Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone Receptor-Positive Breast Cancers

Suriyan Ponnusamy; Sarah Asemota; Lee S Schwartzberg; Fouzia Guestini; Keely M McNamara; Mariaelena Pierobon; Alba Font-Tello; Xintao Qiu; Yingtian Xie; Prakash K Rao; Thirumagal Thiyagarajan; Brandy Grimes; Daniel L Johnson; Martin D Fleming; Frances E Pritchard; Michael P Berry; Roy Oswaks; Richard E Fine; Myles Brown; Hironobu Sasano; Emanuel F Petricoin; Henry W Long; Ramesh Narayanan

doi:10.1016/j.isci.2019.10.038

Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone Receptor-Positive Breast Cancers

iScience. 2019 Nov 22:21:341-358. doi: 10.1016/j.isci.2019.10.038. Epub 2019 Oct 23.

Authors

Suriyan Ponnusamy¹, Sarah Asemota¹, Lee S Schwartzberg², Fouzia Guestini³, Keely M McNamara³, Mariaelena Pierobon⁴, Alba Font-Tello⁵, Xintao Qiu⁵, Yingtian Xie⁵, Prakash K Rao⁵, Thirumagal Thiyagarajan¹, Brandy Grimes², Daniel L Johnson⁶, Martin D Fleming¹, Frances E Pritchard¹, Michael P Berry², Roy Oswaks², Richard E Fine², Myles Brown⁵, Hironobu Sasano³, Emanuel F Petricoin⁴, Henry W Long⁵, Ramesh Narayanan⁷

Affiliations

¹ Department of Medicine, College of Medicine, University of Tennessee Health Science Center, 19, S. Manassas, Room 120, Memphis, TN 38103, USA.
² West Cancer Center, Memphis, TN, USA.
³ Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
⁴ Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
⁵ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Molecular Informatics Core, University of Tennessee Health Science Center, Memphis, TN, USA.
⁷ Department of Medicine, College of Medicine, University of Tennessee Health Science Center, 19, S. Manassas, Room 120, Memphis, TN 38103, USA; West Cancer Center, Memphis, TN, USA. Electronic address: rnaraya4@uthsc.edu.

Abstract

Sustained treatment of estrogen receptor (ER)-positive breast cancer with ER-targeting drugs results in ER mutations and refractory unresponsive cancers. Androgen receptor (AR), which is expressed in 80%-95% of ER-positive breast cancers, could serve as an alternate therapeutic target. Although AR agonists were used in the past to treat breast cancer, their use is currently infrequent due to virilizing side effects. Discovery of tissue-selective AR modulators (SARMs) has renewed interest in using AR agonists to treat breast cancer. Using translational models, we show that AR agonist and SARM, but not antagonist, inhibit the proliferation and growth of ER-positive breast cancer cells, patient-derived tissues, and patient-derived xenografts (PDX). Ligand-activated AR inhibits wild-type and mutant ER activity by reprogramming the ER and FOXA1 cistrome and rendering tumor growth inhibition. These findings suggest that ligand-activated AR may function as a non-canonical inhibitor of ER and that AR agonists may offer a safe and effective treatment for ER-positive breast cancer.

Keywords: Cancer; Molecular Biology; Molecular Mechanism of Gene Regulation.