The mTOR inhibitor AZD8055 overcomes tamoxifen resistance in breast cancer cells by down-regulating HSPB8

• 来源期刊: 中国药理学报（英文版）
• 关键词: tamoxifen resistance HSPB8 AZD8055 estrogen receptor mTOR inhibitor
• 年，卷（期）: 2018,（8）
• 页码范围: 1338-1346
• 页数: 9页
• 语种: 英文
• DOI: 10.1038/aps.2017.181

摘要

Tamoxifen,an important endocrine therapeutic agent,is widely used for the treatment of estrogen receptor positive (ER+) breast cancer.However,de novo or acquired resistance prevents patients from benefitting from endocrine approaches and necessitates alternative treatments.In this study,we report that small heat protein beta-8 (HSPB8) may serve as an important molecule in tamoxifen resistance.HSPB8 expression is enhanced in MCF-7 cells resistant to tamoxifen (MCF-7/R) compared to parent cells.Moreover,high expression of HSPB8 associates with poor prognosis in ER+ breast cancer patients but not in patients without classification.Stimulating ER signaling by heterogeneous expression of ERa or 17β-estradiol promotes HSPB8 expression and reduces the cell population in G1 phase.In contrast,blockage of ER signaling by tamoxifen down-regulates the expression of HSPB8.In addition,knocking down HSPB8 by specific siRNAs induces significant cell cycle arrest at G1 phase.AZDS055 was found to be more potent against the proliferation of MCF-7/R cells than that of parent cells,which was associated with down-regulation of HSPB8.We found that the anti-proliferative activity of AZD8055 was positively correlated with the HSPB8 expression level in ER+ breast cancer cells.Thus,AZD8055 was able to overcome tamoxifen resistance in breast cancer cells,and the expression of HSPB8 may predict the efficacy of AZD8055 in ER+ breast cancer.This hypothesis deserves further investigation.