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1
Arterburn, Jeffrey B., and Eric R. Prossnitz. "G Protein–Coupled Estrogen Receptor GPER: Molecular Pharmacology and Therapeutic Applications." Annual Review of Pharmacology and Toxicology 63, no. 1 (January 20, 2023): 295–320. http://dx.doi.org/10.1146/annurev-pharmtox-031122-121944.
Повний текст джерелаАнотація:
The actions of estrogens and related estrogenic molecules are complex and multifaceted in both sexes. A wide array of natural, synthetic, and therapeutic molecules target pathways that produce and respond to estrogens. Multiple receptors promulgate these responses, including the classical estrogen receptors of the nuclear hormone receptor family (estrogen receptors α and β), which function largely as ligand-activated transcription factors, and the 7-transmembrane G protein–coupled estrogen receptor, GPER, which activates a diverse array of signaling pathways. The pharmacology and functional roles of GPER in physiology and disease reveal important roles in responses to both natural and synthetic estrogenic compounds in numerous physiological systems. These functions have implications in the treatment of myriad disease states, including cancer, cardiovascular diseases, and metabolic disorders. This review focuses on the complex pharmacology of GPER and summarizes major physiological functions of GPER and the therapeutic implications and ongoing applications of GPER-targeted compounds.
2
Mitra, Saikat, Mashia Subha Lami, Avoy Ghosh, Rajib Das, Trina Ekawati Tallei, Fatimawali, Fahadul Islam, et al. "Hormonal Therapy for Gynecological Cancers: How Far Has Science Progressed toward Clinical Applications?" Cancers 14, no. 3 (February 1, 2022): 759. http://dx.doi.org/10.3390/cancers14030759.
Повний текст джерелаАнотація:
In recent years, hormone therapy has been shown to be a remarkable treatment option for cancer. Hormone treatment for gynecological cancers involves the use of medications that reduce the level of hormones or inhibit their biological activity, thereby stopping or slowing cancer growth. Hormone treatment works by preventing hormones from causing cancer cells to multiply. Aromatase inhibitors, anti-estrogens, progestin, estrogen receptor (ER) antagonists, GnRH agonists, and progestogen are effectively used as therapeutics for vulvar cancer, cervical cancer, vaginal cancer, uterine cancer, and ovarian cancer. Hormone replacement therapy has a high success rate. In particular, progestogen and estrogen replacement are associated with a decreased incidence of gynecological cancers in women infected with human papillomavirus (HPV). The activation of estrogen via the transcriptional functionality of ERα may either be promoted or decreased by gene products of HPV. Hormonal treatment is frequently administered to patients with hormone-sensitive recurring or metastatic gynecologic malignancies, although response rates and therapeutic outcomes are inconsistent. Therefore, this review outlines the use of hormonal therapy for gynecological cancers and identifies the current knowledge gaps.
3
Monga, Jyoti, Niladry S. Ghosh, Somdutt Mujwar, and Isha Rani. "IN SILICO STUDIES OF SOME NEWLY DESIGNED BENZIMIDAZOLETHIAZOLIDINONE BASED ANTAGONISTS OF HUMAN ESTROGEN RECEPTOR." INDIAN DRUGS 60, no. 08 (August 28, 2023): 15–30. http://dx.doi.org/10.53879/id.60.08.14087.
Повний текст джерелаАнотація:
Breast cancer is globally associated with majority of the women. Indeed, high estrogen levels are the most common subtype of breast cancer. Three different classes of estrogen receptor antagonists are frequently used to treat such kinds of breast cancers. Each of these interacts directly with the initiation and activation of the estrogen signalling pathway. However, new medicines must be developed because resistance limits the therapeutic effectiveness. In silico studies for drug discovery have become popular in recent years due to their low cost and quick execution. To develop novel therapeutics for breast cancer, three different series of benzimidazole compounds targeting the estrogen receptor were docked. Among these three series, benzimidazole fused with pyrazole showed significant results and the leading compound was 32 based on docking results. The docking data was further validated by executing molecular dynamics (MD) simulations for the stability of designed leads within the macromolecular cavity in relation to time. Therefore, it is proposed that the pyrazole fused benzimidazole nucleus can be a promising pharmacophore for developing novel anticancer therapeutics for breast cancer.
4
Chang, Minsun, Kuan-wei Peng, Irida Kastrati, Cassia R. Overk, Zhi-Hui Qin, Ping Yao, Judy L. Bolton, and Gregory R. J. Thatcher. "Activation of Estrogen Receptor-Mediated Gene Transcription by the Equine Estrogen Metabolite, 4-Methoxyequilenin, in Human Breast Cancer Cells." Endocrinology 148, no. 10 (October 1, 2007): 4793–802. http://dx.doi.org/10.1210/en.2006-1568.
Повний текст джерелаАнотація:
4-Methoxyequilenin (4-MeOEN) is an O-methylated metabolite in equine estrogen metabolism. O-methylation of catechol estrogens is considered as a protective mechanism; however, comparison of the properties of 4-MeOEN with estradiol (E2) in human breast cancer cells showed that 4-MeOEN is a proliferative, estrogenic agent that may contribute to carcinogenesis. 4-MeOEN results from O-methylation of 4-hydroxyequilenin, a major catechol metabolite of the equine estrogens present in hormone replacement therapeutics, which causes DNA damage via quinone formation, raising the possibility of synergistic hormonal and chemical carcinogenesis. 4-MeOEN induced cell proliferation with nanomolar potency and induced estrogen response element (ERE)-mediated gene transcription of an ERE-luciferase reporter and the endogenous estrogen-responsive genes pS2 and TGF-α. These estrogenic actions were blocked by the antiestrogen ICI 182,780. In the standard radioligand estrogen receptor (ER) binding assay, 4-MeOEN showed very weak binding. To test for alternate ligand-ER-independent mechanisms, the possibility of aryl hydrocarbon receptor (AhR) binding and ER-AhR cross talk was examined using a xenobiotic response element-luciferase reporter and using AhR small interfering RNA silencing in the ERE-luciferase reporter assay. The results negated the possibility of AhR-mediated estrogenic activity. Comparison of gene transcription time course, ER degradation, and rapid activation of MAPK/ERK in MCF-7 cells demonstrated that the actions of 4-MeOEN mirrored those of E2 with potency for classical and nonclassical estrogenic pathways bracketing that of E2. Methylation of 4-OHEN may not represent a detoxification pathway because 4-MeOEN is a full, potent estrogen agonist.
5
Shete, Nivida, Jordan Calabrese, and Debra A. Tonetti. "Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches." Cancers 15, no. 14 (July 17, 2023): 3647. http://dx.doi.org/10.3390/cancers15143647.
Повний текст джерелаАнотація:
Estrogen receptor (ER)-positive breast cancer is the most common subtype, representing 70–75% of all breast cancers. Several ER-targeted drugs commonly used include the selective estrogen receptor modulator (SERM), tamoxifen (TAM), aromatase inhibitors (AIs) and selective estrogen receptor degraders (SERDs). Through different mechanisms of action, all three drug classes reduce estrogen receptor signaling. Inevitably, resistance occurs, resulting in disease progression. The counterintuitive action of estrogen to inhibit ER-positive breast cancer was first observed over 80 years ago. High-dose estrogen and diethylstilbestrol (DES) were used to treat metastatic breast cancer accompanied by harsh side effects until the approval of TAM in the 1970s. After the development of TAM, randomized trials comparing TAM to estrogen found similar or slightly inferior efficacy but much better tolerability. After decades of research, it was learned that estrogen induces tumor regression only after a period of long-term estrogen deprivation, and the mechanisms of tumor regression were described. Despite the long history of breast cancer treatment with estrogen, this therapeutic modality is now revitalized due to the development of novel estrogenic compounds with improved side effect profiles, newly discovered predictive biomarkers, the development of non-estrogen small molecules and new combination therapeutic approaches.
6
Petrie, Whitney K., Megan K. Dennis, Chelin Hu, Donghai Dai, Jeffrey B. Arterburn, Harriet O. Smith, Helen J. Hathaway, and Eric R. Prossnitz. "G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth." Obstetrics and Gynecology International 2013 (2013): 1–17. http://dx.doi.org/10.1155/2013/472720.
Повний текст джерелаАнотація:
Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERαand ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activityin vivoprevents estrogen-mediated tumor growth.
7
Medina, Mauricio A., Goldie Oza, Ashutosh Sharma, L. G. Arriaga, José Manuel Hernández Hernández, Vincent M. Rotello, and Jose Tapia Ramirez. "Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies." International Journal of Environmental Research and Public Health 17, no. 6 (March 20, 2020): 2078. http://dx.doi.org/10.3390/ijerph17062078.
Повний текст джерелаАнотація:
Triple-negative breast cancer (TNBC) cells are deficient in estrogen, progesterone and ERBB2 receptor expression, presenting a particularly challenging therapeutic target due to their highly invasive nature and relatively low response to therapeutics. There is an absence of specific treatment strategies for this tumor subgroup, and hence TNBC is managed with conventional therapeutics, often leading to systemic relapse. In terms of histology and transcription profile these cancers have similarities to BRCA-1-linked breast cancers, and it is hypothesized that BRCA1 pathway is non-functional in this type of breast cancer. In this review article, we discuss the different receptors expressed by TNBC as well as the diversity of different signaling pathways targeted by TNBC therapeutics, for example, Notch, Hedgehog, Wnt/b-Catenin as well as TGF-beta signaling pathways. Additionally, many epidermal growth factor receptor (EGFR), poly (ADP-ribose) polymerase (PARP) and mammalian target of rapamycin (mTOR) inhibitors effectively inhibit the TNBCs, but they face challenges of either resistance to drugs or relapse. The resistance of TNBC to conventional therapeutic agents has helped in the advancement of advanced TNBC therapeutic approaches including hyperthermia, photodynamic therapy, as well as nanomedicine-based targeted therapeutics of drugs, miRNA, siRNA, and aptamers, which will also be discussed. Artificial intelligence is another tool that is presented to enhance the diagnosis of TNBC.
8
Ide, Hiroki, and Hiroshi Miyamoto. "Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy." Cells 10, no. 5 (May 11, 2021): 1169. http://dx.doi.org/10.3390/cells10051169.
Повний текст джерелаАнотація:
There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic and anti-estrogenic drugs, apart from their direct anti-tumor activity, to function as sensitizers of such conventional treatment. This article summarizes available data suggesting the involvement of sex hormone receptors, such as androgen receptor, estrogen receptor-α, and estrogen receptor-β, in the progression of urothelial cancer, focusing on their modulation for the efficacy of conventional therapy, and discusses their potential of overcoming therapeutic resistance.
9
Lucà, Rossella, Giorgia di Blasio, Daniela Gallo, Valentina Monteleone, Isabella Manni, Laura Fici, Marianna Buttarelli, et al. "Estrogens Counteract Platinum-Chemosensitivity by Modifying the Subcellular Localization of MDM4." Cancers 11, no. 9 (September 12, 2019): 1349. http://dx.doi.org/10.3390/cancers11091349.
Повний текст джерелаАнотація:
Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impact of estrogens on both MDM4 activities. In Mdm4 transgenic mouse, Mdm4 accelerates the formation of fibrosarcoma and increases tumor sensitivity to cisplatin as well, thus confirming in vivo Mdm4 dual mode of action. Noteworthy, Mdm4 enhances chemo- and radio-sensitivity in male but not in female animals, whereas its tumor-promoting activity is not affected by mouse gender. Combination therapy of transgenic females with cisplatin and fulvestrant, a selective estrogen receptor degrader, was able to recover tumor cisplatin-sensitivity, demonstrating the relevance of estrogens in the observed sexual dimorphism. Molecularly, estrogen receptor-α alters intracellular localization of MDM4 by increasing its nuclear fraction correlated to decreased cell death, in a p53-independent manner. Importantly, MDM4 nuclear localization and intra-tumor estrogen availability correlate with decreased platinum-sensitivity and apoptosis and predicts poor disease-free survival in high-grade serous ovarian carcinoma. These data demonstrate estrogen ability to modulate chemo-sensitivity of MDM4-expressing tumors and to impinge on intracellular trafficking. They support potential usefulness of combination therapy involving anti-estrogenic drugs.
10
Di Zazzo, Galasso, Giovannelli, Di Donato, Bilancio, Perillo, Sinisi, Migliaccio, and Castoria. "Estrogen Receptors in Epithelial-Mesenchymal Transition of Prostate Cancer." Cancers 11, no. 10 (September 23, 2019): 1418. http://dx.doi.org/10.3390/cancers11101418.
Повний текст джерелаАнотація:
Prostate cancer (PC) remains a widespread malignancy in men. Since the androgen/androgen receptor (AR) axis is associated with the pathogenesis of prostate cancer, suppression of AR-dependent signaling by androgen deprivation therapy (ADT) still represents the primary intervention for this disease. Despite the initial response, prostate cancer frequently develops resistance to ADT and progresses. As such, the disease becomes metastatic and few therapeutic options are available at this stage. Although the majority of studies are focused on the role of AR signaling, compelling evidence has shown that estrogens and their receptors control prostate cancer initiation and progression through a still debated mechanism. Epithelial versus mesenchymal transition (EMT) is involved in metastatic spread as well as drug-resistance of human cancers, and many studies on the role of this process in prostate cancer progression have been reported. We discuss here the findings on the role of estrogen/estrogen receptor (ER) axis in epithelial versus mesenchymal transition of prostate cancer cells. The pending questions concerning this issue are presented, together with the impact of the available data in clinical management of prostate cancer patients.
11
Cai, Rong, and Caroline Ajo-Franklin. "Towards Sensing of Breast Cancer Biomarkers: Engineering Glucose Dehydrogenase As an Estrogenic Regulated Protein." ECS Meeting Abstracts MA2022-02, no. 61 (October 9, 2022): 2227. http://dx.doi.org/10.1149/ma2022-02612227mtgabs.
Повний текст джерелаАнотація:
Breast cancer is the second leading cause of cancer-related death in women. Approximately 50% of mortalities arise from estrogen receptor (ER)-positive tumors.[1] The major therapeutics for breast cancer are estrogen antagonists, like tamoxifen. Closely monitoring the antagonist in a patient would increase the efficacy of endocrine therapeutics while alleviating side effects during treatment. However, existing methods such as routine immunohistochemistry cannot effectively monitor estrogen antagonists because of their low throughput and high cost. To address these issues, we have devised a bioelectronic sensor of estrogen antagonists by grafting ER to the point of care (POC) glucometer. Glucometers use a test strip containing glucose dehydrogenase (GDH), an enzyme that reacts with glucose in blood droplets and generates electric signals. To obtain an estrogenic regulated GDH, we inserted the ligand-binding domain of ER at all the 456 amino acids of the GDH. More than 7000 colonies were screened to identify the allosteric insertion sites globally. We find that the estrogenic regulated GDH can electrochemically detect a series of ER modulators as low as 1 nM with ≥40% dynamic range. Successful engineering of the classical glucose dehydrogenase yields a self-power antagonist sensor and establishes a platform for designing personalized diagnostics in a POC fashion. [1] Torre, Lindsey A., et al. "Ovarian cancer statistics, 2018." CA: a cancer journal for clinicians 68.4 (2018): 284-296.
12
Gupta, Ishita, Balsam Rizeq, Semir Vranic, Ala-Eddin Al Moustafa, and Halema Al Farsi. "Circulating miRNAs in HER2-Positive and Triple Negative Breast Cancers: Potential Biomarkers and Therapeutic Targets." International Journal of Molecular Sciences 21, no. 18 (September 15, 2020): 6750. http://dx.doi.org/10.3390/ijms21186750.
Повний текст джерелаАнотація:
Breast cancer is one of the most prevalent diseases among women worldwide and is highly associated with cancer-related mortality. Of the four major molecular subtypes, HER2-positive and triple-negative breast cancer (TNBC) comprise more than 30% of all breast cancers. While the HER2-positive subtype lacks estrogen and progesterone receptors and overexpresses HER2, the TNBC subtype lacks estrogen, progesterone and HER2 receptors. Although advances in molecular biology and genetics have substantially ameliorated breast cancer disease management, targeted therapies for the treatment of estrogen-receptor negative breast cancer patients are still restricted, particularly for TNBC. On the other hand, it has been demonstrated that microRNAs, miRNAs or small non-coding RNAs that regulate gene expression are involved in diverse biological processes, including carcinogenesis. Moreover, circulating miRNAs in serum/plasma are among the most promising diagnostic/therapeutic tools as they are stable and relatively easy to quantify. Various circulating miRNAs have been identified in several human cancers including specific breast cancer subtypes. This review aims to discuss the role of circulating miRNAs as potential diagnostic and prognostic biomarkers as well as therapeutic targets for estrogen-receptor negative breast cancers, HER2+ and triple negative.
13
Vekaria, Mrudul Pravinbhai, and Pravin Tirgar. "Salicin a promising ER, PR and HER2 binding molecule proving lethal against Hormone + and triple negative breast cancer cells." International Journal of Ayurvedic Medicine 12, no. 1 (March 31, 2021): 73–83. http://dx.doi.org/10.47552/ijam.v12i1.1755.
Повний текст джерелаАнотація:
Therapeutics against breast cancer is a major research field, due to inefficiency or partial efficiency of existing therapeutics. An urge to discover better therapeutics always persists. Our objective is to study salicin against breast cancer cells, in order to find its therapeutic properties. To study the effect of salicin on breast cancer cells, we performed MTT assay on MCF-7 (hormone positive) and MDA-MB-231 (triple negative) breast cancer cell lines, we did brine shrimp lethality test (BSLT) assay to see the lethal effects of salicin. By the help of bioinformatics we tried to locate the targets that delineate salicin activity. Salicin was docked with estrogen receptor (ER), progesterone receptor (PR) and Human epidermal growth factor receptor 2 (HER2) to study its binding efficiency and possible targets of salicin. Salicin remarkably reduces cell viability both in MCF-7 and MDA-MB-231, along with being lethal to brine shrimps. These results together opine that salicin can be an effective therapeutics against breast cancer cells. The mechanism of action of salicin is probably through ER, PR and HER2 receptors because it can efficiently bind these receptors with minimum energy required for binding. This explains that salicin can easily bind to these receptors. These results together opine that salicin can be an effective therapeutics against breast cancer cells. The mechanism of action of salicin is probably through ER, PR and HER2 receptors because it can efficiently bind these receptors with minimum binding energy. ER, PR and HER2 are major reasons behind the disease pathogenicity depending on the type of breast cancer. According to our results salicin may either induce apoptosis or reduce cellular mitosis both via P53 dependent and independent pathway, which makes salicin a good choice of both hormone positive and negative breast cancer cells.
14
Shiota, Masaki, Naohiro Fujimoto, Eiji Kashiwagi, and Masatoshi Eto. "The Role of Nuclear Receptors in Prostate Cancer." Cells 8, no. 6 (June 17, 2019): 602. http://dx.doi.org/10.3390/cells8060602.
Повний текст джерелаАнотація:
The nuclear receptor (NR) superfamily consists of 48 members that are divided into seven subfamilies. NRs are transcription factors that play an important role in a number of biological processes. The NR superfamily includes androgen receptor, which is a key player in prostate cancer pathogenesis, suggesting the functional roles of other NRs in prostate cancer. The findings on the roles of NRs in prostate cancer thus far have shown that several NRs such as vitamin D receptor, estrogen receptor β, and mineralocorticoid receptor play antioncogenic roles, while other NRs such as peroxisome proliferator-activated receptor γ and estrogen receptor α as well as androgen receptor play oncogenic roles. However, the roles of other NRs in prostate cancer remain controversial or uninvestigated. Further research on the role of NRs in prostate cancer is required and may lead to the development of novel preventions and therapeutics for prostate cancer.
15
ERZURUMLU, Yalçın, and Hatice Kübra DOĞAN. "Breast cancer and the molecular mechanism of estrogen signaling." Interdisciplinary Medical Journal 14, no. 48 (April 30, 2023): 57–68. http://dx.doi.org/10.17944/interdiscip.1285662.
Повний текст джерелаАнотація:
Cancer is a complex pathology that occurs due to the uncontrolled proliferation and growth of cells in any organ or tissue of the body. Breast cancer is the most frequently diagnosed cancer among women worldwide and is the second leading cause of cancer-related deaths. Breast cancer is a pathology that exhibits heterogeneity in which genetic and environmental risk factors play a role. Although many treatment approaches have been developed for breast cancer today, the frequency of the number of patients diagnosed with breast cancer and lost their lives due to this reason is increasing in the world. The most significant limitation to the success of the treatment approaches developing drug resistance in breast cancer cells, and the disease relapses after a certain period and exhibits a more aggressive profile. Therefore, understanding the molecular biology of breast cancer is essential for developing potent therapeutic approaches. It is known that the development of breast cancer is related to changes in direct and indirect signaling mechanisms mediated by estrogen and estrogen receptor. These signaling mechanisms exhibit highly complex interaction patterns. This review summarizes the pathology of breast cancer, estrogenic compounds, estrogen receptors, genomic and non-genomic molecular signaling mechanisms mediated by estrogen and estrogen receptor.
16
Qian, Hongyan, Jingxiu Xuan, Yuan Liu, and Guixiu Shi. "Function of G-Protein-Coupled Estrogen Receptor-1 in Reproductive System Tumors." Journal of Immunology Research 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/7128702.
Повний текст джерелаАнотація:
The G-protein-coupled estrogen receptor-1 (GPER-1), also known as GPR30, is a novel estrogen receptor mediating estrogen receptor signaling in multiple cell types. The progress of estrogen-related cancer is promoted by GPER-1 activation through mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), and phospholipase C (PLC) signaling pathways. However, this promoting effect of GPER-1 is nonclassic estrogen receptor (ER) dependent manner. In addition, clinical evidences revealed that GPER-1 is associated with estrogen resistance in estrogen-related cancer patients. These give a hint that GPER-1 may be a novel therapeutic target for the estrogen-related cancers. However, preclinical studies also found that GPER-1 activation of its special agonist G-1 inhibits cancer cell proliferation. This review aims to summarize the characteristics and complex functions of GPER-1 in cancers.
17
Ryu, Won-Ji, and Joo Hyuk Sohn. "Molecular Targets and Promising Therapeutics of Triple-Negative Breast Cancer." Pharmaceuticals 14, no. 10 (September 30, 2021): 1008. http://dx.doi.org/10.3390/ph14101008.
Повний текст джерелаАнотація:
Triple-negative breast cancer (TNBC) is one of the most heterogeneous diseases in solid tumors and has limited therapeutic options. Due to the lack of appropriate targetable markers, the mainstay therapeutic strategy for patients with TNBC has been chemotherapy for the last several decades. Indeed, TNBC tumors have no expression of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 (HER2); therefore, they do not respond to hormone therapy and HER2-targeted therapy. In this review paper, the molecular heterogeneities, possible therapeutic targets, and recently approved and upcoming drugs for TNBC will be summarized.
18
Renoir, Jack-Michel, Véronique Marsaud, and Gwendal Lazennec. "Estrogen receptor signaling as a target for novel breast cancer therapeutics." Biochemical Pharmacology 85, no. 4 (February 2013): 449–65. http://dx.doi.org/10.1016/j.bcp.2012.10.018.
Повний текст джерела
19
Pepermans, Richard A., Geetanjali Sharma, and Eric R. Prossnitz. "G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives." Cells 10, no. 3 (March 17, 2021): 672. http://dx.doi.org/10.3390/cells10030672.
Повний текст джерелаАнотація:
Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1. Furthermore, its functions in metabolism and corresponding pathophysiological states, such as obesity and diabetes, are becoming more evident and suggest additional therapeutic value in targeting GPER for both cancer and other diseases. Here, we highlight the roles of GPER in several cancers, as well as in metabolism and immune regulation, and discuss the therapeutic value of targeting this estrogen receptor as a potential treatment for cancer as well as contributing metabolic and inflammatory diseases and conditions.
20
Chi, David, Hari Singhal, Lewyn Li, Tengfei Xiao, Weihan Liu, Matthew Pun, Rinath Jeselsohn, et al. "Estrogen receptor signaling is reprogrammed during breast tumorigenesis." Proceedings of the National Academy of Sciences 116, no. 23 (May 20, 2019): 11437–43. http://dx.doi.org/10.1073/pnas.1819155116.
Повний текст джерелаАнотація:
Limited knowledge of the changes in estrogen receptor (ER) signaling during the transformation of the normal mammary gland to breast cancer hinders the development of effective prevention and treatment strategies. Differences in estrogen signaling between normal human primary breast epithelial cells and primary breast tumors obtained immediately following surgical excision were explored. Transcriptional profiling of normal ER+ mature luminal mammary epithelial cells and ER+ breast tumors revealed significant difference in the response to estrogen stimulation. Consistent with these differences in gene expression, the normal and tumor ER cistromes were distinct and sufficient to segregate normal breast tissues from breast tumors. The selective enrichment of the DNA binding motif GRHL2 in the breast cancer-specific ER cistrome suggests that it may play a role in the differential function of ER in breast cancer. Depletion of GRHL2 resulted in altered ER binding and differential transcriptional responses to estrogen stimulation. Furthermore, GRHL2 was demonstrated to be essential for estrogen-stimulated proliferation of ER+ breast cancer cells. DLC1 was also identified as an estrogen-induced tumor suppressor in the normal mammary gland with decreased expression in breast cancer. In clinical cohorts, loss of DLC1 and gain of GRHL2 expression are associated with ER+ breast cancer and are independently predictive for worse survival. This study suggests that normal ER signaling is lost and tumor-specific ER signaling is gained during breast tumorigenesis. Unraveling these changes in ER signaling during breast cancer progression should aid the development of more effective prevention strategies and targeted therapeutics.
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Schedin, Troy B., Virginia F. Borges, and Elena Shagisultanova. "Overcoming Therapeutic Resistance of Triple Positive Breast Cancer with CDK4/6 Inhibition." International Journal of Breast Cancer 2018 (June 19, 2018): 1–11. http://dx.doi.org/10.1155/2018/7835095.
Повний текст джерелаАнотація:
Triple positive breast cancers overexpress both the human epidermal growth factor receptor 2 (HER2) oncogene and the hormonal receptors (HR) to estrogen and progesterone. These cancers represent a unique therapeutic challenge because of a bidirectional cross-talk between the estrogen receptor alpha (ERα) and HER2 pathways leading to tumor progression and resistance to targeted therapy. Attempts to combine standard of care HER2-targeted drugs with antihormonal agents for the treatment of HR+/HER2+ breast cancer yielded encouraging results in preclinical experiments but did improve overall survival in clinical trial. In this review, we dissect multiple mechanisms of therapeutic resistance typical of HR+/HER2+ breast cancer, summarize prior clinical trials of targeted agents, and describe novel rational drug combinations that include antihormonal agents, HER2-targeted drugs, and CDK4/6 inhibitors for treatment of the HR+/HER2+ breast cancer subtype.
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Breier, Alan, Emily Liffick, Tom Hummer, Jennifer Vohs, Nicole Mehdiyoun, Ziyi Yang, Andrew J. Saykin, Brenna McDonald, and Michael Francis. "S32. ARE SELECTIVE ESTROGEN RECEPTOR BETA AGONISTS POTENTIAL THERAPEUTICS FOR SCHIZOPHRENIA?" Schizophrenia Bulletin 46, Supplement_1 (April 2020): S43—S44. http://dx.doi.org/10.1093/schbul/sbaa031.098.
Повний текст джерелаАнотація:
Abstract Background Estrogen therapies, such as estradiol, have shown promise as therapeutics for schizophrenia; however, safety and tolerability concerns, including feminization effects in men and cancer and stroke risk in pre-menopausal women, may limit their broader use. Estradiol binds to both the estrogen alpha (ERA) and beta (ERB) receptors. ERB receptors appear not to mediate many of the concerning side effects of estrogen therapies. In addition, beta receptors have unique localization in cortical regions (i.e., hippocampus), and improve social behaviors and cognition in some animal models, which has led to interests in these compounds for testing in schizophrenia. To our knowledge, there have been no previous clinical trials of selective ERB agonists in schizophrenia. LY500307 is a highly selective agent for beta receptors without effects on estrogen alpha receptors when doses are constrained. Doses that are too high may engage alpha receptors but the alpha engaging threshold dose has not been fully determined in patient groups. The purpose of this dose-response study was to determine: ERB selectivity doses of LY500307 (i.e., without engaging alpha receptors); safety and tolerability; brain target engagement; and effects on cognition and symptoms. Methods A two-staged, double-blind, 8-week, adjunctive to APDs, adaptive phase 1b/2a trial design was conducted in men with schizophrenia (women were not included because of the lack of toxicology, safety, phase 1 and clinical data supporting use in this population). Three LY500307 doses and placebo were evaluated: 25 mg/day, 75 mg/day, and 150 mg/day. The primary markers for estrogen beta receptor selectivity was lack of effects on total testosterone levels (TT) and no feminization signs. Target engagement was assessed with an N-back working memory fMRI task and the electrophysiology measure mismatch negativity (MMN). Cognitive effects were assessed by the MCCB Composite score. Negative and total symptoms were assessed by the NSA-16 and PANSS, respectively. The primary analyses included all subjects and compared the slope from the three LY500307 dosing arms to the placebo slope in order to evaluate the dose responses. The linear mixed model with random intercept was employed and secondary analyses assessed differences between mean changes of the two higher dose arms combined (75 mg and 150 mg) versus placebo. Results Ninety-four patients were randomized across the placebo and three LY500307 dosing arms. There were no effects on plasma TT levels and no evidence of feminization, suggesting all doses were selective for the beta receptor. No significant adverse events were observed. There were no significant differences between the slopes of the three drug doses versus placebo on the brain target engagement variables (fMRI/N-back: F=0.24, p=0.868; MMN (Duration): F=1.08, p=0.358; MMN (Frequency): F=0.89, p=0.446) or on the cognitive/symptom measures (MCCB composite: F=0.87, p=0.458; NSA-16: F=1.79, p=0.148; and PANSS Total: F=0.69, p=0.558.) Secondary analyses also failed to show any significant effects of LY500307 versus placebo on any of the study variables. Discussion Conclusions: This study indicates that the ERB agonist LY500307 was selective, safe, and well tolerated in patients with schizophrenia. This selective ERB agonist, however, failed to demonstrate any significant effects on brain targets, cognition, negative and total symptoms. Potential issues related to dosing and characteristics of the patient population will be discussed. These data suggest that estrogen alpha receptor activation may be necessary to yield positive results in this patient population. Future studies are needed to confirm these findings.
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Schuler, Linda A., and Fern E. Murdoch. "Endogenous and Therapeutic Estrogens: Maestro Conductors of the Microenvironment of ER+ Breast Cancers." Cancers 13, no. 15 (July 24, 2021): 3725. http://dx.doi.org/10.3390/cancers13153725.
Повний текст джерелаАнотація:
Estrogen receptor alpha (ERα) marks heterogeneous breast cancers which display a repertoire of somatic genomic mutations and an immune environment that differs from other breast cancer subtypes. These cancers also exhibit distinct biological behaviors; despite an overall better prognosis than HER2+ or triple negative breast cancers, disseminated dormant cells can lead to disease recurrence decades after the initial diagnosis and treatment. Estrogen is the best studied driver of these cancers, and antagonism or reduction of estrogen activity is the cornerstone of therapeutic approaches. In addition to reducing proliferation of ERα+ cancer cells, these treatments also alter signals to multiple other target cells in the environment, including immune cell subpopulations, cancer-associated fibroblasts, and endothelial cells via several distinct estrogen receptors. In this review, we update progress in our understanding of the stromal cells populating the microenvironments of primary and metastatic ER+ tumors, the effects of estrogen on tumor and stromal cells to modulate immune activity and the extracellular matrix, and net outcomes in experimental and clinical studies. We highlight new approaches that will illuminate the unique biology of these cancers, provide the foundation for developing new treatment and prevention strategies, and reduce mortality of this disease.
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Voutsadakis, Ioannis A. "The TSH/Thyroid Hormones Axis and Breast Cancer." Journal of Clinical Medicine 11, no. 3 (January 28, 2022): 687. http://dx.doi.org/10.3390/jcm11030687.
Повний текст джерелаАнотація:
Breast cancer, the most prevalent female carcinoma, is characterized by the expression of steroid nuclear receptors in a subset of cases. The most important nuclear receptor with prognostic and therapeutic implications is the Estrogen Receptor (ER), which is expressed in about three out of four breast cancers. The Progesterone Receptor (PR) and the Androgen Receptor (AR) are also commonly expressed. Moreover, non-steroid nuclear receptors, including the vitamin D receptor (VDR) and the thyroid receptors (TRs), are also present in breast cancers and have pathophysiologic implications. Circulating thyroid hormones may influence breast cancer risk and breast cancer cell survival, through ligating their canonical receptors TRα and TRβ but also through additional membrane receptors that are expressed in breast cancer. The expression of TR subtypes and their respective isotypes have diverse effects in breast cancers through co-operation with ER and influence on other cancer-associated pathways. Other components of the TSH/thyroid hormone axis, such as TSH and selenoiodinase enzymes, have putative effects in breast cancer pathophysiology. This paper reviews the pathophysiologic and prognostic implications of the thyroid axis in breast cancer and provides a brief therapeutic perspective.
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Saha Roy, Sudipa, and Ratna K. Vadlamudi. "Role of Estrogen Receptor Signaling in Breast Cancer Metastasis." International Journal of Breast Cancer 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/654698.
Повний текст джерелаАнотація:
Metastatic breast cancer is a life-threatening stage of cancer and is the leading cause of death in advanced breast cancer patients. Estrogen signaling and the estrogen receptor (ER) are implicated in breast cancer progression, and the majority of the human breast cancers start out as estrogen dependent. Accumulating evidence suggests that ER signaling is complex, involving coregulatory proteins and extranuclear actions. ER-coregualtory proteins are tightly regulated under normal conditions with miss expression primarily reported in cancer. Deregulation of ER coregualtors or ER extranuclear signaling has potential to promote metastasis in ER-positive breast cancer cells. This review summarizes the emerging role of ER signaling in promoting metastasis of breast cancer cells, discusses the molecular mechanisms by which ER signaling contributes to metastasis, and explores possible therapeutic targets to block ER-driven metastasis.
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Stein, R. A., та D. P. McDonnell. "Estrogen-related receptor α as a therapeutic target in cancer". Endocrine-Related Cancer 13, Supplement_1 (грудень 2006): S25—S32. http://dx.doi.org/10.1677/erc.1.01292.
Повний текст джерелаАнотація:
The orphan receptor estrogen-related receptor α (ERRα) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. This protein is structurally most related to the canonical estrogen receptor and has been shown to modulate estrogen signaling in some contexts. These observations have heightened interest in ERRα as a therapeutic target in both breast and ovarian cancer and in other estrogenopathies. This review details our present understanding of ERRα action with a view to highlight specific aspects of its signal-transduction pathway in breast cancer that may be amenable to pharmaceutical manipulation.
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Seachrist, Darcie D., Lindsey J. Anstine, and Ruth A. Keri. "FOXA1: A Pioneer of Nuclear Receptor Action in Breast Cancer." Cancers 13, no. 20 (October 17, 2021): 5205. http://dx.doi.org/10.3390/cancers13205205.
Повний текст джерелаАнотація:
The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor (ER) transcriptional programs and drives endocrine-resistant disease. However, ER is not the sole nuclear receptor (NR) expressed in breast cancers, nor is it the only NR for which FOXA1 serves as a licensing factor. Receptors for androgens, glucocorticoids, and progesterone are also found in the majority of breast cancers, and their functions are also impacted by FOXA1. These NRs interface with ER transcriptional programs and, depending on their activation level, can reprogram FOXA1-ER cistromes. Thus, NR interplay contributes to endocrine therapy response and resistance and may provide a vulnerability for future therapeutic benefit in patients. Herein, we review what is known regarding FOXA1 regulation of NR function in breast cancer in the context of cell identity, endocrine resistance, and NR crosstalk in breast cancer progression and treatment.
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Zattarin, Emma, Rita Leporati, Francesca Ligorio, Riccardo Lobefaro, Andrea Vingiani, Giancarlo Pruneri, and Claudio Vernieri. "Hormone Receptor Loss in Breast Cancer: Molecular Mechanisms, Clinical Settings, and Therapeutic Implications." Cells 9, no. 12 (December 9, 2020): 2644. http://dx.doi.org/10.3390/cells9122644.
Повний текст джерелаАнотація:
Hormone receptor-positive breast cancer (HR+ BC) accounts for approximately 75% of new BC diagnoses. Despite the undisputable progresses obtained in the treatment of HR+ BC in recent years, primary or acquired resistance to endocrine therapies still represents a clinically relevant issue, and is largely responsible for disease recurrence after curative surgery, as well as for disease progression in the metastatic setting. Among the mechanisms causing primary or acquired resistance to endocrine therapies is the loss of estrogen/progesterone receptor expression, which could make BC cells independent of estrogen stimulation and, consequently, resistant to estrogen deprivation or the pharmacological inhibition of estrogen receptors. This review aims at discussing the molecular mechanisms and the clinical implications of HR loss as a result of the therapies used in the neoadjuvant setting or for the treatment of advanced disease in HR+ BC patients.
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Xia, Song, and Qiong Lin. "Estrogen Receptor Bio-Activities Determine Clinical Endocrine Treatment Options in Estrogen Receptor-Positive Breast Cancer." Technology in Cancer Research & Treatment 21 (January 2022): 153303382210903. http://dx.doi.org/10.1177/15330338221090351.
Повний текст джерелаАнотація:
In estrogen receptor positive (ER+) breast cancer therapy, estrogen receptors (ERs) are the major targeting molecules. ER-targeted therapy has provided clinical benefits for approximately 70% of all breast cancer patients through targeting the ERα subtype. In recent years, mechanisms underlying breast cancer occurrence and progression have been extensively studied and largely clarified. The PI3K/AKT/mTOR pathway, microRNA regulation, and other ER downstream signaling pathways are found to be the effective therapeutic targets in ER+ BC therapy. A number of the ER+ (ER+) breast cancer biomarkers have been established for diagnosis and prognosis. The ESR1 gene mutations that lead to endocrine therapy resistance in ER+ breast cancer had been identified. Mutations in the ligand-binding domain of ERα which encoded by ESR1 gene occur in most cases. The targeted drugs combined with endocrine therapy have been developed to improve the therapeutic efficacy of ER+ breast cancer, particularly the endocrine therapy resistance ER+ breast cancer. The combination therapy has been demonstrated to be superior to monotherapy in overall clinical evaluation. In this review, we focus on recent progress in studies on ERs and related clinical applications for targeted therapy and provide a perspective view for therapy of ER+ breast cancer.
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Shaleen Jain and Dr. Asmita Das. "Virtual screening of natural compounds as combinatorial agents from indian medicinal plants against estrogen positive breast cancer." International Journal on Integrated Education 3, no. 10 (October 20, 2020): 266–75. http://dx.doi.org/10.31149/ijie.v3i10.750.
Повний текст джерелаАнотація:
Facing worldwide challenges associated with multifactorial etiology of breast cancer, designing of combinatorial therapies using natural compounds is currently the emergent way of treating several cancers including breast cancer in a synergistic way, which may mitigate several problems associated with multiple receptor targeting. In this research, Estrogen receptor positive breast cancer was taken as prototype and several key receptors associated with this particular disease were targeted by virtual screening of natural compounds found in Indian originated medicinal plants using Computer aided Drug Designing (CADD) strategies. We found the combination of Carpusin, Paulownin Cornigerine, Nororientaline, Oryzalexin B, Romucosine H and Colchicine as effective against six potential receptors i.e. FGFR2, ESR1, PIK3CA, PIK3CB, PIK3CD and AR in Estrogen receptor positive breast cancer with their binding energies in the range of ∆G ≤ -8.0 Kcal/mol as well as significant number of common amino acid binding residues as compared with binding sites of receptors. Thus this research holds significant implications for the designing of combinatorial therapeutic agents against breast cancer which can be further tested in-vitro and in-vivo to prove their synergistic efficiency.
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Hsu, Li-Han, Nei-Min Chu, Yung-Feng Lin, and Shu-Huei Kao. "G-Protein Coupled Estrogen Receptor in Breast Cancer." International Journal of Molecular Sciences 20, no. 2 (January 14, 2019): 306. http://dx.doi.org/10.3390/ijms20020306.
Повний текст джерелаАнотація:
The G-protein coupled estrogen receptor (GPER), an alternate estrogen receptor (ER) with a structure distinct from the two canonical ERs, being ERα, and ERβ, is expressed in 50% to 60% of breast cancer tissues and has been presumed to be associated with the development of tamoxifen resistance in ERα positive breast cancer. On the other hand, triple-negative breast cancer (TNBC) constitutes 15% to 20% of breast cancers and frequently displays a more aggressive behavior. GPER is prevalent and involved in TNBC and can be a therapeutic target. However, contradictory results exist regarding the function of GPER in breast cancer, proliferative or pro-apoptotic. A better understanding of the GPER, its role in breast cancer, and the interactions with the ER and epidermal growth factor receptor will be beneficial for the disease management and prevention in the future.
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Alsous, Lina, and Sanaa Bardaweel. "Selective Estrogen Receptor Modulators (SERMs) Synergize with Cisplatin, Induce Apoptosis and Suppress Cellular Migration and Colony Formation of Lung Cancer Cells." Anti-Cancer Agents in Medicinal Chemistry 22, no. 9 (May 2022): 1826–36. http://dx.doi.org/10.2174/1871520621666210908110902.
Повний текст джерелаАнотація:
Background: Lung cancer remains the leading cause of cancer-related deaths worldwide. Hence, novel therapeutic approaches targeting crucial pathways are needed to improve its treatment. Previous studies have verified the involvement of the estrogen pathway, mediated through estrogen receptor β (ERβ), in the development and progression of lung carcinogenesis. Selective estrogen receptor modulators (SERMs) are a group of estrogen receptor agonists/antagonists that have tissue selective effects. Many of the available SERMs are used for the management of breast cancer. However, their role in lung cancer is still under investigation. Objectives: The aim of this research is to investigate the anti-tumorigenic activity of the selective estrogen receptor modulators, tamoxifen, raloxifene, and toremifene, against different lung cancer cell lines. Methods: The anti-proliferative and combined effects of SERMs with standard chemotherapy were evaluated by MTT assay. Cell migration was assessed using a wound-healing assay. The mechanism of cell death was determined using the Annexin V-FITC/ propidium iodide staining flow cytometry method. Cells’ capability to form colonies was evaluated by soft agar colony formation assay. Estrogen receptors expression was determined using real-time PCR. Results: Our results have demonstrated the presence of ERβ in A549, H1299, and H661 lung cancer cells. Cellular proliferation assay suggested that SERMs have significantly reduced lung cancer cells proliferation in a time and concentration- dependent manner. Additionally, SERMs exhibited a synergistic effect against A549 cells when combined with cisplatin. SERMs treatment have increased cell apoptosis and resulted in concentration-dependent inhibition of cell migration and colony formation of A549 cells. Conclusion: Selective estrogen receptor modulators may possess potential therapeutic utility for the treatment of lung cancer as monotherapy or in combination with standard chemotherapy.
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Hafezi, Shirin A., and Wael M. Abdel-Rahman. "The Endocrine Disruptor Bisphenol A (BPA) Exerts a Wide Range of Effects in Carcinogenesis and Response to Therapy." Current Molecular Pharmacology 12, no. 3 (July 29, 2019): 230–38. http://dx.doi.org/10.2174/1874467212666190306164507.
Повний текст джерелаАнотація:
Background: Bisphenol A (BPA) is a synthetic plasticizer that is commonly used in the production of polycarbonate plastics and epoxy resins. Human exposure occurs when BPA migrates from food and beverage containers into the contents when heated or even under normal conditions of use. BPA exerts endocrine disruptor action due to its weak binding affinity for the estrogen receptors ERα and ERβ. BPA exerts other effects by activating the membrane receptor GPER (GPR30) and/or other receptors such as the estrogen-related receptors (ERRs). Objective: This review summarizes emerging data on BPA and cancer. These include data linking exposure to BPA with an increased risk of hormone-related cancers such as those of the ovary, breast, prostate, and even colon cancer. BPA can also induce resistance to various chemotherapeutics such as doxorubicin, cisplatin, and vinblastine in vitro. The development of chemoresistance to available therapeutics is an emerging significant aspect of BPA toxicity because it worsens the prognosis of many tumors. Conclusion: Recent findings support a causal role of BPA at low levels in the development of cancers and in dictating their response to cytotoxic therapy. Accurate knowledge and consideration of these issues would be highly beneficial to cancer prevention and management.
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Skliris, George P., Etienne Leygue, Peter H. Watson, and Leigh C. Murphy. "Estrogen receptor alpha negative breast cancer patients: Estrogen receptor beta as a therapeutic target." Journal of Steroid Biochemistry and Molecular Biology 109, no. 1-2 (March 2008): 1–10. http://dx.doi.org/10.1016/j.jsbmb.2007.12.010.
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Gérard, Céline, Mélanie Mestdagt, Ekaterine Tskitishvili, Laudine Communal, Anne Gompel, Elisabete Silva, Jean-François Arnal, et al. "Combined Estrogenic and Antiestrogenic Properties of Estetrol on Breast Cancer may provide a Safe Therapeutic Window for the Treatment of Menopausal Symptoms." Journal of SAFOMS 3, no. 1 (2015): 31–33. http://dx.doi.org/10.5005/jsafoms-3-1-31.
Повний текст джерелаАнотація:
Abstract Increased risk of breast cancer is a critical side-effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a promising compound for clinical use in MHT. However, its impact on breast cancer is controversial and poorly defined. In this preclinical study, we show that E4 acts as a weak estrogen by stimulating the growth of hormone-dependent breast cancer only at concentrations exceeding menopausal therapeutic needs. Estetrol (E4) presents also an antitumor activity by decreasing the strong proliferative effect of estradiol (E2). While estrogen receptor alpha (ERá) is the predominant receptor mediating its effects, the dual weak-estrogenic/antiestrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extranuclear signaling pathway are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. Altogether, our results highlight that E4 has a limited impact on breast cancer and may offer a safe therapeutic window for the treatment of menopausal symptoms.
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Terrisse, Safae, Laurence Zitvogel, and Guido Kroemer. "Impact of microbiota on breast cancer hormone therapy." Cell Stress 7, no. 3 (March 13, 2023): 12–19. http://dx.doi.org/10.15698/cst2023.03.277.
Повний текст джерелаАнотація:
Recent observations indicate that the pathogenesis and prognosis of hormone-receptor breast cancer is not only dictated by the properties of the malignant cells but also by immune and microbial parameters. Thus, the immunosurveillance system retards the development of hormone-positive breast cancer and contributes to the therapeutic efficacy of es-trogen receptor antagonists and aromatase inhibitors. Moreover, the anticancer immune response is profoundly modulated by the local and intestinal microbiota, which influences cancer cell-intrinsic signaling pathways, affects the composition and function of the immune infiltrate present in the tumor microenvironment and modulates the metabolism of estrogens. Indeed, specific bacteria in the gut produce enzymes that affect the enterohepatic cycle of estrogen metabolites, convert estro-gens into androgens or generate estrogen-like molecules. The knowledge of these circuitries is in its infancy, calling for further in-depth analyses.
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Pedroza, Diego A., Ramadevi Subramani, and Rajkumar Lakshmanaswamy. "Classical and Non-Classical Progesterone Signaling in Breast Cancers." Cancers 12, no. 9 (August 27, 2020): 2440. http://dx.doi.org/10.3390/cancers12092440.
Повний текст джерелаАнотація:
Much emphasis is placed on estrogen (E2) and estrogen receptor (ER) signaling as most research is focused on understanding E2 and ER’s ability to enhance proliferative signals in breast cancers. Progesterone (P4) is important for normal mammary gland development, function and menstrual control. However, P4 and its receptors (PRs) in breast cancer etiology continue to be understudied and its role in breast cancer remains controversial. The Women’s Health Initiative (WHI) clinical trial clearly demonstrated the importance of progestogens in breast cancer development. P4 has historically been associated with classical-signaling through nuclear receptors, however non-classical P4 signaling via membrane receptors has been described. Progestogens have the ability to bind to nuclear and membrane receptors and studies have demonstrated that both can promote breast cancer cell proliferation and breast tumor growth. In this review, we attempt to understand the classical and non-classical signaling role of P4 in breast cancers because both nuclear and membrane receptors could become viable therapeutic options for breast cancer patients.
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Dika, Emi, Annalisa Patrizi, Martina Lambertini, Nicholas Manuelpillai, Michelangelo Fiorentino, Annalisa Altimari, Manuela Ferracin, et al. "Estrogen Receptors and Melanoma: A Review." Cells 8, no. 11 (November 19, 2019): 1463. http://dx.doi.org/10.3390/cells8111463.
Повний текст джерелаАнотація:
In the last three decades cutaneous melanoma has been widely investigated as a steroid hormone-sensitive cancer. Following this hypothesis, many epidemiological studies have investigated the relationship between estrogens and melanoma. No evidence to date has supported this association due to the great complexity of genetic, external and environmental factors underlying the development of this cancer. Molecular mechanisms through which estrogen and their receptor exert a role in melanoma genesis are still under investigation with new studies increasingly focusing on the discovery of new molecular targets for therapeutic treatments.
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Oualla, Karima, Heba M. El-Zawahry, Banu Arun, James M. Reuben, Wendy A. Woodward, Heba Gamal El-Din, Bora Lim, Nawfel Mellas, Naoto T. Ueno, and Tamer M. Fouad. "Novel therapeutic strategies in the treatment of triple-negative breast cancer." Therapeutic Advances in Medical Oncology 9, no. 7 (June 13, 2017): 493–511. http://dx.doi.org/10.1177/1758834017711380.
Повний текст джерелаАнотація:
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that is defined by negative estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Treating patients with TNBC remains clinically challenging, as patients are not candidates for endocrine or HER2-directed therapy. As a result, chemotherapy with traditional agents such as anthracyclines and taxanes remains the only available option with moderate success. Recent discoveries have revealed that TNBC is a heterogeneous disease at the clinical, histological and molecular levels. The use of biomarkers to identify distinct subsets of TNBC that derive the greatest benefit from presently approved as well as novel therapeutics has become the main focus of current research. The aim of this review is to explore the clinical and biological complexity of TNBC as well as identify novel therapeutic options that target the various molecular subsets of TNBC.
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Mulligan, Michael P., Matthew W. Boudreau, David J. Shapiro, Timothy M. Fan, Paul J. Hergenrother, Kerry Barnhart, David Azorsa, Jeff Kiefer, and Spyro Mousses. "Abstract 522: Selective estrogen receptor a-UPR activators (SERA): a novel class of small molecules that eradicate estrogen receptor positive tumors." Cancer Research 83, no. 7_Supplement (April 4, 2023): 522. http://dx.doi.org/10.1158/1538-7445.am2023-522.
Повний текст джерелаАнотація:
Abstract While therapy of estrogen receptor alpha positive (ERα+) breast cancer is often initially successful with ERα modulating or inhibiting drugs, eventual drug resistance is universal and such treatments are rarely curative. To address this considerable medical need, several generations of novel anti-tumor small molecule agents specifically targeting the estrogen-ERα interaction have been synthesized and characterized. We are pursuing an alternative approach, activation of an endogenous cell death pathway downstream of ERα with non-competitive Selective Estrogen Receptor Activators (SERAs). These compounds exhibit their effects by dysregulating calcium homeostasis in ERα+ tumor cells leading to hyper-activation of the anticipatory unfolded protein response (a-UPR) and necrotic cell death, a mechanism distinct from current breast cancer therapeutics. These molecules cause increases in P-EIF2a and P-AMPK, and cleavage of ATF6α, which are all hallmarks of the hyper-activation of a-UPR. SERA molecules cause death of ERα+ breast cancer cells in culture with 24hr IC50 values in the low nanomolar range, including breast cancer cell lines harboring ERα mutations known to contribute to acquired ERα modulator therapy resistance, while IC50 values in ERα-negative cells are orders of magnitude higher. In the MCF-7 ERα+ breast cancer xenograft model, once weekly IV injections of SERA2 at 10mg/kg cause durable, complete tumor regression, and SERA2 also has impressive activity in a challenging-to-treat PDX model that is resistant to fulvestrant and tamoxifen. SERAs are well-tolerated after multiple intravenous injections in mice, rats, and dogs, and clinical trial-compatible formulations have been developed. These findings suggest that SERA molecules can address the important unmet clinical need for more effective therapies for patients with ERα+ tumors who progress on conventional SERM, SERD, and targeted therapies. Citation Format: Michael P. Mulligan, Matthew W. Boudreau, David J. Shapiro, Timothy M. Fan, Paul J. Hergenrother, Kerry Barnhart, David Azorsa, Jeff Kiefer, Spyro Mousses. Selective estrogen receptor a-UPR activators (SERA): a novel class of small molecules that eradicate estrogen receptor positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 522.
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Sakaguchi, K., H. Nakajima, I. Fujiwara, N. Mizuta, and J. Magae. "A novel therapeutic strategy for ER-negative human breast cancers, targeting AP-1 activity." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14129. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14129.
Повний текст джерелаАнотація:
14129 Background: While agents targeting estrogen receptors are the most effective in adjuvant therapy for human breast cancers expressing estrogen receptor(ER), breast cancers lacking ER are clinically serious, because they are highly malignant and exhibit resistance to the usual anti-cancer drugs, including estrogen receptor-antagonists and DNA breaking agents. Although a transcription factor, AP-1, is known to be related to tumor malignancy including metastasis, invasion and drug-resistance, it remains to be elucidated how AP-1 plays in development and expression of malignant characters of human breast cancers. Methods and Results: Here, we used MX-1, a human breast cancer cell line lacking ER and several ER positive cell lines, to clarify the roles of AP-1 and the therapeutic efficacy of ascochlorin, a newly developed prenylphenol antibiotic on ER-negative breast cancer. We found that MX-1 exhibited higher AP-1 activity and expressed higher levels of c-Jun, c-Fos and Fra-1 when compared with conventional ER-positive human breast cancer cell lines. Consistent with this study in vitro, histological study on human breast cancer tissues suggests that ER-negative cancers express high Fra-1 protein, and that paclitaxel- sensitive cancers express low Fra-1 protein. The ascochlorin, which inhibits AP-1 through the Erk signaling pathway, suppressed the AP-1 activity of MX-1 cells, and selectively killed MX-1 cells, partly due to induction of apoptosis. Moreover, administration of ascochlorin elongated life span of mice intraperitoneally implanted with murine mammary carcinoma cells. Conclusions: Our results suggest that AP-1 is an effective clinical target molecule for the treatment of ER-negative human breast cancer, and that ascochlorin is promising therapeutic agent for these refractory breast cancers. No significant financial relationships to disclose.
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Miller, Manisha, Lynn Schoenfield, Mohamed Abdel-Rahman, and Colleen M. Cebulla. "Is Uveal Melanoma a Hormonally Sensitive Cancer? A Review of the Impact of Sex Hormones and Pregnancy on Uveal Melanoma." Ocular Oncology and Pathology 7, no. 4 (2021): 239–50. http://dx.doi.org/10.1159/000514650.
Повний текст джерелаАнотація:
<b><i>Background:</i></b> Despite a higher incidence and worse prognosis of uveal melanoma (UM) in men, there have been many case reports of pregnant patients with aggressive UM. This has led researchers to explore the influence of sex hormones and pregnancy on the development and progression of UM and hormones as potential therapeutic targets. <b><i>Summary:</i></b> A systematic literature review was conducted. More work is needed to elucidate the basis of sex differences in UM incidence and survival. The evaluation of germline <i>BAP1</i> mutation would be beneficial in patients with UM presenting at a young age. Importantly, multiple studies reported no significant difference between the 5-year survival and 5-year metastasis-free survival rates between nonpregnant women with UM and pregnant women with UM. Multiple case-control studies disagree on how parity affects risk of UM. However, most studies agree that oral contraceptives and hormone replacement therapy have no effect on the incidence of UM. Current treatment strategies for pregnant patients with UM are discussed. Looking forward, this review reports recent research on targeted receptor-based chemotherapy, which is based on evidence of estrogen receptor (ER), estrogen-related receptor alpha (ERRα), and luteinizing hormone-releasing hormone (LHRH) receptor expression in UM. <b><i>Key Messages:</i></b> Based on review of the literature, UM is not a contraindication to oral contraceptives, hormone replacement therapy, or pregnancy. Globe-sparing radiation can be used as a treatment option for pregnant patients. Due to the presence of ER on a subset of unselected UM, its potential for adjunctive targeted therapy with agents like tamoxifen should be explored. Lessons from cutaneous melanoma regarding tissue ratios of estrogen receptors (ERα:ERβ) should be applied to assess their therapeutic predictive value. In addition, ERRα-targeted therapeutics and LHRH analogs are worthy of further exploration in UM.
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Shen, Minqian, Mengyang Xu, Fanyi Zhong, McKenzie C. Crist, Anjali B. Prior, Kundi Yang, Danielle M. Allaire, Fouad Choueiry, Jiangjiang Zhu, and Haifei Shi. "A Multi-Omics Study Revealing the Metabolic Effects of Estrogen in Liver Cancer Cells HepG2." Cells 10, no. 2 (February 20, 2021): 455. http://dx.doi.org/10.3390/cells10020455.
Повний текст джерелаАнотація:
Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women suggests the protective roles of estrogen in HCC development and progression. To begin to understand the mechanisms involving estrogenic metabolic effects, we compared cell number, viability, cytotoxicity, and apoptosis among HCC-derived HepG2 cells that were treated with different concentrations of 2-deoxy-d-glucose (2-DG) that blocks glucose metabolism, oxamate that inhibits lactate dehydrogenase and glycolysis, or oligomycin that blocks ATP synthesis and mitochondrial oxidative phosphorylation. We confirmed that HepG2 cells primarily utilized glycolysis followed by lactate fermentation, instead of mitochondrial oxidative phosphorylation, for cell growth. We hypothesized that estrogen altered energy metabolism via its receptors to carry out its anticancer effects in HepG2 cells. We treated cells with 17β-estradiol (E2), 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) an estrogen receptor (ER) α (ERα) agonist, or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), an ERβ agonist. We then used transcriptomic and metabolomic analyses and identified differentially expressed genes and unique metabolite fingerprints that are produced by each treatment. We further performed integrated multi-omics analysis, and identified key genes and metabolites in the gene–metabolite interaction contributed by E2 and ER agonists. This integrated transcriptomic and metabolomic study suggested that estrogen acts on estrogen receptors to suppress liver cancer cell growth via altering metabolism. This is the first exploratory study that comprehensively investigated estrogen and its receptors, and their roles in regulating gene expression, metabolites, metabolic pathways, and gene–metabolite interaction in HCC cells using bioinformatic tools. Overall, this study provides potential therapeutic targets for future HCC treatment.
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Moga, Marius Alexandru, Oana Gabriela Dimienescu, Andreea Bălan, Lorena Dima, Sebastian Ionut Toma, Nicușor Florin Bîgiu, and Alexandru Blidaru. "Pharmacological and Therapeutic Properties of Punica granatum Phytochemicals: Possible Roles in Breast Cancer." Molecules 26, no. 4 (February 17, 2021): 1054. http://dx.doi.org/10.3390/molecules26041054.
Повний текст джерелаАнотація:
Background: Pomgranate (Punica granatum) represents a high source of polyphenols with great bioavailability. The role of this fruit in the prevention and treatment of various malignant pathologies has been long time cited in both scientific and non-scientific literature, making thus important to identify its involvement in the pathophysiological processes. The treatment for breast cancer had focused on the inhibition of the mechanisms that governs the estrogen activity. These mechanisms are covered either by the antagonism of the estrogen receptor (ER) or by the inhibition of the estrogen synthesis. Our interest in identifying a bioactive compound rich in polyphenols, which induces both the antagonism of the estrogen receptor, and the inhibition of the estrogen synthesis, revealed us the pomegranate fruit and its derivatives: peel and seeds. Pomegranates’ chemical composition include many biological active substances such as flavonols, flavanols, anthocyanins, proanthocyanidins, ellagitannins and gallotannins. Materials and Methods: We performed a review of the scientific literature by using the following keywords: “pomegranate”, “breast cancer”, “Punica granatum”, “pomegranate polyphenols”. Our search was performed in the PubMed and Google Scholar databases, and it included only original research written in English from the last 20 years. None of the articles were excluded due to affiliation. A total number of 28 original papers, which mentioned the beneficial activity of pomegranate against breast cancer, were selected. Both clinical and preclinical studies were considered for this review. Results: Recent discoveries pointed out that polyphenols from Punica granatum possess strong anti-cancer activity, exhibited by a variety of mechanisms, such as anti-estrogenic, anti-proliferative, anti-angiogenetic, anti-inflammatory, and anti-metastatic. Pomegranate extracts induced cell cycle arrest in the G0/G1 phase, and induced cytotoxicity in a dose- and time-dependent manner. Moreover, several polyphenols extracted from pomegranate inhibited the invasion potential, migration and viability of breast cancer cells. The effects of pomegranate juice on serum estrogens and other sexual hormones levels were also investigated on two human cohorts. Conclusions: Punica granatum represents a promising area in oncology. The large availability and low cost, associated with the lack of side effects, made from this natural product a great strategy for the management of breast cancer. There are several mechanistic studies in mouse models and in breast cancer cell lines, suggesting the possible pathways through which polyphenols from pomegranate extracts act, but larger and better-controlled studies are necessary in the future. Only two small clinical trials were conducted on humans until now, but their results are contradictory and should be considered preliminary.
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Cipolletti, Manuela, Stefania Bartoloni, Claudia Busonero, Martina Parente, Stefano Leone та Filippo Acconcia. "A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells". International Journal of Molecular Sciences 22, № 6 (13 березня 2021): 2915. http://dx.doi.org/10.3390/ijms22062915.
Повний текст джерелаАнотація:
17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.
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Asemota, Sarah, Suriyan Ponnusamy, Thirumagal Thiyagarajan, and Ramesh Narayanan. "Abstract 1777: Androgen receptor (AR) agonists inhibit AR- and estrogen-receptor-positive breast cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1777. http://dx.doi.org/10.1158/1538-7445.am2022-1777.
Повний текст джерелаАнотація:
Abstract Introduction: Breast cancer is the most common cancer diagnosed in women. About 13% of women will develop invasive breast carcinoma in their lifetime and it is estimated that about 280,000 new cases will be diagnosed in 2021. Seventy-percent of diagnosed breast cancers are estrogen receptor (ER)-positive and about 90% of the ER-positive breast cancers are androgen receptor (AR)-positive. We have previously shown that AR agonists inhibit ER-positive breast cancer growth by sequestering the pioneer-transcription factor FOXA1 from ER-cistrome. Tissue-selective AR modulators (SARMs) such as enobosarm are in clinical trials to treat ER-positive breast cancers. Since resistance is a major impediment to sutained treatment, it is important to identify new therapeutic strategies and their mechanisms of resistance. Here, we evaluated the possible mechanisms of resistance to AR agonists in ER-positive breast cancer. Description: ER-positive breast cancer cell line xenografts and patient-derived xenografts (PDX) were used as experimental models. Once tumors grew to ~100-300 mm3, mice were randomized and treated orally with vehicle or enobosarm (30 mg/kg/day). Animals were sacrificed after 4 weeks when the tumors responded to treatment and after 10 weeks once resistance developed to treatment. Tumor volumes were measured twice weekly and tumors were collected at sacrifice for further analyses. RNA-seq and ChIP-seq were performed on tumor tissues. Summary: AR agonists, enobosarm and dihydrotestosterone (DHT), inhibited the proliferation of ER-positive breast cancer cells ZR-75-1 and T47D. Transcriptome analysis revealed that AR agonists activate AR in ER-positive breast cancer cells and inhibit ER-target gene signature. AR agonists inhibited the growth of breast cancer cell line xenograft T47D and breast cancer PDXs HCI-7 that express wildtype ER, and HCI-13 and WHIM-23, two models that express Y537S mutant ER. Treatment of WHIM-23 and T47D xenograft for over ten weeks resulted in resistance and regrowth. AR agonist-sensitive and -resistant tumors were analyzed using RNA-seq, ChIP-seq, and ATAC-seq to understand the mechanism of resistance development. The results indicate that the prolonged activation of AR will result in resistance. These mechanisms of resistance can be utilized as possible therapeutic targets. Conclusion: These results suggest that the AR is a promising therapeutic target in the treatment of ER-positive breast cancer. However, resistance development is possible with AR agonists and the mechanism provides suggestions for future combination therapies. Disclosure: This work was supported by an NCI grant (CA229164 and CA229164S1 to RN) and by a DOD grant (W81XWH2110055 to RN). Citation Format: Sarah Asemota, Suriyan Ponnusamy, Thirumagal Thiyagarajan, Ramesh Narayanan. Androgen receptor (AR) agonists inhibit AR- and estrogen-receptor-positive 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 1777.
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Voutsadakis, Ioannis A. "Hormone Receptors in Serous Ovarian Carcinoma: Prognosis, Pathogenesis, and Treatment Considerations." Clinical Medicine Insights: Oncology 10 (January 2016): CMO.S32813. http://dx.doi.org/10.4137/cmo.s32813.
Повний текст джерелаАнотація:
A few breakthroughs have been accomplished for the treatment of ovarian cancer, the most deadly gynecologic carcinoma, in the current era of targeted oncologic treatment. The estrogen receptor was the first target of such treatments with the introduction of tamoxifen four decades ago in breast cancer therapeutics. Attempts to duplicate the success of hormonal therapies in ovarian cancer met with mixed results, which may be due to an inferior degree of hormone dependency in this cancer. Alternatively, this may be due to the failure to clearly identify the subsets of ovarian cancer with hormone sensitivity. This article reviews the expression of hormone receptors by ovarian cancer cells, the prognostic value of these expressions, and their predictive capacity for response to hormonal agents. The possible ways ahead are briefly discussed.
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Bommi-Reddy, Archana, Sungmi Park-Chouinard, David N. Mayhew, Esteban Terzo, Aparna Hingway, Michael J. Steinbaugh, Jonathan E. Wilson, Robert J. Sims, and Andrew R. Conery. "CREBBP/EP300 acetyltransferase inhibition disrupts FOXA1-bound enhancers to inhibit the proliferation of ER+ breast cancer cells." PLOS ONE 17, no. 3 (March 30, 2022): e0262378. http://dx.doi.org/10.1371/journal.pone.0262378.
Повний текст джерелаАнотація:
Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer.
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Gustafsson Sheppard, Nina, Nina Heldring та Karin Dahlman-Wright. "Estrogen receptor-α, RBCK1, and protein kinase C β 1 cooperate to regulate estrogen receptor-α gene expression". Journal of Molecular Endocrinology 49, № 3 (5 жовтня 2012): 277–87. http://dx.doi.org/10.1530/jme-12-0073.
Повний текст джерелаАнотація:
Estrogen receptor α (ERα) is initially overexpressed in two-thirds of all breast cancers and is involved in its development and proliferation. We previously reported that the RanBP-type and C3HC4-type zinc finger containing 1 (RBCK1) interacts with the ERα promoter and that RBCK1 expression positively correlates with ERα levels, expression of ERα downstream target genes, and proliferation of breast cancer cells. Based on this, and that RBCK1 positively correlates with ERα expression in breast cancer samples, we propose RBCK1 as a potential therapeutic target in breast cancer acting as a modulator of ERα expression. To further explore this, the molecular mechanism by which RBCK1 regulates ERα expression has to be defined. Here, we show that ERα, RBCK1, and the RBCK1-interacting protein protein kinase C β 1 (PKCβI) co-occupy a previously identified ERα binding region in the proximal ERα promoter. We describe a number of mechanistic details of this complex including that RBCK1 recruitment to the ERα promoter B is facilitated by ERα, which in turn facilitates PKCβI recruitment and PKCβI-dependent histone modifications. Furthermore, ERα regulation of its own mRNA expression is facilitated by RBCK1 recruitment, suggesting an ERα coactivator function of RBCK1. The interaction between RBCK1 and ERα was dependent on the E3 ubiquitin ligase domain of RBCK1 and the activating function-1 domain of ERα. The ligand-binding function of ERα does not influence the interaction with RBCK1. In summary, our data provide insight into the molecular mechanism by which ERα expression is modulated in breast cancer cells.
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Doan, Tram B., J. Dinny Graham, and Christine L. Clarke. "Emerging functional roles of nuclear receptors in breast cancer." Journal of Molecular Endocrinology 58, no. 3 (April 2017): R169—R190. http://dx.doi.org/10.1530/jme-16-0082.
Повний текст джерелаАнотація:
Nuclear receptors (NRs) have been targets of intensive drug development for decades due to their roles as key regulators of multiple developmental, physiological and disease processes. In breast cancer, expression of the estrogen and progesterone receptor remains clinically important in predicting prognosis and determining therapeutic strategies. More recently, there is growing evidence supporting the involvement of multiple nuclear receptors other than the estrogen and progesterone receptors, in the regulation of various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming and breast cancer migration and metastasis.