Pharmacological Targeting of Androgen Receptor Elicits Context-Specific Effects in Estrogen Receptor–Positive Breast Cancer

Lixuan Wei, Huanyao Gao, Jia Yu, Huan Zhang, Thanh Thanh L. Nguyen, Yayun Gu, Marie R. Passow, Jodi M. Carter, Bo Qin, Judy C. Boughey, Matthew P. Goetz, Richard M. Weinshilboum, James N. Ingle, Liewei Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Androgen receptor (AR) is expressed in 80% to 90% of estrogen receptor α–positive (ER+) breast cancers. Accumulated evidence has shown that AR is a tumor suppressor and that its expression is associated with improved prognosis in ER+ breast cancer. However, both a selective AR agonist (RAD140) and an AR inhibitor (enzalutamide, ENZ) have shown a therapeutic effect on ER+ breast cancer, so the potential for clinical application of AR-targeting therapy for ER+ breast cancer is still in dispute. In this study, we evaluated the efficacy of ENZ and RAD140 in vivo and in vitro in AR+/ER+ breast cancer models, characterizing the relationship of AR and ER levels to response to AR-targeting drugs and investigating the alterations of global gene expression and chromatin binding of AR and ERα after ENZ treatment. In the AR-low setting, ENZ directly functioned as an ERα antagonist. Cell growth inhibition by ENZ in breast cancer with low AR expression was independent of AR and instead dependent on ER. In AR-high breast cancer models, AR repressed ERα signaling and ENZ promoted ERα signaling by antagonizing AR. In contrast, RAD140 activated AR signaling and suppressed AR-high tumor growth by deregulating ERα expression and blocking ERα function. Overall, analysis of the dynamic efficacies and outcomes of AR agonist, and antagonist in the presence of different AR and ERα levels reveals regulators of response and supports the clinical investigation of ENZ in selected ER+ tumors with a low AR/ER ratio and AR agonists in tumors with a high AR/ER ratio.

Original languageEnglish (US)
Pages (from-to)456-470
Number of pages15
JournalCancer research
Volume83
Issue number3
DOIs
StatePublished - Feb 1 2023

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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