Journal of Endocrinology and Reproduction

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Epigenetic Regulation of Tamoxifen-Resistant Breast Cancer: An Update


Affiliations
1 Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur - 603203, Chengalpattu, India
     

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Breast cancer is the most common cause of death in women around the world. Epigenetic changes modulate transcriptional activity in several diseases, including cancer. Cancer epigenetics explains gene expression changes without DNA mutations. Aberrant DNA methylation, histone modifications, and mRNA expression promote tumоr growth and metastasis. In cancer cells, chemo-resistance occurs via Multidrug Resistance (MDR), apoptotic suppression, DNA damage response, epigenetic alterations, and competitive endogenous RNA. Owing to drug resistance, quiescence, and varied cancer cell production, Cancer Stem Cells (CSCs) are critical to tumоr formation, metastasis, and recurrence after therapy. In addition, MDR promotes drug efflux, enhanced secretion of growth factors, and DNA modifications in cancer patients, thereby causing fatalities in cancer patients. Heterogeneity and epigenetic plasticity cause drug resistance due to various factors. However, the molecular mechanism of epigenetic drug resistance is still unravelled completely. Overexpressed c-MYC leads to cancer and tamoxifen resistance. Despite the molecular underpinning of cancer development, drug resistance is continued in a myriad number of cases. Epigenetic changes affect CSCs viability and tumоr aggressiveness. These processes can be blocked by medicines. Tamoxifen is used widely for breast cancer treatment; however, latent treatments have emerged as a tamoxifen-resistant phenotype. Epigenetic modifications cause resistance by upregulating and altering the tumоr microenvironment and deregulating the immune response. The knowledge of epigenetic pathways in clinical treatment resistance may enhance the outcome of cancer patients. Multifactorial heterogeneous resistance is common in many targeted therapies. Many resistance mechanisms to targeted therapy may converge, including route reactivation. This review summarizes the epigenetic alterations, MDR, and development of tamoxifen resistance in breast cancer.

Keywords

Breast Cancer, Cancer Epigenetics, Cancer Stem Cells, Multidrug Resistance, Tamoxifen Resistance.
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  • Hackshaw A, Roughton M, Forsyth S, et al. Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer. J Clin Oncol. 2011; 29(13):1657-63. https://doi.org/10.1200/ JCO.2010.32.2933 PMID:21422412

  • Chlebowski RT, Aragaki AK, Pan K. Breast cancer prevention: Time for change. JCO Oncology Practice. 2021; 17(12):709-16. https://doi.org/10.1200/OP.21.00343 PMID:34319769 PMCID:PMC8677965

  • Yao J, Deng K, Huang J, et al. Progress in the understanding of the mechanism of tamoxifen resistance in breast cancer. Front Pharmacol. 2020; 11:592912. https://doi.org/10.3389/fphar.2020.592912 PMID:33362547 PMCID:PMC7758911

  • Ali S, Rasool M, Chaoudhry H, et al. Molecular mechanisms and mode of tamoxifen resistance in breast cancer. Bioinformation. 2016; 12(3):135-9. https://doi.org/10.6026/97320630012135 PMID:28149048 PMCID:PMC5267957

  • Day CM, Hickey SM, Song Y, et al. Novel tamoxifen nanoformulations for improving breast cancer treatment: Old wine in new bottles. Molecules. 2020; 25(5). https://doi.org/10.3390/molecules25051182 PMID:32151063 PMCID:PMC7179425

  • Bebchuk JM, Arfken CL, Dolan-Manji S, et al. A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. Arch Gen Psychiatry. 2000; 57(1):95-7. https://doi.org/10.1001/archpsyc.57.1.95 PMID:10632242

  • Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018; 20(2):97-170. https://doi.org/10.1111/bdi.12609 PMID:29536616 PMCID:PMC5947163

  • Jordan VC. Molecular mechanisms of antiestrogen action in breast cancer. Breast Cancer Res Treat. 1994; 31(1):41-52. https:// doi.org/10.1007/BF00689675 PMID:7981455

  • Manji HK, Zarate CA. Molecular and cellular mechanisms underlying mood stabilization in bipolar disorder: Implications for the development of improved therapeutics. Mol Psychiatry. 2002; 7 Suppl 1:S1-7. https://doi.org/10.1038/sj.mp.4001068 PMID:11986989

  • Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov. 2003; 2(3):205-13. https://doi.org/10.1038/ nrd1031 PMID:12612646

  • Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005; 97(22):1652-62. https://doi.org/10.1093/jnci/ dji372 PMID:16288118

  • Dhingra K. Antiestrogens--tamoxifen, SERMs and beyond. Invest New Drugs. 1999; 17(3):285-311. https://doi. org/10.1023/A:1006348907994 PMID:10665480

  • Grainger DJ, Metcalfe JC. Tamoxifen: Teaching an old drug new tricks? Nat Med. 1996; 2(4):381-5. https://doi.org/10.1038/ nm0496-381 PMID:8597938

  • Banerjee S, Saxena N, Sengupta K, et al. 17alpha-estradiol-induced VEGF-A expression in rat pituitary tumor cells is mediated through ER independent but PI3K-Akt dependent signaling pathway. Biochem Biophys Res Commun. 2003; 300(1):209-15. https://doi.org/10.1016/S0006-291X(02)02830-9 PMID:12480545

  • Chang XZ, Li DQ, Hou YF, et al. Identification of the functional role of peroxiredoxin 6 in the progression of breast cancer. Breast Cancer Res. 2007; 9(6):R76. https://doi.org/10.1186/bcr1789 PMID:17980029 PMCID:PMC2246172

  • Rasha F, Sharma M, Pruitt K. Mechanisms of endocrine therapy resistance in breast cancer. Mol Cell Endocrinol. 2021; 532:111322. https://doi.org/10.1016/j.mce.2021.111322 PMID:34000350

  • Riggins RB, Schrecengost RS, Guerrero MS, et al. Pathways to tamoxifen resistance. Cancer Lett. 2007; 256(1):1-24. https://doi. org/10.1016/j.canlet.2007.03.016 PMID:17475399 PMCID:PMC2533271

  • Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: An overview. Cancers (Basel). 2014; 6(3):1769-92. https://doi. org/10.3390/cancers6031769 PMID:25198391 PMCID:PMC4190567

  • Bolhuis H, van Veen HW, Poolman B, et al. Mechanisms of multidrug transporters. FEMS Microbiol Rev. 1997; 21(1):55-84. https://doi.org/10.1111/j.1574-6976.1997.tb00345.x PMID:9299702

  • Baguley BC. Multiple drug resistance mechanisms in cancer. Mol Biotechnol. 2010; 46(3):308-16. https://doi.org/10.1007/ s12033-010-9321-2 PMID:20717753

  • Chang YC, Cheung CHA, Kuo YL. Tamoxifen Rechallenge decreases metastatic potential but increases cell viability and clonogenicity in a tamoxifen-mediated cytotoxicity-resistant subline of human breast MCF7 cancer cells. Front Cell Dev Biol. 2020; 8:485. https://doi.org/10.3389/fcell.2020.00485 PMID:32695778 PMCID:PMC7338790

  • Wiebe VJ, Osborne CK, Fuqua SAW, et al. Tamoxifen resistance in breast cancer. Critical Reviews in Oncology/Hematology. 1993; 14(3):173-88. https://doi.org/10.1016/1040-8428(93)90008-R PMID:8397846

  • Garcia-Becerra R, Santos N, Diaz L, et al. Mechanisms of resistance to endocrine therapy in breast cancer: focus on signaling pathways, miRNAs and genetically based resistance. Int J Mol Sci. 2012; 14(1):108-45. https://doi.org/10.3390/ijms14010108 PMID:23344024 PMCID:PMC3565254

  • Shah K, Rawal RM. Genetic and epigenetic modulation of drug resistance in cancer: challenges and opportunities. Curr Drug Metab. 2019; 20(14):1114-31. https://doi.org/10.2174/1389200221666200103111539 PMID:31902353

  • Corriden R, Hollands A, Olson J, et al. Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide. Nat Commun. 2015; 6:8369. https://doi.org/10.1038/ncomms9369 PMID:26458291 PMCID:PMC4610010

  • Behjati S, Frank MH. The effects of tamoxifen on immunity. Curr Med Chem. 2009; 16(24):3076-80. https://doi. org/10.2174/092986709788803042 PMID:19689284 PMCID:PMC2902982

  • Levenson AS, Wolf DM, Catherino WH, et al. Understanding the antiestrogenic actions of raloxifene and a mechanism of drug resistance to tamoxifen. Breast Cancer. 1998; 5(2):99-106. https://doi.org/10.1007/BF02966681 PMID:11091634

  • Badia E, Oliva J, Balaguer P, et al. Tamoxifen resistance and epigenetic modifications in breast cancer cell lines. Curr Med Chem. 2007; 14(28):3035-45. https://doi.org/10.2174/092986707782794023 PMID:18220739 PMCID:PMC2789301

  • Brown R, Curry E, Magnani L, et al. Poised epigenetic states and acquired drug resistance in cancer. Nat Rev Cancer. 2014; 14(11):747-53. https://doi.org/10.1038/nrc3819 PMID:25253389

  • Chang M. Tamoxifen resistance in breast cancer. Biomol Ther (Seoul). 2012; 20(3):256-67. https://doi.org/10.4062/ biomolther.2012.20.3.256 PMID:24130921 PMCID:PMC3794521

  • Jordan VC. The development of tamoxifen for breast cancer therapy: A tribute to the late Arthur L. Walpole. Breast Cancer Res Treat. 1988;11(3):197-209. https://doi.org/10.1007/BF01807278 PMID:3048447

  • Harper MJ, Walpole AL. Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature. 1966; 212(5057):87. https://doi.org/10.1038/212087a0 PMID:5965580

  • Jordan VC. Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer. Br J Pharmacol. 2006; 147(Suppl 1):S269-76. https://doi.org/10.1038/sj.bjp.0706399 PMID:16402113 PMCID:PMC1760730

  • Jordan VC. Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. European Journal of Cancer (1965). 1976; 12(6):419-24. https://doi.org/10.1016/0014-2964(76)90030-X

  • Jordan VC, Allen KE. Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA∗∗DMBA; 7,12-dimethylbenz(a)anthracene.-induced rat mammary carcinoma model. European Journal of Cancer (1965). 1980; 16(2):239-51. https://doi.org/10.1016/0014-2964(80)90156-5

  • Jordan VC. Tamoxifen as the first targeted long-term adjuvant therapy for breast cancer. Endocr Relat Cancer. 2014; 21(3):R235- 46. https://doi.org/10.1530/ERC-14-0092 PMID:24659478 PMCID:PMC4029058

  • Jordan VC. Tamoxifen: catalyst for the change to targeted therapy. Eur J Cancer. 2008; 44(1):30-8. https://doi.org/10.1016/j. ejca.2007.11.002 PMID:18068350 PMCID:PMC2566958

  • Buchanan RB, Blamey RW, Durrant KR, et al. A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer. J Clin Oncol. 1986; 4(9):1326-30. https://doi.org/10.1200/JCO.1986.4.9.1326 PMID:3528402

  • Tamoxifen for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998; 351(9114):1451-67. https://doi.org/10.1016/S0140-6736(97)11423-4

  • Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. The Lancet. 2005; 365(9472):1687-717. https://doi.org/10.1016/S0140-6736(05)66544-0 PMID:15894097

  • Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment, with illustrative cases. Trans Med Chir Soc Edinb. 1896; 15:153-79. https://doi.org/10.1016/S0140-6736(01)72384-7 PMID:29584099

  • Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med. 2014; 7:203-15. https://doi.org/10.2147/PGPM.S52762 PMID:25206307 PMCID:PMC4157397

  • Newberne JW, Kuhn WL, Elsea JR. Toxicologic studies on clomiphene. Toxicol Appl Pharmacol. 1966; 9(1):44-56. https://doi. org/10.1016/0041-008X(66)90029-9 PMID:5967566

  • Kistner RW. Induction of ovulation with clomiphene citrate (clomid). Obstet Gynecol Surv. 1965; 20(6):873-900. https://doi. org/10.1097/00006254-196512000-00001 PMID:5321936

  • Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer. 2004; 11(4):643-58. https://doi.org/10.1677/ erc.1.00776 PMID:15613444

  • Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002; 2(2):101- 12. https://doi.org/10.1038/nrc721 PMID:12635173

  • Kent Osborne C. Mechanisms for tamoxifen resistance in breast cancer: Possible role of tamoxifen metabolism. The Journal of Steroid Biochemistry and Molecular Biology. 1993; 47(1):83-9. https://doi.org/10.1016/0960-0760(93)90060-A PMID:8274445

  • Jordan VC. Fourteenth Gaddum Memorial lecture. A current view of tamoxifen for the treatment and prevention of breast cancer. Br J Pharmacol. 1993; 110(2):507-17. https://doi.org/10.1111/j.1476-5381.1993.tb13840.x PMID:8242225 PMCID:PMC2175926

  • Pollak MN, Huynh HT, Lefebvre SP. Tamoxifen reduces serum insulin-like growth factor I (IGF-I). Breast Cancer Res Treat. 1992; 22(1):91-100. https://doi.org/10.1007/BF01833337 PMID:1421427

  • Derman O, Kanbur NO, Tokur TE. The effect of tamoxifen on sex hormone binding globulin in adolescents with pubertal gynecomastia. J Pediatr Endocrinol Metab. 2004; 17(8):1115-9. https://doi.org/10.1515/JPEM.2004.17.8.1115 PMID:15379424

  • Sakai F, Cheix F, Clavel M, et al. Increases in steroid binding globulins induced by tamoxifen in patients with carcinoma of the breast. J Endocrinol. 1978; 76(2):219-26. https://doi.org/10.1677/joe.0.0760219 PMID:564384

  • Radin DP, Patel P. Delineating the molecular mechanisms of tamoxifen’s oncolytic actions in estrogen receptor-negative cancers. Eur J Pharmacol. 2016; 781:173-80. https://doi.org/10.1016/j.ejphar.2016.04.017 PMID:27083550

  • Brandt S, Kopp A, Grage B, et al. Effects of tamoxifen on transcriptional level of transforming growth factor beta (TGF-beta) isoforms 1 and 2 in tumor tissue during primary treatment of patients with breast cancer. Anticancer Res. 2003; 23(1a):223-9.

  • Skoda AM, Simovic D, Karin V, et al. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn J Basic Med Sci. 2018; 18(1):8-20. https://doi.org/10.17305/bjbms.2018.2756 PMID:29274272 PMCID:PMC5826678

  • Lee W-L, Cheng M-H, Chao H-T, et al. The role of selective estrogen receptor modulators on breast cancer: From tamoxifen to raloxifene. Taiwanese Journal of Obstetrics and Gynecology. 2008; 47(1):24-31. https://doi.org/10.1016/S1028-4559(08)60051-0 PMID:18400579

  • Taniguchi-Takizawa T, Kato N, Shimizu M, et al. Different substrate elimination rates of model drugs pH-dependently mediated by flavin-containing monooxygenases and cytochromes P450 in human liver microsomes. Drug Metab Pharmacokinet. 2021; 40:100412. https://doi.org/10.1016/j.dmpk.2021.100412 PMID:34352706

  • Cronin-Fenton DP, Damkier P, Lash TL. Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014; 10(1):107-22. https://doi.org/10.2217/fon.13.168 PMID:24328412 PMCID:PMC4319217

  • Wakeling AE, Valcaccia B, Newboult E, et al. Non-steroidal antioestrogens--receptor binding and biological response in rat uterus, rat mammary carcinoma and human breast cancer cells. J Steroid Biochem. 1984; 20(1):111-20. https://doi.org/10.1016/0022- 4731(84)90197-3 PMID:6538611

  • Colletta AA, Benson JR, Baum M. Alternative mechanisms of action of anti-oestrogens. Breast Cancer Res Treat. 1994; 31(1):5-9. https://doi.org/10.1007/BF00689672 PMID:7981456

  • Schafer JM, Liu H, Bentrem DJ, et al. Allosteric silencing of activating function 1 in the 4-hydroxytamoxifen estrogen receptor complex is induced by substituting glycine for aspartate at amino acid 3511. Cancer Research. 2000; 60(18):5097-105.

  • Butta A, MacLennan K, Flanders KC, et al. Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res. 1992; 52(15):4261-4.

  • Ho GH, Ji CY, Phang BH, et al. Tamoxifen alters levels of serum insulin-like growth factors and binding proteins in postmenopausal breast cancer patients: a prospective paired cohort study. Ann Surg Oncol. 1998; 5(4):361-7. https://doi.org/10.1007/BF02303501 PMID:9641459

  • Cullen KJ, Lippman ME, Chow D, et al. Insulin-like growth factor-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression. Mol Endocrinol. 1992; 6(1):91-100. https://doi.org/10.1210/mend.6.1.1310798 PMID:1310798

  • Haran EF, Maretzek AF, Goldberg I, et al. Tamoxifen enhances cell death in implanted MCF7 breast cancer by inhibiting endothelium growth. Cancer Res. 1994; 54(21):5511-4.

  • Anzai Y, Holinka CF, Kuramoto H, et al. Stimulatory effects of 4-hydroxytamoxifen on proliferation of human endometrial adenocarcinoma cells (Ishikawa line). Cancer Res. 1989; 49(9):2362-5.

  • Condorelli R, Vaz-Luis I. Managing side effects in adjuvant endocrine therapy for breast cancer. Expert Rev Anticancer Ther. 2018; 18(11):1101-12. https://doi.org/10.1080/14737140.2018.1520096 PMID:30188738

  • Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011; 62:233-47. https://doi. org/10.1146/annurev-med-070909-182917 PMID:20887199 PMCID:PMC3656649

  • Fullwood MJ, Liu MH, Pan YF, et al. An oestrogen-receptor-alpha-bound human chromatin interactome. Nature. 2009; 462(7269):58-64. https://doi.org/10.1038/nature08497 PMID:19890323 PMCID:PMC2774924

  • Carroll JS, Liu XS, Brodsky AS, et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell. 2005; 122(1):33-43. https://doi.org/10.1016/j.cell.2005.05.008 PMID:16009131

  • Thomas C, Gustafsson JA. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer. 2011; 11(8):597-608. https://doi.org/10.1038/nrc3093 PMID:21779010

  • Hartman J, Lindberg K, Morani A, et al. Estrogen receptor beta inhibits angiogenesis and growth of T47D breast cancer xenografts. Cancer Res. 2006; 66(23):11207-13. https://doi.org/10.1158/0008-5472.CAN-06-0017 PMID:17145865

  • Strom A, Hartman J, Foster JS, et al. Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proc Natl Acad Sci U S A. 2004; 101(6):1566-71. https://doi.org/10.1073/pnas.0308319100 PMID:14745018 PMCID:PMC341775

  • Speirs V, Malone C, Walton DS, et al. Increased expression of estrogen receptor beta mRNA in tamoxifen-resistant breast cancer patients. Cancer Res. 1999; 59(21):5421-4.

  • Speirs V, Parkes AT, Kerin MJ, et al. Coexpression of estrogen receptor alpha and beta: Poor prognostic factors in human breast cancer? Cancer Res. 1999; 59(3):525-8.

  • Taylor SE, Martin-Hirsch PL, Martin FL. Oestrogen receptor splice variants in the pathogenesis of disease. Cancer Lett. 2010; 288(2):133-48. https://doi.org/10.1016/j.canlet.2009.06.017 PMID:19608332

  • Yan Y, Yu L, Castro L, et al. ERalpha36, a variant of estrogen receptor alpha, is predominantly localized in mitochondria of human uterine smooth muscle and leiomyoma cells. PLoS One. 2017; 12(10):e0186078. https://doi.org/10.1371/journal.pone.0186078 PMID:29020039 PMCID:PMC5636123

  • Ohe K, Miyajima S, Abe I, et al. HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells. J Steroid Biochem Mol Biol. 2018; 182:21-6. https://doi.org/10.1016/j.jsbmb.2018.04.007 PMID:29678492

  • Shaaban AM, Green AR, Karthik S, et al. Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients. Clin Cancer Res. 2008; 14(16):5228-35. https://doi.org/10.1158/1078- 0432.CCR-07-4528 PMID:18698041

  • Madeira M, Mattar A, Logullo AF, et al. Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness-a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer. BMC Cancer. 2013; 13:425. https://doi.org/10.1186/1471-2407-13-425 PMID:24047421 PMCID:PMC3851532

  • Guillette TC, Jackson TW, Belcher SM. Duality of estrogen receptor beta action in cancer progression. Curr Opin Pharmacol. 2018; 41:66-73. https://doi.org/10.1016/j.coph.2018.05.001 PMID:29772419 PMCID:PMC8008732

  • Kelly MJ, Levin ER. Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab. 2001; 12(4):152-6. https:// doi.org/10.1016/S1043-2760(01)00377-0 PMID:11295570

  • Levin ER, Pietras RJ. Estrogen receptors outside the nucleus in breast cancer. Breast Cancer Res Treat. 2008; 108(3):351-61. https://doi.org/10.1007/s10549-007-9618-4 PMID:17592774

  • Fan P, Wang J, Santen RJ, et al. Long-term treatment with tamoxifen facilitates translocation of estrogen receptor alpha out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. Cancer Res. 2007; 67(3):1352-60. https://doi. org/10.1158/0008-5472.CAN-06-1020 PMID:17283173

  • Tonetti DA, Jordan VC. The role of estrogen receptor mutations in tamoxifen-stimulated breast cancer. J Steroid Biochem Mol Biol. 1997; 62(2-3):119-28. https://doi.org/10.1016/S0960-0760(97)00034-4 PMID:9393947

  • Alluri PG, Speers C, Chinnaiyan AM. Estrogen receptor mutations and their role in breast cancer progression. Breast Cancer Res. 2014; 16(6):494. https://doi.org/10.1186/s13058-014-0494-7 PMID:25928204 PMCID:PMC4429420

  • Clusan L, Le Goff P, Flouriot G, et al. A Closer Look at Estrogen receptor mutations in breast cancer and their implications for estrogen and antiestrogen responses. Int J Mol Sci. 2021; 22(2). https://doi.org/10.3390/ijms22020756 PMID:33451133 PMCID:PMC7828590

  • Altwegg KA, Vadlamudi RK. Role of estrogen receptor coregulators in endocrine resistant breast cancer. Explor Target Antitumor Ther. 2021; 2:385-400. https://doi.org/10.37349/etat.2021.00052 PMID:34528025 PMCID:PMC8439438

  • Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998; 95(7):927-37. https://doi.org/10.1016/S0092-8674(00)81717-1 PMID:9875847

  • Haque MM, Desai KV. Pathways to endocrine therapy resistance in breast cancer. Front Endocrinol (Lausanne). 2019; 10:573. https://doi.org/10.3389/fendo.2019.00573 PMID:31496995 PMCID:PMC6712962

  • Weiner M, Skoog L, Fornander T, et al. Oestrogen receptor co-activator AIB1 is a marker of tamoxifen benefit in postmenopausal breast cancer. Ann Oncol. 2013; 24(8):1994-9. https://doi.org/10.1093/annonc/mdt159 PMID:23670096 PMCID:PMC3718507

  • Lavinsky RM, Jepsen K, Heinzel T, et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci U S A. 1998; 95(6):2920-5. https://doi.org/10.1073/pnas.95.6.2920 PMID:9501191 PMCID:PMC19670

  • Ranganathan P, Nadig N, Nambiar S. Non-canonical estrogen signaling in endocrine resistance. Frontiers in Endocrinology. 2019; 10. https://doi.org/10.3389/fendo.2019.00708 PMID:31749762 PMCID:PMC6843063

  • Schiff R, Reddy P, Ahotupa M, et al. Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo. J Natl Cancer Inst. 2000; 92(23):1926-34. https://doi.org/10.1093/jnci/92.23.1926 PMID:11106684

  • Johnston SR, Lu B, Scott GK, et al. Increased activator protein-1 DNA binding and c-Jun NH2-terminal kinase activity in human breast tumors with acquired tamoxifen resistance. Clin Cancer Res. 1999; 5(2):251-6.

  • Jeselsohn R, Cornwell M, Pun M, et al. Embryonic transcription factor SOX9 drives breast cancer endocrine resistance. Proc Natl Acad Sci U S A. 2017; 114(22):E4482-E91. https://doi.org/10.1073/pnas.1620993114 PMID:28507152 PMCID:PMC5465894

  • Hurtado A, Holmes KA, Ross-Innes CS, et al. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet. 2011; 43(1):27-33. https://doi.org/10.1038/ng.730 PMID:21151129 PMCID:PMC3024537

  • Robinson JL, Carroll JS. FoxA1 is a key mediator of hormonal response in breast and prostate cancer. Front Endocrinol (Lausanne). 2012; 3:68. https://doi.org/10.3389/fendo.2012.00068 PMID:22649425 PMCID:PMC3355944

  • Magnani L, Stoeck A, Zhang X, et al. Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer. Proc Natl Acad Sci U S A. 2013; 110(16):E1490-9. https://doi.org/10.1073/pnas.1219992110 PMID:23576735 PMCID:PMC3631697

  • Yun J, Pannuti A, Espinoza I, et al. Crosstalk between PKCalpha and Notch-4 in endocrine-resistant breast cancer cells. Oncogenesis. 2013; 2:e60. https://doi.org/10.1038/oncsis.2013.26 PMID:23917222 PMCID:PMC3759125

  • Kalyanaraman A, Gnanasampanthapandian D, Shanmughan P, et al. Tamoxifen induces stem-like phenotypes and multidrug resistance by altering epigenetic regulators in ERalpha+ breast cancer cells. Stem Cell Investig. 2020; 7:20. https://doi. org/10.21037/sci-2020-020 PMID:33294429 PMCID:PMC7715663

  • Nicholson RI, Hutcheson IR, Jones HE, et al. Growth factor signalling in endocrine and anti-growth factor resistant breast cancer. Rev Endocr Metab Disord. 2007; 8(3):241-53. https://doi.org/10.1007/s11154-007-9033-5 PMID:17486454

  • Knowlden JM, Hutcheson IR, Barrow D, et al. Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor. Endocrinology. 2005; 146(11):4609-18. https://doi.org/10.1210/ en.2005-0247 PMID:16037379

  • Giuliano M, Trivedi MV, Schiff R. Bidirectional Crosstalk between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 Signaling Pathways in Breast Cancer: Molecular Basis and Clinical Implications. Breast Care (Basel). 2013; 8(4):256- 62. https://doi.org/10.1159/000354253 PMID:24415978 PMCID:PMC3808214

  • Hasson SP, Rubinek T, Ryvo L, et al. Endocrine resistance in breast cancer: focus on the phosphatidylinositol 3-kinase/akt/ mammalian target of rapamycin signaling pathway. Breast Care (Basel). 2013; 8(4):248-55. https://doi.org/10.1159/000354757 PMID:24415977 PMCID:PMC3808218

  • Benz CC, Scott GK, Sarup JC, et al. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat. 1992; 24(2):85-95. https://doi.org/10.1007/BF01961241 PMID:8095168

  • Chung YL, Sheu ML, Yang SC, et al. Resistance to tamoxifen-induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer. Int J Cancer. 2002; 97(3):306-12. https://doi.org/10.1002/ ijc.1614 PMID:11774281

  • He H, Sinha I, Fan R, et al. c-Jun/AP-1 overexpression reprograms ERalpha signaling related to tamoxifen response in ERalphapositive breast cancer. Oncogene. 2018;37(19):2586-600. https://doi.org/10.1038/s41388-018-0165-8 PMID:29467493

  • Sasser AK, Sullivan NJ, Studebaker AW, et al. Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer. FASEB J. 2007; 21(13):3763-70. https://doi.org/10.1096/fj.07-8832com PMID:17586727

  • Gottardis MM, Ricchio ME, Satyaswaroop PG, et al. Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. Cancer Res. 1990; 50(11):3189-92.

  • Han XL, Liehr JG. Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res. 1992; 52(5):1360-3.

  • Arpino G, Green SJ, Allred DC, et al. HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptorpositive metastatic breast cancer: A southwest oncology group study. Clin Cancer Res. 2004; 10(17):5670-6. https://doi. org/10.1158/1078-0432.CCR-04-0110 PMID:15355892

  • Gee JM, Robertson JF, Gutteridge E, et al. Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer. Endocr Relat Cancer. 2005; 12 Suppl 1:S99-S111. https://doi.org/10.1677/ erc.1.01005 PMID:16113104

  • Dowsett M, Johnston S, Martin LA, et al. Growth factor signalling and response to endocrine therapy: the Royal Marsden Experience. Endocr Relat Cancer. 2005; 12 Suppl 1:S113-7. https://doi.org/10.1677/erc.1.01044 PMID:16113087

  • Gutierrez MC, Detre S, Johnston S, et al. Molecular changes in tamoxifen-resistant breast cancer: Relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol. 2005; 23(11):2469-76. https://doi.org/10.1200/ JCO.2005.01.172 PMID:15753463

  • Kirkegaard T, Witton CJ, McGlynn LM, et al. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol. 2005; 207(2):139-46. https://doi.org/10.1002/path.1829 PMID:16088978

  • Fex G, Adielsson G, Mattson W. Oestrogen-like effects of tamoxifen on the concentration of proteins in plasma. Acta Endocrinol (Copenh). 1981; 97(1):109-13. https://doi.org/10.1530/acta.0.0970109 PMID:6784425

  • Jordan VC, Fritz NF, Tormey DC. Endocrine effects of adjuvant chemotherapy and long-term tamoxifen administration on node-positive patients with breast cancer. Cancer Res. 1987; 47(2):624-30.

  • Ferrazzi E, Cartei G, Mattarazzo R, et al. Oestrogen-like effect of tamoxifen on vaginal epithelium. Br Med J. 1977; 1(6072):1351- 2. https://doi.org/10.1136/bmj.1.6072.1351-e PMID:861624 PMCID:PMC1607200

  • Murphy LC, Sutherland RL. A high-affinity binding site for the antioestrogens, tamoxifen and CI 628, in immature rat uterine cytosol which is distinct from the oestrogen receptor. J Endocrinol. 1981; 91(1):155-61. https://doi.org/10.1677/joe.0.0910155 PMID:7028904

  • Sudo K, Monsma FJ, Jr., Katzenellenbogen BS. Antiestrogen-binding sites distinct from the estrogen receptor: Subecellular localization, ligand specificity, and distribution in tissues of the rat. Endocrinology. 1983; 112(2):425-34. https://doi.org/10.1210/ endo-112-2-425 PMID:6848356

  • Miller MA, Katzenellenbogen BS. Characterization and quantitation of antiestrogen binding sites in estrogen receptor-positive and -negative human breast cancer cell lines. Cancer Res. 1983; 43(7):3094-100.

  • Katzenellenbogen BS, Miller MA, Mullick A, et al. Antiestrogen action in breast cancer cells: modulation of proliferation and protein synthesis, and interaction with estrogen receptors and additional antiestrogen binding sites. Breast Cancer Res Treat. 1985; 5(3):231-43. https://doi.org/10.1007/BF01806018 PMID:4027393

  • O’Brian CA, Liskamp RM, Solomon DH, et al. Inhibition of protein kinase C by tamoxifen. Cancer Res. 1985; 45(6):2462-5.

  • Lam HY. Tamoxifen is a calmodulin antagonist in the activation of cAMP phosphodiesterase. Biochem Biophys Res Commun. 1984; 118(1):27-32. https://doi.org/10.1016/0006-291X(84)91062-3 PMID:6320825

  • Brandes LJ, Macdonald LM, Bogdanovic RP. Evidence that the antiestrogen binding site is a histamine or histamine-like receptor. Biochem Biophys Res Commun. 1985; 126(2):905-10. https://doi.org/10.1016/0006-291X(85)90271-2 PMID:2858205

  • Hiemke C, Ghraf R. Interaction of non-steroidal antiestrogens with dopamine receptor binding. J Steroid Biochem. 1984; 21(6):663-7. https://doi.org/10.1016/0022-4731(84)90028-1 PMID:6098784

  • Ben-Baruch G, Schreiber G, Sokolovsky M. Cooperativity pattern in the interaction of the antiestrogen drug clomiphene with the Muscarinic receptors. Mol Pharmacol. 1982; 21(2):287-93.

  • Saji S, Hirose M, Toi M. Clinical significance of estrogen receptor beta in breast cancer. Cancer Chemother Pharmacol. 2005; 56 Suppl 1:21-6. https://doi.org/10.1007/s00280-005-0107-3 PMID:16273360

  • Murphy LC, Watson PH. Is oestrogen receptor-beta a predictor of endocrine therapy responsiveness in human breast cancer? Endocr Relat Cancer. 2006; 13(2):327-34. https://doi.org/10.1677/erc.1.01141 PMID:16728566

  • Matthews J, Wihlen B, Tujague M, et al. Estrogen Receptor (ER) beta modulates ERalpha-mediated transcriptional activation by altering the recruitment of c-Fos and c-Jun to estrogen-responsive promoters. Mol Endocrinol. 2006; 20(3):534-43. https://doi. org/10.1210/me.2005-0140 PMID:16293641

  • Stossi F, Barnett DH, Frasor J, et al. Transcriptional profiling of estrogen-regulated gene expression via Estrogen Receptor (ER) alpha or ERbeta in human osteosarcoma cells: distinct and common target genes for these receptors. Endocrinology. 2004; 145(7):3473-86. https://doi.org/10.1210/en.2003-1682 PMID:15033914

  • Chang EC, Frasor J, Komm B, et al. Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells. Endocrinology. 2006; 147(10):4831-42. https://doi.org/10.1210/en.2006-0563 PMID:16809442

  • Wang X, Zhang H, Chen X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2019; 2:141-60. https://doi.org/10.20517/cdr.2019.10 PMID:34322663 PMCID:PMC8315569

  • Vaidya FU, Sufiyan Chhipa A, Mishra V, et al. Molecular and cellular paradigms of multidrug resistance in cancer. Cancer Rep (Hoboken). 2020 :e1291. https://doi.org/10.1002/cnr2.1291 PMID:33052041 PMCID:PMC9780431

  • Bekele RT, Venkatraman G, Liu RZ, et al. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: Implications for tamoxifen therapy and resistance. Sci Rep. 2016; 6:21164. https://doi.org/10.1038/srep21164 PMID:26883574 PMCID:PMC4756695

  • Mansoori B, Mohammadi A, Davudian S, et al. The Different Mechanisms of Cancer Drug Resistance: A Brief Review. Adv Pharm Bull. 2017; 7(3):339-48. https://doi.org/10.15171/apb.2017.041 PMID:29071215 PMCID:PMC5651054

  • Bekele RT, Venkatraman G, Liu RZ, I. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: Implications for tamoxifen therapy and resistance. Sci Rep. 2016; 6:21164. https://doi.org/10.1038/srep21164 PMID:26883574 PMCID:PMC4756695

  • Liu Y, Li Q, Zhou L, et al. Cancer drug resistance: redox resetting renders a way. Oncotarget. 2016; 7(27):42740-61. https://doi. org/10.18632/oncotarget.8600 PMID:27057637 PMCID:PMC5173169

  • Choi HK, Yang JW, Roh SH, et al. Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells. Endocr Relat Cancer. 2007; 14(2):293-303. https://doi.org/10.1677/ERC-06-0016 PMID:17639045

  • Kathawala RJ, Gupta P, Ashby CR, Jr., et al. The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade. Drug Resist Updat. 2015; 18:1-17. https://doi.org/10.1016/j.drup.2014.11.002 PMID:25554624

  • Wilkens S. Structure and mechanism of ABC transporters. F1000Prime Rep. 2015; 7:14. https://doi.org/10.12703/P7-14 PMID:25750732 PMCID:PMC4338842

  • Dean M, Rzhetsky A, Allikmets R. The human ATP-Binding Cassette (ABC) transporter superfamily. Genome Res. 2001; 11(7):1156-66. https://doi.org/10.1101/gr.184901 PMID:11435397

  • Theile D, Wizgall P. Acquired ABC-transporter overexpression in cancer cells: transcriptional induction or Darwinian selection? Naunyn Schmiedebergs Arch Pharmacol. 2021; 394(8):1621-32. https://doi.org/10.1007/s00210-021-02112-3 PMID:34236499 PMCID:PMC8298356

  • Xue X, Liang XJ. Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology. Chin J Cancer. 2012; 31(2):100-9. https://doi.org/10.5732/cjc.011.10326 PMID:22237039 PMCID:PMC3777470

  • Lu JF, Pokharel D, Bebawy M. MRP1 and its role in anticancer drug resistance. Drug Metab Rev. 2015; 47(4):406-19. https://doi. org/10.3109/03602532.2015.1105253 PMID:26541366

  • The UniProt C. UniProt: The universal protein knowledgebase. Nucleic Acids Res. 2017; 45(D1):D158-D69. https://doi. org/10.1093/nar/gkw1099 PMID:27899622 PMCID:PMC5210571

  • Liu W, Xie Y, Ma J, et al. IBS: An illustrator for the presentation and visualization of biological sequences. Bioinformatics. 2015; 31(20):3359-61. https://doi.org/10.1093/bioinformatics/btv362 PMID:26069263 PMCID:PMC4595897

  • Wang X, Li Y, Qian Y, et al. Extracellular ATP, as an energy and phosphorylating molecule, induces different types of drug resistances in cancer cells through ATP internalization and intracellular ATP level increase. Oncotarget. 2017; 8(50):87860-77. https://doi.org/10.18632/oncotarget.21231 PMID:29152126 PMCID:PMC5675678

  • Schneider V, Krieger ML, Bendas G, et al. Contribution of intracellular ATP to cisplatin resistance of tumor cells. J Biol Inorg Chem. 2013; 18(2):165-74. https://doi.org/10.1007/s00775-012-0960-6 PMID:23183891

  • Qian Y, Wang X, Liu Y, et al. Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells. Cancer Lett. 2014; 351(2):242-51. https://doi.org/10.1016/j.canlet.2014.06.008 PMID:24973521

  • Yin Y, Li W, Deng M, et al. Extracellular high mobility group box chromosomal protein 1 promotes drug resistance by increasing the expression of Pglycoprotein expression in gastric adenocarcinoma cells. Mol Med Rep. 2014; 9(4):1439-43. https://doi. org/10.3892/mmr.2014.1961 PMID:24549588

  • Callaghan R, Higgins CF. Interaction of tamoxifen with the multidrug resistance P-glycoprotein. Br J Cancer. 1995; 71(2):294-9. https://doi.org/10.1038/bjc.1995.59 PMID:7841043 PMCID:PMC2033580

  • Wilting RH, Dannenberg JH. Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resist Updat. 2012; 15(1-2):21-38. https://doi.org/10.1016/j.drup.2012.01.008 PMID:22356866

  • Berdasco M, Esteller M. Clinical epigenetics: Seizing opportunities for translation. Nat Rev Genet. 2019; 20(2):109-27. https:// doi.org/10.1038/s41576-018-0074-2 PMID:30479381

  • Garcia-Martinez L, Zhang Y, Nakata Y, et al. Epigenetic mechanisms in breast cancer therapy and resistance. Nat Commun. 2021; 12(1):1786. https://doi.org/10.1038/s41467-021-22024-3 PMID:33741974 PMCID:PMC7979820

  • Zeller C, Brown R. Therapeutic modulation of epigenetic drivers of drug resistance in ovarian cancer. Ther Adv Med Oncol. 2010; 2(5):319-29. https://doi.org/10.1177/1758834010375759 PMID:21789144 PMCID:PMC3126026

  • Glasspool RM, Teodoridis JM, Brown R. Epigenetics as a mechanism driving polygenic clinical drug resistance. Br J Cancer. 2006; 94(8):1087-92. https://doi.org/10.1038/sj.bjc.6603024 PMID:16495912 PMCID:PMC2361257

  • Teodoridis JM, Strathdee G, Brown R. Epigenetic silencing mediated by CpG island methylation: potential as a therapeutic target and as a biomarker. Drug Resist Updat. 2004; 7(4-5):267-78. https://doi.org/10.1016/j.drup.2004.06.005 PMID:15533764

  • Martin HL, Smith L, Tomlinson DC. Multidrug-resistant breast cancer: current perspectives. Breast Cancer (Dove Med Press). 2014; 6:1-13. https://doi.org/10.2147/BCTT.S37638 PMID:24648765 PMCID:PMC3929252

  • Watanabe T, Oba T, Tanimoto K, et al. Tamoxifen resistance alters sensitivity to 5-fluorouracil in a subset of estrogen receptorpositive breast cancer. PLoS One. 2021; 16(6):e0252822. https://doi.org/10.1371/journal.pone.0252822 PMID:34101751 PMCID:PMC8186817

  • Behbahani GD, Khani S, Hosseini HM, et al. The role of exosomes contents on genetic and epigenetic alterations of recipient cancer cells. Iran J Basic Med Sci. 2016; 19(10):1031-9.

  • Qian Z, Shen Q, Yang X, et al. The role of extracellular vesicles: An epigenetic view of the cancer microenvironment. Biomed Res Int. 2015; 2015:649161. https://doi.org/10.1155/2015/649161 PMID:26582468 PMCID:PMC4637039

  • Guo QR, Wang H, Yan YD, et al. The role of exosomal microRNA in cancer drug resistance. Front Oncol. 2020;10:472. https:// doi.org/10.3389/fonc.2020.00472 PMID:32318350 PMCID:PMC7154138

  • Johnson AB, O’Malley BW. Steroid receptor coactivators 1, 2, and 3: Critical regulators of nuclear receptor activity and Steroid Receptor Modulator (SRM)-based cancer therapy. Mol Cell Endocrinol. 2012; 348(2):430-9. https://doi.org/10.1016/j. mce.2011.04.021 PMID:21664237 PMCID:PMC3202666

  • Murakami S, Nagari A, Kraus WL. Dynamic assembly and activation of estrogen receptor alpha enhancers through coregulator switching. Genes Dev. 2017; 31(15):1535-48. https://doi.org/10.1101/gad.302182.117 PMID:28887413 PMCID:PMC5630019

  • Yi P, Wang Z, Feng Q, et al. Structure of a biologically active estrogen receptor-coactivator complex on DNA. Mol Cell. 2015; 57(6):1047-58. https://doi.org/10.1016/j.molcel.2015.01.025 PMID:25728767 PMCID:PMC4369429

  • Li W, Notani D, Ma Q, et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature. 2013; 498(7455):516-20. https://doi.org/10.1038/nature12210 PMID:23728302 PMCID:PMC3718886

  • Fan S, Wang J, Yuan R, et al. BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science. 1999; 284(5418):1354- 6. https://doi.org/10.1126/science.284.5418.1354 PMID:10334989

  • Jozwik KM, Carroll JS. Pioneer factors in hormone-dependent cancers. Nat Rev Cancer. 2012; 12(6):381-5. https://doi. org/10.1038/nrc3263 PMID:22555282

  • He J, Feng C, Zhu H, et al. Grainyhead-like 2 as a double-edged sword in development and cancer. Am J Transl Res. 2020; 12(2):310-31.

  • Chi D, Singhal H, Li L, et al. Estrogen receptor signaling is reprogrammed during breast tumorigenesis. Proc Natl Acad Sci U S A. 2019; 116(23):11437-43. https://doi.org/10.1073/pnas.1819155116 PMID:31110002 PMCID:PMC6561257

  • Zhou W, Slingerland JM. Links between oestrogen receptor activation and proteolysis: Relevance to hormone-regulated cancer therapy. Nat Rev Cancer. 2014; 14(1):26-38. https://doi.org/10.1038/nrc3622 PMID:24505618

  • Teyssier C, Le Romancer M, Sentis S, et al. Protein arginine methylation in estrogen signaling and estrogen-related cancers. Trends Endocrinol Metab. 2010; 21(3):181-9. https://doi.org/10.1016/j.tem.2009.11.002 PMID:20005732

  • Manavathi B, Samanthapudi VS, Gajulapalli VN. Estrogen receptor coregulators and pioneer factors: The orchestrators of mammary gland cell fate and development. Front Cell Dev Biol. 2014; 2:34. https://doi.org/10.3389/fcell.2014.00034 PMID:25364741 PMCID:PMC4207046

  • Holding AN, Giorgi FM, Donnelly A, et al. Correction to: VULCAN integrates ChIP-seq with patient-derived co-expression networks to identify GRHL2 as a key co-regulator of ERa at enhancers in breast cancer. Genome Biol. 2019; 20(1):122. https:// doi.org/10.1186/s13059-019-1733-0 PMID:31200751 PMCID:PMC6567503

  • Chan HL, Morey L. Emerging Roles for Polycomb-Group Proteins in Stem Cells and Cancer. Trends Biochem Sci. 2019; 44(8):688-700. https://doi.org/10.1016/j.tibs.2019.04.005 PMID:31085088

  • Shi B, Liang J, Yang X, et al. Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol. 2007; 27(14):5105-19. https://doi.org/10.1128/MCB.00162-07 PMID:17502350 PMCID:PMC1951944

  • Lee JY, Won HY, Park JH, et al. MEL-18 loss mediates estrogen receptor-alpha downregulation and hormone independence. J Clin Invest. 2015; 125(5):1801-14. https://doi.org/10.1172/JCI73743 PMID:25822021 PMCID:PMC4463188


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  • Epigenetic Regulation of Tamoxifen-Resistant Breast Cancer: An Update

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Authors

Dibyashree Chhetri
Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur - 603203, Chengalpattu, India
Dhanavathy Gnanasampanthapandian
Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur - 603203, Chengalpattu, India
Kanagaraj Palaniyandi
Cancer Science Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur - 603203, Chengalpattu, India

Abstract


Breast cancer is the most common cause of death in women around the world. Epigenetic changes modulate transcriptional activity in several diseases, including cancer. Cancer epigenetics explains gene expression changes without DNA mutations. Aberrant DNA methylation, histone modifications, and mRNA expression promote tumоr growth and metastasis. In cancer cells, chemo-resistance occurs via Multidrug Resistance (MDR), apoptotic suppression, DNA damage response, epigenetic alterations, and competitive endogenous RNA. Owing to drug resistance, quiescence, and varied cancer cell production, Cancer Stem Cells (CSCs) are critical to tumоr formation, metastasis, and recurrence after therapy. In addition, MDR promotes drug efflux, enhanced secretion of growth factors, and DNA modifications in cancer patients, thereby causing fatalities in cancer patients. Heterogeneity and epigenetic plasticity cause drug resistance due to various factors. However, the molecular mechanism of epigenetic drug resistance is still unravelled completely. Overexpressed c-MYC leads to cancer and tamoxifen resistance. Despite the molecular underpinning of cancer development, drug resistance is continued in a myriad number of cases. Epigenetic changes affect CSCs viability and tumоr aggressiveness. These processes can be blocked by medicines. Tamoxifen is used widely for breast cancer treatment; however, latent treatments have emerged as a tamoxifen-resistant phenotype. Epigenetic modifications cause resistance by upregulating and altering the tumоr microenvironment and deregulating the immune response. The knowledge of epigenetic pathways in clinical treatment resistance may enhance the outcome of cancer patients. Multifactorial heterogeneous resistance is common in many targeted therapies. Many resistance mechanisms to targeted therapy may converge, including route reactivation. This review summarizes the epigenetic alterations, MDR, and development of tamoxifen resistance in breast cancer.

Keywords


Breast Cancer, Cancer Epigenetics, Cancer Stem Cells, Multidrug Resistance, Tamoxifen Resistance.

References





DOI: https://doi.org/10.18519/jer%2F2022%2Fv26%2F222220