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01-05-2010 | Preclinical study

Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells

Authors: Francesca De Amicis, Janagi Thirugnansampanthan, Yukun Cui, Jennifer Selever, Amanda Beyer, Irma Parra, Nancy L. Weigel, Matthew H. Herynk, Anna Tsimelzon, Michael T. Lewis, Gary C. Chamness, Susan G. Hilsenbeck, Sebastiano Andò, Suzanne A. W. Fuqua

Published in: Breast Cancer Research and Treatment | Issue 1/2010

Abstract

Although the androgen receptor (AR) is a known clinical target in prostate cancer, little is known about its possible role in breast cancer. We have investigated the role of AR expression in human breast cancer in response to treatment with the antiestrogen tamoxifen. Resistance to tamoxifen is a major problem in treating women with breast cancer. By gene expression profiling, we found elevated AR and reduced estrogen receptor (ER) α mRNA in tamoxifen-resistant tumors. Exogenous overexpression of AR rendered ERα-positive MCF-7 breast cancer cells resistant to the growth-inhibitory effects of tamoxifen in anchorage-independent growth assays and in xenograft studies in athymic nude mice. AR-overexpressing cells remained sensitive to growth stimulation with dihydrotestosterone. Treatment with the AR antagonist Casodex™ (bicalutamide) reversed this resistance, demonstrating the involvement of AR signaling in tamoxifen resistance. In AR-overexpressing cells, tamoxifen induced transcriptional activation by ERα that could be blocked by Casodex, suggesting that AR overexpression enhances tamoxifen’s agonistic properties. Our data suggest a role for AR overexpression as a novel mechanism of hormone resistance, so that AR may offer a new clinical therapeutic target in human breast cancers.

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Title: Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells
Authors: Francesca De Amicis
Janagi Thirugnansampanthan
Yukun Cui
Jennifer Selever
Amanda Beyer
Irma Parra
Nancy L. Weigel
Matthew H. Herynk
Anna Tsimelzon
Michael T. Lewis
Gary C. Chamness
Susan G. Hilsenbeck
Sebastiano Andò
Suzanne A. W. Fuqua
Publication date: 01-05-2010
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2010
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-009-0436-8

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