Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
Cell Res. 2018 Mar;28(3):336-358. doi: 10.1038/cr.2018.15. Epub 2018 Feb 2.
The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer.
66 kDa 雌激素受体 α（ERα66）是内分泌治疗（如他莫昔芬治疗）的主要分子靶点。然而，许多患者出现了耐药性，但其机制尚不清楚。在一项对接受手术后接受他莫昔芬治疗的乳腺癌患者进行的大型队列研究中，我们证明 ERα36（ERα66 的一种变体）与预后不良相关。从机制上讲，他莫昔芬直接结合并激活 ERα36，通过转录刺激醛脱氢酶 1A1（ALDH1A1）来增强乳腺癌细胞的干性和转移。一致地，通过 ALDH1 抑制剂或特定的 ERα36 抗体可以减弱他莫昔芬诱导的干性和转移。因此，他莫昔芬在乳腺癌细胞中作为 ERα36 的激动剂发挥作用，这导致了激素治疗耐药和乳腺癌转移。我们的研究不仅揭示了 ERα36 作为内分泌治疗的分层标志物，而且为治疗他莫昔芬耐药的乳腺癌提供了有希望的治疗途径。
