Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Oncogene. 2021 Feb;40(5):997-1011. doi: 10.1038/s41388-020-01563-x. Epub 2020 Dec 15.
Estrogen receptor alpha gene (ESR1) mutations occur frequently in ER-positive metastatic breast cancer, and confer clinical resistance to aromatase inhibitors. Expression of the ESR1 Y537S mutation induced an epithelial-mesenchymal transition (EMT) with cells exhibiting enhanced migration and invasion potential in vitro. When small subpopulations of Y537S ESR1 mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases. Y537S mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen (Tam) as well as to estradiol (E) withdrawal. Y537S ESR1 mutant primary tumors metastasized efficiently in the absence of E; however, Tam treatment significantly inhibited metastasis to distant sites. We identified a nine-gene expression signature, which predicted clinical outcomes of ER-positive breast cancer patients, as well as breast cancer metastasis to the lung. Androgen receptor (AR) protein levels were increased in mutant models, and the AR agonist dihydrotestosterone significantly inhibited estrogen-regulated gene expression, EMT, and distant metastasis in vivo, suggesting that AR may play a role in distant metastatic progression of ESR1 mutant tumors.
雌激素受体 alpha 基因（ESR1）突变在 ER 阳性转移性乳腺癌中频繁发生，并导致对芳香酶抑制剂的临床耐药性。ESR1 Y537S 突变的表达诱导上皮-间充质转化（EMT），使细胞在体外表现出增强的迁移和侵袭潜能。当少量 Y537S ESR1 突变细胞与 WT 亲本细胞一起注射时，肿瘤生长增强，突变细胞成为远处转移中的主要群体。Y537S 突变型原发性异种移植肿瘤对雌激素拮抗剂他莫昔芬（Tam）以及雌二醇（E）耗竭均具有耐药性。Y537S ESR1 突变型原发性肿瘤在没有 E 的情况下有效地转移；然而，Tam 治疗显著抑制了远处部位的转移。我们确定了一个由九个基因组成的表达谱，该表达谱可预测 ER 阳性乳腺癌患者的临床结局以及乳腺癌向肺部的转移。在突变模型中，雄激素受体（AR）蛋白水平增加，AR 激动剂二氢睾酮显著抑制体内雌激素调节基因表达、EMT 和远处转移，表明 AR 可能在 ESR1 突变型肿瘤的远处转移进展中发挥作用。
