Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, P.R. China.
Department of Oncology, Yixing Hospital Affiliated to Jiangsu University, Yixing, Jiangsu 214200, P.R. China.
Oncol Rep. 2019 Mar;41(3):1901-1910. doi: 10.3892/or.2019.6978. Epub 2019 Jan 22.
Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely used endocrine therapy for patients with ER‑positive breast cancer. However, ~30% of tamoxifen‑treated breast cancers do not initially respond to tamoxifen, and neither do they eventually develop tamoxifen resistance. Bcl‑2‑associated athanogene 1 (BAG‑1) is a multifunctional protein that interacts with a wide range of molecules to protect cells from apoptosis otherwise induced by cytotoxic drugs, growth factor withdrawal, radiation and stress. The aim of the present study was to investigate the function of BAG‑1 in tamoxifen resistance. Immunohistochemistry techniques were used to determine BAG‑1 expression in 119 stage I‑III primary breast cancer tissues and it was identified that BAG‑1 was significantly overexpressed in ER‑positive breast cancer (P=0.001). Knockdown of BAG‑1 by short interfering RNA was revealed to downregulate ER, and upregulate phospho (p)‑protein kinase B (Akt) and p‑mammalian target of rapamycin (mTOR) levels. Furthermore, significantly decreased tamoxifen‑induced apoptosis (41.70±1.93 vs. 55.03±2.39%; P=0.012) was observed in T47D cells following the silencing of BAG‑1. In contrast, overexpression of BAG‑1 long enhanced apoptosis (65.10±2.35 vs. 55.03±2.39%; P=0.039) in T47D cells treated with tamoxifen. Combination treatment of tamoxifen and an mTOR inhibitor restored the inhibitory effects of tamoxifen in T47D cells exhibiting low BAG‑1 expression levels (66.87±2.27 vs. 57.07±2.46%; P=0.037). In conclusion, there results of the present study indicated that suppression of BAG‑1 expression may activate the phosphoinositide 3‑kinase/Akt/mTOR pathway and protect ER‑positive breast cancer cells from tamoxifen‑induced inhibition of proliferation. ER‑positive breast cancer cells exhibiting low BAG‑1 expression appeared to be more sensitive to treatment with the mTOR inhibitor rapamycin. Furthermore, the results indicated that combination treatment targeting ER with tamoxifen and targeting mTOR with rapamycin may significantly potentiate the inhibitory effect in BAG‑1‑silenced cells.
他莫昔芬是一种选择性雌激素受体（ER）调节剂，是 ER 阳性乳腺癌患者最广泛使用的内分泌治疗药物。然而，约 30%的他莫昔芬治疗的乳腺癌最初对他莫昔芬没有反应，最终也没有产生他莫昔芬耐药性。Bcl-2 相关抗凋亡基因 1（BAG-1）是一种多功能蛋白，可与多种分子相互作用，以防止细胞凋亡，否则会被细胞毒药物、生长因子缺失、辐射和应激诱导。本研究旨在探讨 BAG-1 在他莫昔芬耐药性中的作用。采用免疫组织化学技术检测 119 例Ⅰ-Ⅲ期原发性乳腺癌组织中 BAG-1 的表达，结果发现 BAG-1 在 ER 阳性乳腺癌中明显过表达（P=0.001）。用短发夹 RNA 敲低 BAG-1 可下调 ER，并上调磷酸化（p）-蛋白激酶 B（Akt）和 p-哺乳动物雷帕霉素靶蛋白（mTOR）水平。此外，在沉默 BAG-1 后，T47D 细胞中观察到他莫昔芬诱导的凋亡明显减少（41.70±1.93%比 55.03±2.39%；P=0.012）。相反，在 T47D 细胞中过表达 BAG-1 长时可显著增强他莫昔芬诱导的凋亡（65.10±2.35%比 55.03±2.39%；P=0.039）。联合使用他莫昔芬和 mTOR 抑制剂可恢复在 BAG-1 低表达水平的 T47D 细胞中他莫昔芬的抑制作用（66.87±2.27%比 57.07±2.46%；P=0.037）。综上所述，本研究结果表明，抑制 BAG-1 的表达可能会激活磷酸肌醇 3-激酶/Akt/mTOR 通路，并保护 ER 阳性乳腺癌细胞免受他莫昔芬抑制增殖的影响。在 BAG-1 低表达的 ER 阳性乳腺癌细胞中，对 mTOR 抑制剂雷帕霉素的治疗更为敏感。此外，结果表明，针对 ER 的他莫昔芬与针对 mTOR 的雷帕霉素联合靶向治疗可能会显著增强沉默 BAG-1 细胞的抑制作用。
