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
Affiliations
Suriyan Ponnusamy
Department of Medicine, College of Medicine, University of Tennessee Health Science Center, 19, S. Manassas, Room 120, Memphis, TN 38103, USA
Sarah Asemota
Department of Medicine, College of Medicine, University of Tennessee Health Science Center, 19, S. Manassas, Room 120, Memphis, TN 38103, USA
Lee S. Schwartzberg
West Cancer Center, Memphis, TN, USA
Fouzia Guestini
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
Keely M. McNamara
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
Mariaelena Pierobon
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
Alba Font-Tello
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Xintao Qiu
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Yingtian Xie
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Prakash K. Rao
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Thirumagal Thiyagarajan
Department of Medicine, College of Medicine, University of Tennessee Health Science Center, 19, S. Manassas, Room 120, Memphis, TN 38103, USA
Brandy Grimes
West Cancer Center, Memphis, TN, USA
Daniel L. Johnson
Molecular Informatics Core, University of Tennessee Health Science Center, Memphis, TN, USA
Martin D. Fleming
Department of Medicine, College of Medicine, University of Tennessee Health Science Center, 19, S. Manassas, Room 120, Memphis, TN 38103, USA
Frances E. Pritchard
Department of Medicine, College of Medicine, University of Tennessee Health Science Center, 19, S. Manassas, Room 120, Memphis, TN 38103, USA
Michael P. Berry
West Cancer Center, Memphis, TN, USA
Roy Oswaks
West Cancer Center, Memphis, TN, USA
Richard E. Fine
West Cancer Center, Memphis, TN, USA
Myles Brown
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Hironobu Sasano
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
Emanuel F. Petricoin
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA
Henry W. Long
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
Ramesh Narayanan
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; Corresponding author
Summary: 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. : Molecular Biology; Molecular Mechanism of Gene Regulation; Cancer Subject Areas: Molecular Biology, Molecular Mechanism of Gene Regulation, Cancer
