表观遗传修饰-他莫昔芬耐药机制研究的新方向

中国临床药理学与治疗学 ›› 2015, Vol. 20 ›› Issue (4): 460-465.

表观遗传修饰-他莫昔芬耐药机制研究的新方向

娄晓亚¹, 孙红^1,2, 周宏灏¹

¹中南大学临床药理研究所,中南大学湘雅医学院临床药理研究所,遗传药理湖南省重点实验室,长沙 410078,湖南;
²福建医科大学省立临床学院,福州 350001,福建

收稿日期:2014-11-22 修回日期:2015-04-01 发布日期:2015-05-07
通讯作者: 周宏灏,男,中国工程院院士,博士生导师,研究方向:临床药理和遗传药理学。Tel: 0731-84805380 E-mail: hhzhou2003@163.com
作者简介:娄晓亚,女,博士,研究方向:临床药理和遗传药理学。Tel: 0731-84805380 E-mail: 23296306@qq.com
基金资助:
国家自然科学基金(81403021);福建省自然科学基金(2013J01364)

Epigenetic modulation——A novel therapeutic strategy for tamoxifen resistance

LOU Xiao-ya¹, SUN Hong^1,2, ZHOU Hong-hao¹

¹ Institute of Clinical Pharmacology, Xiangya Hospital, Central South University and Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, Hunan, China;
² Department of Pharmacy, Provincial Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, Fujian, China

Received:2014-11-22 Revised:2015-04-01 Published:2015-05-07

摘要/Abstract

摘要： 他莫昔芬(tamoxifen,TAM)为人工合成的非甾体类抗雌激素药物,被广泛用于雌激素受体(estrogen receptor,ER)阳性的乳腺癌患者的治疗。但是仍有约40%的ER阳性乳腺癌患者对TAM产生继发性耐药。目前对TAM耐药机制研究众多,而表观遗传学是最新的研究方向。在本综述中,我们将从表观遗传调控方面阐述当前对TAM耐药机制研究的新进展,以便更好地了解TAM耐药,并为乳腺癌治疗提供新的策略。

关键词: 乳腺癌, 他莫昔芬耐药, 表观遗传修饰, DNA甲基化, 转录沉默

Abstract: Tamoxifen (TAM) is a synthetic non-steroid anti-estrogen drug, which is widely used to treat estrogen receptor (ER) positive breast cancer patients. However, about 40% ER positive patients develop acquired-resistance of TAM. Epigenetics is a totally new research direction. In this review, we will focus on the current progress of epigenetic regulation of mechanisms underlying TAM resistance, in order to get a better understand of TAM resistance and provide a new strategy for breast cancer therapy.

Key words: breast cancer, tamoxifen resistance, epigenetic modulation, DNA methylation, transcriptional silencing

中图分类号:

R968

娄晓亚, 孙红, 周宏灏. 表观遗传修饰-他莫昔芬耐药机制研究的新方向[J]. 中国临床药理学与治疗学, 2015, 20(4): 460-465.

LOU Xiao-ya, SUN Hong, ZHOU Hong-hao. Epigenetic modulation——A novel therapeutic strategy for tamoxifen resistance[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(4): 460-465.

参考文献

[1] Dai M, Ren JS, Li N,et al. Estimation and prediction on cancer related incidence and mortality in China, 2008[J]. Zhonghua Liu Xing Bing Xue Za Zhi, 2012, 33: 57-61.
[2] Chen WY, Hankinson SE, Schnitt SJ, et al. Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma[J]. Cancer, 2004, 101: 1490-1500.
[3] Osborne CK, Boldt DH, Clark GM, et al. Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase[J]. Cancer Res,1983, 43: 3583-3585.
[4] Ring A, Dowsett M. Mechanisms of tamoxifen resistance[J]. Endocr Relat Cancer, 2004, 11: 643-58.
[5] Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer[J]. Nat Rev Cancer, 2009, 9: 631-643.
[6] Chang HG, Kim SJ, Chung KW, et al. Tamoxifen-resistant breast cancers show less frequent methylation of the estrogen receptor beta but not the estrogen receptor alpha gene[J]. J Mol Med (Berl), 2005, 83: 132-139.
[7] Osborne CK. Tamoxifen in the treatment of breast cancer[J]. N Engl J Med, 1998, 339: 1609-1618.
[8] Johnston SR, Saccani-Jotti G, Smith IE, et al. Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer[J]. Cancer Res, 1995, 55: 3331-3338.
[9] Ring A, Dowsett M. Mechanisms of tamoxifen resistance[J]. Endocr Relat Cancer, 2004, 11: 643-658.
[10]Pettersson K, Delaunay F, Gustafsson JA. Estrogen receptor beta acts as a dominant regulator of estrogen signaling[J]. Oncogene, 2000, 19: 4970-4978.
[11]Murphy LC, Watson PH. Is oestrogen receptor-beta a predictor of endocrine therapy responsiveness in human breast cancer[J]. Endocr Relat Cancer, 2006, 13: 327-334.
[12]Paech K, Webb P, Kuiper GG, et al. Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites[J]. Science, 1997, 277: 1508-1510.
[13]Nair HB, Kirma NB, Ganapathy M, et al. Estrogen receptor-beta activation in combination with letrozole blocks the growth of breast cancer tumors resistant to letrozole therapy[J]. Steroids, 2011, 76: 792-796.
[14]Speirs V, Malone C, Walton DS, et al. Increased expression of estrogen receptor beta mRNA in tamoxifen-resistant breast cancer patients[J]. Cancer Res, 1999, 59(21): 5421-5424.
[15]Klinge CM, Riggs KA, Wickramasinghe NS, et al. Estrogen receptor alpha 46 is reduced in tamoxifen resistant breast cancer cells and re-expression inhibits cell proliferation and estrogen receptor alpha 66-regulated target gene transcription[J]. Mol Cell Endocrinol, 2010, 323: 268-276.
[16]Shi L, Dong B, Li Z, et al. Expression of ER-{alpha}36, a novel variant of estrogen receptor {alpha}, and resistance to tamoxifen treatment in breast cancer[J]. J Clin Oncol, 2009, 27: 3423-3429.
[17]Luco RF, Allo M, Schor IE, et al. Epigenetics in alternative pre-mRNA splicing[J]. Cell, 2011, 144: 16-26.
[18]Zhou Y, Yau C, Gray JW, et al. Enhanced NF kappa B and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer[J]. BMC Cancer, 2007, 7: 59-64.
[19]Fleming FJ, Myers E, Kelly G, et al. Expression of SRC-1, AIB1, and PEA3 in HER2 mediated endocrine resistant breast cancer; a predictive role for SRC-1[J]. J Clin Pathol, 2004, 57: 1069-1074.
[20]Mann M, Cortez V, Vadlamudi RK. Epigenetics of estrogen receptor signaling: role in hormonal cancer progression and therapy[J]. Cancers (Basel), 2011, 3: 1691-1707.
[21]Lavinsky RM, Jepsen K, Heinzel T, et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes[J]. Proc Natl Acad Sci U S A, 1998, 95: 2920-2925.
[22]Knowlden JM, Hutcheson IR, Jones HE, et al. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells[J]. Endocrinology, 2003, 144: 1032-1044.
[23]De Laurentiis M, Arpino G, Massarelli E, et al. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer[J]. Clin Cancer Res, 2005, 11: 4741-4748.
[24]Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer[J]. N Engl J Med, 2005, 353: 1673-1684.
[25]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[J]. Cancer Res, 2007, 67(3): 1352-1360.
[26]Chong K, Subramanian A, Sharma A, et al. Measuring IGF-1, ER-alpha and EGFR expression can predict tamoxifen-resistance in ER-positive breast cancer[J]. Anticancer Res, 2011, 31(1): 23-32.
[27]Skliris GP, Nugent ZJ, Rowan BG, et al. A phosphorylation code for oestrogen receptor-alpha predicts clinical outcome to endocrine therapy in breast cancer[J]. Endocr Relat Cancer, 2010, 17: 589-597.
[28]Allen KE, Weiss GJ. Resistance may not be futile: microRNA biomarkers for chemoresistance and potential therapeutics[J]. Mol Cancer Ther, 2010, 9: 3126-3136.
[29]Miller TE, Ghoshal K, Ramaswamy B, et al. MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1[J]. J Biol Chem, 2008, 283: 29897-29903.
[30]Ward A, Shukla K, Balwierz A, et al. MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer[J]. J Pathol, 2014, 233: 368-379.
[31]Kim SJ, Kang HS, Jung SY, et al. Methylation patterns of genes coding for drug-metabolizing enzymes in tamoxifen-resistant breast cancer tissues[J]. J Mol Med (Berl), 2010, 88: 1123-1131.
[32]Khan S, Kumagai T, Vora J, et al. PTEN promoter is methylated in a proportion of invasive breast cancers[J]. Int J Cancer, 2004, 112: 407-410.
[33]Shoman N, Klassen S, McFadden A, et al. Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen[J]. Mod Patho, 2005, 18: 250-259.
[34]Phuong NT, Kim SK, Lim SC, et al. Role of PTEN promoter methylation in tamoxifen-resistant breast cancer cells[J]. Breast Cancer Res Treat, 2011, 130: 73-83.
[35]Waltersson MA, Askmalm MS, Nordenskjold B, et al. Altered expression of cyclin E and the retinoblastoma protein influences the effect of adjuvant therapy in breast cancer[J]. Int J Oncol, 2009, 34: 441-448.
[36]Butt AJ, McNeil CM, Musgrove EA, et al. Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E[J]. Endocr Relat Cancer. 2005, Suppl : S47-59.
[37]Barone I, Brusco L, Gu G, et al. Loss of Rho GDIalpha and resistance to tamoxifen via effects on estrogen receptor alpha[J]. J Natl Cancer Inst, 2011, 103: 538-552.
[38]Raha P, Thomas S, Munster PN. Epigenetic modulation: a novel therapeutic target for overcoming hormonal therapy resistance[J]. Epigenomics, 2011, 3(4): 451-470.