Hormonal modulation of ESR1 mutant metastasis

• Published in: Oncogene Vol. 40; no. 5; pp. 997 - 1011
• Main Authors: Gu, Guowei, Tian, Lin, Herzog, Sarah K., Rechoum, Yassine, Gelsomino, Luca, Gao, Meng, Du, Lili, Kim, Jin-Ah, Dustin, Derek, Lo, Hin Ching, Beyer, Amanda R., Edwards, David G., Gonzalez, Thomas, Tsimelzon, Anna, Huang, Helen J., Fernandez, Natalie M., Grimm, Sandra L., Hilsenbeck, Susan G., Liu, Dan, Xu, Jun, Alaniz, Alyssa, Li, Shunqiang, Mills, Gordon B., Janku, Filip, Kittler, Ralf, Zhang, Xiang H. -F., Coarfa, Cristian, Foulds, Charles E., Symmans, W. Fraser, Andò, Sebastiano, Fuqua, Suzanne A. W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2021; Nature Publishing Group
• Subjects: 14/63; 17β-Estradiol; 38/109; 38/39; 38/61; 38/70; 631/337/2019; 631/67/1347; 631/67/322; 631/67/70; 64/60; 82/80; 96/1; Androgen receptors; Animals; Antiestrogens; Apoptosis; Aromatase; Aromatase Inhibitors - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Care and treatment; Cell Biology; Cell Line, Tumor; Cell migration; Complications and side effects; Dihydrotestosterone; Dihydrotestosterone - pharmacology; Estradiol - metabolism; Estrogen; Estrogen Receptor alpha - genetics; Estrogen receptors; Estrogens; Estrogens - genetics; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene mutations; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Lung cancer; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mice; Mutants; Mutation; Mutation - genetics; Neoplasm Metastasis; Oncology; Receptors; Receptors, Androgen - drug effects; Receptors, Androgen - genetics; Tamoxifen; Tamoxifen - pharmacology; Tumors; Xenograft Model Antitumor Assays; Xenografts; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01563-x

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 2 ) withdrawal. Y537S ESR1 mutant primary tumors metastasized efficiently in the absence of E 2 ; 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.