Hormonal modulation of ESR1 mutant metastasis

Guowei Gu, Lin Tian, Sarah K. Herzog, Yassine Rechoum, Luca Gelsomino, Meng Gao, Lili Du, Jin Ah Kim, Derek Dustin, Hin Ching Lo, Amanda R. Beyer, David G. Edwards, Thomas Gonzalez, Anna Tsimelzon, Helen J. Huang, Natalie M. Fernandez, Sandra L. Grimm, Susan G. Hilsenbeck, Dan Liu, Jun XuAlyssa Alaniz, Shunqiang Li, Gordon B. Mills, Filip Janku, Ralf Kittler, Xiang H.F. Zhang, Cristian Coarfa, Charles E. Foulds, W. Fraser Symmans, Sebastiano Andò, Suzanne A.W. Fuqua

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)997-1011
Number of pages15
JournalOncogene
Volume40
Issue number5
DOIs
StatePublished - Feb 4 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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