferentiated carcinoma, respectively. Therefore, the cases were referred to as endometriosis-associated intestinal tumors (EIATs). Actionable variants (all frameshift mutations) were identified in tumor suppressor genes ARID1A, PTEN, and p53; however, no oncogenic variants were identified. Both cases were microsatellite stable. The patient with undifferentiated carcinoma exhibited hypermutator and homologous recombination deficiency phenotypes. The dominant mutation signatures were signature 30 (small subset of breast cancers) and 19 (pilocytic astrocytoma) in patient 1, and signature 5 (small subset of breast cancers) and 3 (breast, ovarian, and pancreatic cancers) in patient 2. Immunohistochemistry revealed positive CD8 and PD-1 expression in both patients; patient 1 also showed positive PDL-1 expression. Our results suggest that RSEAC is associated with variants of tumor suppressor genes as epigenetic alterations. Mutation signature-based whole-exome sequencing could be useful to select an adjuvant chemotherapy regimen. High CD8 and PD-1 expression in RSEAC suggests that immune checkpoint inhibitors are useful for treatment.
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Stolz, Ailine, Norman Ertych, and Holger Bastians. "Loss of the tumour-suppressor genes CHK2 and BRCA1 results in chromosomal instability." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1704–8. http://dx.doi.org/10.1042/bst0381704.
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CHK2 (checkpoint kinase 2) and BRCA1 (breast cancer early-onset 1) are tumour-suppressor genes that have been implicated previously in the DNA damage response. Recently, we have identified CHK2 and BRCA1 as genes required for the maintenance of chromosomal stability and have shown that a Chk2-mediated phosphorylation of Brca1 is required for the proper and timely assembly of mitotic spindles. Loss of CHK2, BRCA1 or inhibition of its Chk2-mediated phosphorylation inevitably results in the transient formation of abnormal spindles that facilitate the establishment of faulty microtubule–kinetochore attachments associated with the generation of lagging chromosomes. Importantly, both CHK2 and BRCA1 are lost at very high frequency in aneuploid lung adenocarcinomas that are typically induced in knockout mice exhibiting chromosomal instability. Thus these results suggest novel roles for Chk2 and Brca1 in mitosis that might contribute to their tumour-suppressor functions.
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Zafar, Shazia, Sathish Srinivasan, and Zafar Nawaz. "E6-Associated Protein (E6-AP): A Potential Tumor Suppressor Protein for Non-Hodgkin Lymphoma." Blood 108, no. 11 (November 16, 2006): 4336. http://dx.doi.org/10.1182/blood.v108.11.4336.4336.
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Abstract Over the past decade considerable progress has been made in cloning and characterization of potential tumor suppressor genes. Tumor suppressors have a repressive effect on the regulation of the cell cycle or promote apoptosis and sometimes do both. The function of tumor suppressor proteins fall into several categories, tumor suppressor genes are presumed to encode negative regulator of proliferation and inhibit mitotic activity. Loss of tumor suppressor protein or function of a tumor suppressor protein has been shown to be associated with the cancer formation. Continued investigation into the biochemical and cell biological functions of the tumor suppressor is critical to elucidate the mechanisms by which they normally inhibit proliferation/tumor development and to provide a molecular explanation for their frequent inactivation in cancer. Our laboratory has previously shown that the expression of E6-associated protein (E6-AP), which is an E3 ubiquitin-protein ligase and a coactivator of nuclear hormone receptors, is significantly reduced in human cancers having epithelial cell origin such as breast cancer. In this prospective study, we want to extend our observation to the cancers originating from lymphoid tissue. Non-Hodgkin lymphoma is a cancer of lymphoid tissue. The main cell type found in lymphoid tissue is the lymphocyte. The 2 main types of lymphocytes are B-lymphocytes (B-cells) and T-lymphocytes (T-cells). B-cell lymphomas are much more common than T-cell lymphomas. In the U. S., 85% of all cases of non-Hodgkin lymphoma come from B lymphocytes (B-cell) and 15% from T lymphocytes (T-cell). We performed immunohistochemistry analysis to investigate the expression pattern of E6-AP in normal lymph nodes and lymphoid tumors. Tissue micro arrays representing samples from 60 different patients were analyzed in this study. Our analysis suggest that on an average there was about 55 % reduction in E6-AP protein levels in B-cell lymphomas (P =0.0001) and 98.5 % reduction in E6-AP levels in T-cell lymphomas (P =0.0002) compared to normal lymph node. Based on our previous studies in breast and prostate tumors and considering our current finding of reduced/loss of E6-AP in lymphoid tumors, we propose that E6-AP may act as a potential tumor suppressor protein. This proposed idea is consistent with our in vivo data generated from E6-AP null mice which shows that the number of B- and T-cells are significantly increased in spleen compared to normal wild-type animals. Taken together our data establish the role of E6-AP as a potential growth and tumor suppressor protein.
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Heydaran, Sogand. "Concurrent Down-regulation of the EAF1 and the EAF2 Genes in the Invasive Ductal Carcinoma Type of Breast Cancer." Revista Gestão Inovação e Tecnologias 11, no. 2 (June 5, 2021): 1620–28. http://dx.doi.org/10.47059/revistageintec.v11i2.1785.
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In mammals, the EAF1 and EAF2 genes build an active transcription module with other components. These genes code for factors acting as potent inhibitor of the Wnt-β catenin pathway, which might be due to their function as tumor suppressor gene. Recently, the involvement of both above-mentioned factors was described in some human tumors, but not yet in breast cancer. Breast cancer is one of the most cancer cases in Iran after colon and stomach carcinoma. We aimed therefore to investigate for the first time a possible correlation between breast cancer and the EAF1 and the EAF2 gene expression. We collected invasive ductal carcinoma tumor grading (grade 1 to 3) with marginal normal tissue from forty women diagnosed with breast cancer with the average age of 50 years old. All patients underwent triple marker test (ER/PR and Her2/neu), indeed the most of them were triple positive with few triple negative individuals. After RNA extraction, cDNA was synthesized for subsequent real-time polymerase chain reaction. The humanRPL27 gene wasusedas endogenous control. Analysis of real-time PCR results showeda significant down-regulation of EAF1 (p-value: 0.028), and of EAF2 (p-value: 0.0134) in tumor tissue samples in comparison to normal one.There was no correlation between clinical parameters and the target genes. We could find significant connection between both tumor suppressor genes in triple positive and triple negative breast cancer patients, which deserves more attention.
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Rangel, Roberto, Liliana Guzman-Rojas, Takahiro Kodama, Michiko Kodama, Justin Y. Newberg, Neal G. Copeland, and Nancy A. Jenkins. "Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer." Cancer Research 77, no. 15 (July 19, 2017): 4089–101. http://dx.doi.org/10.1158/0008-5472.can-17-0785.
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Yamashita, Hiroko, Shunzo Kobayashi, Hirotaka Iwase, Yukashi Itoh, Tatsuya Kuzushima, Hiroji Iwata, Kazuko Itoh, et al. "Analysis of Oncogenes and Tumor Suppressor Genes in Human Breast Cancer." Japanese Journal of Cancer Research 84, no. 8 (August 1993): 871–78. http://dx.doi.org/10.1111/j.1349-7006.1993.tb02060.x.
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Mahara, Sylvia, Puay Leng Lee, Min Feng, Vinay Tergaonkar, Wee Joo Chng, and Qiang Yu. "HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer." Proceedings of the National Academy of Sciences 113, no. 26 (June 14, 2016): E3735—E3744. http://dx.doi.org/10.1073/pnas.1602079113.
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Despite the established oncogenic function of Polycomb repressive complex 2 (PRC2) in human cancers, its role as a tumor suppressor is also evident; however, the mechanism underlying the regulation of the paradoxical functions of PRC2 in tumorigenesis is poorly understood. Here we show that hypoxia-inducible factor 1, α-subunit (HIFI-α) is a crucial modulator of PRC2 and enhancer of zeste 2 (EZH2) function in breast cancer. Interrogating the genomic expression of breast cancer indicates high HIF1A activity correlated with high EZH2 expression but low PRC2 activity in triple-negative breast cancer compared with other cancer subtypes. In the absence of HIFIA activation, PRC2 represses the expression of matrix metalloproteinase genes (MMPs) and invasion, whereas a discrete Ezh2 complexed with Forkhead box M1 (FoxM1) acts to promote the expression of MMPs. HIF1-α induction upon hypoxia results in PRC2 inactivation by selective suppression of the expression of suppressor of zeste 12 protein homolog (SUZ12) and embryonic ectoderm development (EED), leading to a functional switch toward Ezh2/FoxM1-dependent induction of the expression of MMPs and invasion. Our study suggests a tumor-suppressive function of PRC2, which is restricted by HIF1-α, and an oncogenic function of Ezh2, which cooperates with FoxM1 to promote invasion in triple-negative breast cancer.
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Pavel, Ana B., and Cristian I. Vasile. "Identifying cancer type specific oncogenes and tumor suppressors using limited size data." Journal of Bioinformatics and Computational Biology 14, no. 06 (December 2016): 1650031. http://dx.doi.org/10.1142/s0219720016500311.
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Cancer is a complex and heterogeneous genetic disease. Different mutations and dysregulated molecular mechanisms alter the pathways that lead to cell proliferation. In this paper, we explore a method which classifies genes into oncogenes (ONGs) and tumor suppressors. We optimize this method to identify specific (ONGs) and tumor suppressors for breast cancer, lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and colon adenocarcinoma (COAD), using data from the cancer genome atlas (TCGA). A set of genes were previously classified as ONGs and tumor suppressors across multiple cancer types (Science 2013). Each gene was assigned an ONG score and a tumor suppressor score based on the frequency of its driver mutations across all variants from the catalogue of somatic mutations in cancer (COSMIC). We evaluate and optimize this approach within different cancer types from TCGA. We are able to determine known driver genes for each of the four cancer types. After establishing the baseline parameters for each cancer type, we identify new driver genes for each cancer type, and the molecular pathways that are highly affected by them. Our methodology is general and can be applied to different cancer subtypes to identify specific driver genes and improve personalized therapy.
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Wolf, I., J. O’kelly, T. Rubinek, M. Tong, B. T. Lin, H. Tai, B. Y. Karlan, and H. P. Koeffler. "15-Hydroxyprostaglandin dehydrogenase (PGDH) is an aberrant tumor suppressor in human breast cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10550. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10550.
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10550 Background: Prostaglandin E2 plays a growth stimulatory role in breast cancer; and the rate-limiting enzyme in its synthesis, cyclooxygenase-2 (COX-2), is over-expressed in breast cancers. However, little is known about the expression pattern and activities of the key prostaglandin catabolic enzyme PGDH, in breast cancer pathogenesis. Methods: 5-aza-2’-deoxycytidine and suberoyl anilide bishydroxamide (SAHA) were used to unmask epigenetically silenced genes. DNA and RNA were extracted from tumors and cell lines using standard methods, and bisulfite sequencing was used for methylation analysis. Western blotting and real time PCR were used for expression analysis, and PGDH expression vector and PGDH-directed siRNA were used for overexpression and downregulation of PGDH, respectively. Athymic mice were utilized for xenograft models. Results: Using a pharmacologically based, genome-wide screen for epigenetically silenced genes, we found low levels of PGDH in MDA-MB-231 cells (estrogen receptor- (ER) and HER2-negative), but high levels in MCF-7 cells (ER-positive, HER2-negative), and observed upregulation of this enzyme following demethylation treatment. Methylation analysis revealed methylation of the PGDH promoter in one breast cancer cell line and in 3 of 10 primary tumors. Analysis of PGDH expression demonstrated low levels in 40% of primary breast tumors and identified a correlation between PGDH and ER expression. Upregulation of PGDH levels in MDA-MB-231 cells decreased their clonal growth and reduced their ability to form tumors in athymic mice. In contrast, silencing of PGDH in MCF-7 cells increased proliferation and enhanced in-vivo tumorigenicity. Further analysis revealed upregulation of aromatase following silencing of PGDH and inhibition of the ER pathway by forced expression of the enzyme. PGDH levels were downregulated by estrogen but upregulated by the tumor suppressor gene C/EBPα. Conclusions: Our results identify for the first time, that PGDH, the COX-2 antagonist, is aberrantly silenced in breast cancer. Activation of this enzyme, particularly in ER- and HER2-negative tumors, now becomes an interesting target for clinical studies. No significant financial relationships to disclose.
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Krasteva, M., Sv Angelova, and Zl Gospodinova. "Molecular-Genetic Aspects of Breast Cancer." Acta Medica Bulgarica 41, no. 2 (December 1, 2014): 67–79. http://dx.doi.org/10.1515/amb-2014-0024.
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Summary Breast cancer is the most frequent malignancy among women. Advances in breast cancer knowledge have deciphered the involvement of a number of tumor suppressor genes and proto-oncogenes in disease pathogenesis. These genes are part of the complex biochemical pathways, which enable cell cycle control and maintenance of genome integrity. Their function may be disrupted as a result of alterations in gene sequence or misregulation of gene expression including alterations in DNA methylation pattern. The present review summarizes the main findings on major breast cancer related genes BRCA1/2, p53, ATM, CHEK2, HER2, PIK3CA and their tumorigenic inactivation/activation. The potential clinical importance of these genes with respect to patients’ prognosis and therapy are also discussed. The possible implication of other putative breast cancer related genes is also outlined. The first elaborate data on the genetic and epigenetic status of the above mentioned genes concerning Bulgarian patients with the sporadic form of the disease are presented. The studies indicate for a characteristic mutational spectrum in some of the genes for the Bulgarian patients and specific correlation between the status of different genes and clinicopathological characteristics.
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Hesson, Luke B., Wendy N. Cooper, and Farida Latif. "The Role of RASSF1A Methylation in Cancer." Disease Markers 23, no. 1-2 (2007): 73–87. http://dx.doi.org/10.1155/2007/291538.
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Tumour suppressor gene inactivation is critical to the pathogenesis of cancers; such loss of function may be mediated by irreversible processes such as gene deletion or mutation. Alternatively tumour suppressor genes may be inactivated via epigenetic processes a reversible mechanism that promises to be more amenable to treatment by therapeutic agents. The CpG dinucleotide is under-represented in the genome, but it is found in clusters within the promoters of some genes, and methylation of these CpG islands play a critical role in the control of gene expression. Inhibitors of the DNA methyltransferases DNMT1 and DNMT3b have been used in a clinical setting, these nucleotide analogues lack specificity but the side effects of low dose treatments were minimal and in 2004 Vidaza (5-azacitidine) was licensed for use in myelodysplastic syndrome. Methylation inhibitors are also entering trials in conjunction with another class of epigenetic modifiers, the histone deacetylase inhibitors and this epigenetic double bullet offers hope of improved treatment regimes. Recently there has been a plethora of reports demonstrating epigenetic inactivation of genes that play important roles in development of cancer, including Ras-association domain family of genes. Epigenetic inactivation ofRASSF1A(Ras-association domain family 1, isoform A) is one of the most common molecular changes in cancer. Hypermethylation of theRASSF1Apromoter CpG island silences expression of the gene in many cancers including lung, breast, prostate, glioma, neuroblastoma and kidney cancer. Several recent studies have illustrated the diagnostic and prognostic potential ofRASSF1Amethylation. This presentsRASSF1Amethylation as an attractive biomarker for early cancer detection which, for most cancers, results in improved clinical outcome. DNA methylation analysis is applicable to a range of body fluids including serum, urine, bronchioalveolar lavage and sputum. The ease with which these body fluids can be acquired negates the need for invasive procedures to obtain biopsy material. This review will discuss the feasibility of usingRASSF1Amethylation as a diagnostic and prognostic marker in cancer management.
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Luo, Yanxin, Andrew Kaz, Samornmas Kanngurn, and William M. Grady. "NTRK3 as a novel tumor suppressor gene in colorectal cancer." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 469. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.469.
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469 Background: Neurotrophin tyrosine kinase receptor 3 (NTRK3) is a receptor tyrosine kinase that has been shown to be an oncogene in breast cancer and possibly in hepatocellular carcinoma. NTRK3 is a trophic dependence receptor, which is a recently described class of receptors that initiate signaling in both the ligand bound and unbound states. Through a genome-wide screen for aberrantly methylated genes, we identified aberrantly methylated NTRK3 as a frequently methylated gene in colon cancer. The aim for the present study is to determine if NTRK3 is an epigenetically silenced tumor suppressor gene in colorectal cancer. Methods: NTRK3 promoter methylation was analyzed in human colon cancer cell lines, normal colon epithelium tissue, colorectal adenomas and colorectal cancers using quantitative methylation-specific PCR and bisulfite sequencing. NTRK3 mRNA and protein expression were studied using quantitative real-time PCR, immunohistochemistry and western blotting respectively. The tumor suppressor function of NTRK3 was examined by assessing the effect of NTRK3 on cell apoptosis, cell migration and in vitro colony formation assays in colon cancer cell lines stably transfected with an NTRK3 expression construct in the presence or absence of NT-3. Results: NTRK3 is methylated in 60% of colon adenomas and in 57% of colorectal cancers. The aberrant methylation of NTRK3 suppresses NTRK3 expression and releases colon cancer cells from NTRK3 mediated apoptosis induced by the expression of NTRK3 in the absence of the ligand NT-3 via the activation of MAPK/ERK pathway. Methylation of NTRK3 also releases colon cancer cells from NTRK3 mediated suppression of motility and anchorage independent growth. The addition of NT3 to colon cancer cells transfected with NTRK3 inhibits the tumor suppressor effects of NTRK3. Conclusions: The aberrant methylation of NTRK3 is likely functionally relevant for colorectal cancer formation as NTRK3 appears to be a conditional tumor suppressor gene in the colon depending on the expression status of its ligand NT-3. NTRK3 is a novel aberrantly methylated conditional tumor suppressor gene that is frequently methylated in colon adenomas and cancers and whose discovery reveals possible novel treatment approaches to colon cancer.
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Malik, Navdeep, Hualong Yan, Howard H. Yang, Gamze Ayaz, Wendy DuBois, Yu-Chou Tseng, Young-Im Kim, et al. "CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer." PLOS Genetics 17, no. 5 (May 4, 2021): e1009553. http://dx.doi.org/10.1371/journal.pgen.1009553.
Full textAbstract:
The CBFB gene is frequently mutated in several types of solid tumors. Emerging evidence suggests that CBFB is a tumor suppressor in breast cancer. However, our understanding of the tumor suppressive function of CBFB remains incomplete. Here, we analyze genetic interactions between mutations of CBFB and other highly mutated genes in human breast cancer datasets and find that CBFB and TP53 mutations are mutually exclusive, suggesting a functional association between CBFB and p53. Integrated genomic studies reveal that TAp73 is a common transcriptional target of CBFB and p53. CBFB cooperates with p53 to maintain TAp73 expression, as either CBFB or p53 loss leads to TAp73 depletion. TAp73 re-expression abrogates the tumorigenic effect of CBFB deletion. Although TAp73 loss alone is insufficient for tumorigenesis, it enhances the tumorigenic effect of NOTCH3 overexpression, a downstream event of CBFB loss. Immunohistochemistry shows that p73 loss is coupled with higher proliferation in xenografts. Moreover, TAp73 loss-of-expression is a frequent event in human breast cancer tumors and cell lines. Together, our results significantly advance our understanding of the tumor suppressive functions of CBFB and reveal a mechanism underlying the communication between the two tumor suppressors CBFB and p53.
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Carta, Alessia, Rachel Chetcuti, and Duncan Ayers. "An Introspective Update on the Influence of miRNAs in Breast Carcinoma and Neuroblastoma Chemoresistance." Genetics Research International 2014 (December 4, 2014): 1–13. http://dx.doi.org/10.1155/2014/743050.
Full textAbstract:
Chemoresistance to conventional cytotoxic drugs may occur in any type of cancer and this can either be inherent or develop through time. Studies have linked this acquired resistance to the abnormal expression of microRNAs (miRNAs) that normally silence genes. At abnormal levels, miRNAs can either gain ability to silence tumour suppressor genes or else lose ability to silence oncogenes. miRNAs can also affect pathways that are involved in drug metabolism, such as drug efflux pumps, resulting in a resistant phenotype. The scope of this review is to provide an introspective analysis on the specific niches of breast carcinoma and neuroblastoma research.