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National Institute of Environmental Health Sciences

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Publication Detail

Title: Hormonal modulation of ESR1 mutant metastasis.

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

Published In Oncogene, (2021 Feb)

Abstract: 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 (E2) withdrawal. Y537S ESR1 mutant primary tumors metastasized efficiently in the absence of E2; 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.

PubMed ID: 33323970 Exiting the NIEHS site

MeSH Terms: Animals; Aromatase Inhibitors/pharmacology; Breast Neoplasms/drug therapy*; Breast Neoplasms/genetics; Breast Neoplasms/pathology; Cell Line, Tumor; Dihydrotestosterone/pharmacology; Estradiol/metabolism; Estrogen Receptor alpha/genetics*; Estrogens/genetics; Female; Gene Expression Regulation, Neoplastic/drug effects; Humans; Mice; Mutation/genetics; Neoplasm Metastasis; Receptors, Androgen/drug effects; Receptors, Androgen/genetics*; Tamoxifen/pharmacology*; Xenograft Model Antitumor Assays

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