Huang Wen-Tsung, Tsai Yu-Hsuan, Chen Shang-Hung, Kuo Ching-Wen, Kuo Yao-Lung, Lee Kuo-Ting, Chen Wen-Chung, Wu Pei Chih, Chuang Chun-Yu, Cheng Siao Muk, Lin Chun-Hui, Leung Euphemia Yee, Chang Yung-Chieh, Cheung Chun Hei Antonio
Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan.
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Front Pharmacol. 2017 Dec 13;8:902. doi: 10.3389/fphar.2017.00902. eCollection 2017.
Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER) breast cancer patients. Even though dysregulations of histone deacetylases (HDACs) are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER hormone-dependent ZR-75-1 breast cancer cells . Kaplan-Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.
雌激素受体阳性（ER）乳腺癌患者中，常出现对激素疗法的内在或获得性耐药。尽管已知组蛋白脱乙酰酶（HDACs）失调会促进癌细胞存活，但不同HDACs在ER乳腺癌激素疗法耐药诱导中的作用仍不清楚。Survivin是一种众所周知的促肿瘤存活分子，而miR-125a-5p是最近发现的肿瘤抑制因子。在本研究中，我们发现与亲代他莫昔芬敏感的MCF7乳腺癌细胞相比，ER、激素非依赖性、他莫昔芬耐药的MCF7-TamC3细胞中HDAC2、HDAC5和survivin的表达增加，但miR-125a-5p的表达降低。HDAC2、HDAC5和survivin的分子下调以及miR-125a-5p的异位过表达增加了MCF7-TamC3细胞对雌激素剥夺的敏感性，并恢复了对他莫昔芬的敏感性。相同处理还进一步增加了ER激素依赖性ZR-75-1乳腺癌细胞对雌激素剥夺的敏感性。对乳腺肿瘤表达队列的Kaplan-Meier分析和受试者工作特征曲线分析表明，HDAC2和survivin高表达以及miR-125a-5p低表达水平与内分泌治疗和他莫昔芬治疗的ER乳腺癌患者无复发生存期差相关。进一步的分子分析表明，在ER MCF7、MCF7-TamC3和ZR-75-1乳腺癌细胞中，HDAC2和HDAC5正向调节survivin的表达，并负向调节miR-125a-5p的表达。这些发现表明，HDAC2和HDAC5失调部分通过survivin和miR-125a-5p的表达调控促进了ER乳腺癌细胞中激素非依赖性和他莫昔芬耐药的发展。
