賀爾蒙療法常做為雌激素受體陽性乳癌患者的輔助性治療，儘管許多先天或後天抗藥性的雌激素受體陽性的乳癌病患經常被發現及探討，但是雌激素受體陽性的乳癌患者對賀爾蒙療法產生抗藥性之分子機制尚未完全清楚。而在本篇研究中，我們發現表觀遺傳調節因子-組蛋白去乙醯化酶2（HDAC2）和組蛋白去乙醯化酶5（HDAC5）過度表現於MCF7分離出來的雌激素受體陽性、非雌激素依賴型和具有泰莫西芬抗藥性的MCF7-TamC3乳癌細胞中，更重要的是，透過Kaplan-Meier分析的結果顯示，在泰莫西芬/內分泌治療的雌激素受體陽性乳癌患者同類群組分析中，高表現量的HDAC2和HDAC5與較差的病患整體存活率相關。在分子機制分析的層面中發現，當過度表達HDAC2和HDAC5時，會增加MCF7-TamC3細胞中抗凋亡分子-存活素的表現，而且降低腫瘤抑制因子miR-125a-5p的表現，我們接著進一步利用Kaplan-Meier分析，發現在泰莫西芬治療的雌激素受體陽性乳癌患者中，高表現量的存活素與低表現量的miR-125a-5p和較差的病患整體存活率相關。當本研究藉由siRNA的方式降低HDAC2，HDAC5和survivin的表現時，會增加MCF7-TamC3細胞對缺乏雌激素的敏感性，並恢復對泰莫西芬的敏感性。此外，當過度表達miR-125a-5p時，也會恢復MCF7-TamC3細胞中對泰莫西芬的敏感性。這些發現顯示由HDAC2 / 5調節的存活素與miR-125a-5p在控制雌激素受體陽性乳癌細胞對泰莫西芬與缺乏雌激素的敏感性中扮演重要的角色。標靶HDAC2和HDAC5或其下游調節分子如存活素和miR-125a-5p會是未來讓雌激素受體陽性乳癌患者克服賀爾蒙治療抗藥性的潛勢策略。

Typically, hormone therapy is used as an adjuvant to treat patients with estrogen receptor positive (ER+) breast cancer. Despite intrinsic or acquired resistance to hormone therapy in ER+ breast cancer patient is frequently reported, the molecular mechanism underlying the induction of hormone therapy resistance in ER+ breast cancer is still incompletely understood. In this study, we found that the epigenetic regulators, histone deacetylase 2 (HDAC2) and histone deacetylase 5 (HDAC5), are overexpressed in the MCF7-dervided ER+ estrogen-independent tamoxifen-resistant MCF7-TamC3 breast cancer cells. Importantly, Kaplan-Meier analysis of expression cohorts of breast tumor showed that high HDAC2 and HDAC5 expression levels correlate with poor overall survival in tamoxifen/endocrine therapy-treated ER+ breast cancer patients. Mechanistic analysis revealed that the upregulated HDAC2 and HDAC5 increase the expression of the anti-apoptotic molecule, survivin, and decrease the expression of the tumor suppressor, miR-125a-5p, in MCF7-TamC3 cells. Kaplan-Meier analysis further revealed that high survivin expression and low miR-125a-5p expression levels correlate with poor overall survival in tamoxifen-treated ER+ breast cancer patients. Molecular downregulation of HDAC2, HDAC5, and survivin by siRNA increased the sensitivity to estrogen deprivation and restored the sensitivity to tamoxifen in MCF7-TamC3 cells. Ectopic overexpression of miR-125a-5p also restored the sensitivity to tamoxifen in MCF7-TamC3 cells. These findings indicate that HDAC2/5-regulated survivin and miR-125a-5p play an important role in regulating the sensitivity to tamoxifen and estrogen deprivation in ER+ breast cancer cells. Targeting HDAC2 and HDAC5, or their downstream regulating molecules like survivin and miR-125a-5p, may be a potential strategy for overcoming resistance to hormone therapy in patients with ER+ breast cancer.

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