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

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 SasanoEmanuel F. Petricoin, Henry W. Long, Ramesh Narayanan

MED - Medical Sciences

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

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.

Original language	English
Pages (from-to)	341-358
Number of pages	18
Journal	iScience
Volume	21
DOIs	https://doi.org/10.1016/j.isci.2019.10.038
Publication status	Published - 2019 Nov 22

Keywords

Cancer
Molecular Biology
Molecular Mechanism of Gene Regulation

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2019.10.038

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Ponnusamy, S., Asemota, S., Schwartzberg, L. S., Guestini, F., McNamara, K. M., Pierobon, M., Font-Tello, A., Qiu, X., Xie, Y., Rao, P. K., Thiyagarajan, T., Grimes, B., Johnson, D. L., Fleming, M. D., Pritchard, F. E., Berry, M. P., Oswaks, R., Fine, R. E., Brown, M., ... Narayanan, R. (2019). Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone Receptor-Positive Breast Cancers. iScience, 21, 341-358. https://doi.org/10.1016/j.isci.2019.10.038

Ponnusamy, S, Asemota, S, Schwartzberg, LS, Guestini, F, McNamara, KM, Pierobon, M, Font-Tello, A, Qiu, X, Xie, Y, Rao, PK, Thiyagarajan, T, Grimes, B, Johnson, DL, Fleming, MD, Pritchard, FE, Berry, MP, Oswaks, R, Fine, RE, Brown, M, Sasano, H, Petricoin, EF, Long, HW & Narayanan, R 2019, 'Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone Receptor-Positive Breast Cancers', iScience, vol. 21, pp. 341-358. https://doi.org/10.1016/j.isci.2019.10.038

@article{13952c461c2647b8968c0e694e9361f7,

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

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",

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

note = "Funding Information: The authors thank UTHSC molecular resource center for their help with microarray experiments. The authors thank Dr. Dejian Ma, department of pharmaceutical sciences, UTHSC Mass Spectrometry core for his help with the LC-MS/MS measurement of drug concentration. The studies were partially funded by a research grant from GTx, Inc. SP, SA, and TT performed all animal experiments, ex vivo sponge cultures, RNA isolation and gene expression studies, and ChIP-PCR assay. RN conceived and designed the experiments and managed the overall project. LSS managed the clinical aspects of the project with the help of BG, MDF, FEP, MPB, RO, and REF. HS and KMM designed the IHC part, which were executed by FG. HL and MB planned and managed the ChIP-Seq experiments, whereas AFT and PKR performed the experiments. XQ, YX, and DLJ provided bioinformatics and statistical support. EFP planned the RPPA studies, whereas MP performed the experiments. RN is a consultant to GTx, Inc. Memphis. This role has not influenced the conduct of experiments and the interpretation of results. Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = nov,

day = "22",

doi = "10.1016/j.isci.2019.10.038",

language = "English",

volume = "21",

pages = "341--358",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier Inc.",

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TY - JOUR

T1 - Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone Receptor-Positive Breast Cancers

AU - Ponnusamy, Suriyan

AU - Asemota, Sarah

AU - Schwartzberg, Lee S.

AU - Guestini, Fouzia

AU - McNamara, Keely M.

AU - Pierobon, Mariaelena

AU - Font-Tello, Alba

AU - Qiu, Xintao

AU - Xie, Yingtian

AU - Rao, Prakash K.

AU - Thiyagarajan, Thirumagal

AU - Grimes, Brandy

AU - Johnson, Daniel L.

AU - Fleming, Martin D.

AU - Pritchard, Frances E.

AU - Berry, Michael P.

AU - Oswaks, Roy

AU - Fine, Richard E.

AU - Brown, Myles

AU - Sasano, Hironobu

AU - Petricoin, Emanuel F.

AU - Long, Henry W.

AU - Narayanan, Ramesh

N1 - Funding Information: The authors thank UTHSC molecular resource center for their help with microarray experiments. The authors thank Dr. Dejian Ma, department of pharmaceutical sciences, UTHSC Mass Spectrometry core for his help with the LC-MS/MS measurement of drug concentration. The studies were partially funded by a research grant from GTx, Inc. SP, SA, and TT performed all animal experiments, ex vivo sponge cultures, RNA isolation and gene expression studies, and ChIP-PCR assay. RN conceived and designed the experiments and managed the overall project. LSS managed the clinical aspects of the project with the help of BG, MDF, FEP, MPB, RO, and REF. HS and KMM designed the IHC part, which were executed by FG. HL and MB planned and managed the ChIP-Seq experiments, whereas AFT and PKR performed the experiments. XQ, YX, and DLJ provided bioinformatics and statistical support. EFP planned the RPPA studies, whereas MP performed the experiments. RN is a consultant to GTx, Inc. Memphis. This role has not influenced the conduct of experiments and the interpretation of results. Publisher Copyright: © 2019 The Author(s)

PY - 2019/11/22

Y1 - 2019/11/22

N2 - 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.

AB - 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.

KW - Cancer

KW - Molecular Biology

KW - Molecular Mechanism of Gene Regulation

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UR - http://www.scopus.com/inward/citedby.url?scp=85074339898&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2019.10.038

DO - 10.1016/j.isci.2019.10.038

M3 - Article

AN - SCOPUS:85074339898

SN - 2589-0042

VL - 21

SP - 341

EP - 358

JO - iScience

JF - iScience

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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