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Breast Cancer Research
Published in: Breast Cancer Research 1/2014

Open Access 01-02-2014 | Research article

Estrogen receptor beta as a novel target of androgen receptor action in breast cancer cell lines

Authors: Pietro Rizza, Ines Barone, Domenico Zito, Francesca Giordano, Marilena Lanzino, Francesca De Amicis, Loredana Mauro, Diego Sisci, Stefania Catalano, Karin Dahlman Wright, Jan-ake Gustafsson, Sebastiano Andò

Published in: Breast Cancer Research | Issue 1/2014

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Abstract

Introduction

The two isoforms of estrogen receptor (ER) alpha and beta play opposite roles in regulating proliferation and differentiation of breast cancers, with ER-alpha mediating mitogenic effects and ER-beta acting as a tumor suppressor. Emerging data have reported that androgen receptor (AR) activation inhibits ER-positive breast cancer progression mainly by antagonizing ER-alpha signaling. However, to date no studies have specifically evaluated a potential involvement of ER-beta in the inhibitory effects of androgens.

Methods

ER-beta expression was examined in human breast cancer cell lines using real-time PCR, Western blotting and small interfering RNA (siRNA) assays. Mutagenesis studies, electromobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis were performed to assess the effects of mibolerone/AR on ER-beta promoter activity and binding.

Results

In this study, we demonstrate that mibolerone, a synthetic androgen ligand, up-regulates ER-beta mRNA and protein levels in ER-positive breast cancer cells. Transient transfection experiments, using a vector containing the human ER-beta promoter region, show that mibolerone increases basal ER-beta promoter activity. Site-directed mutagenesis and deletion analysis reveal that an androgen response element (ARE), TGTTCT motif located at positions −383 and −377, is critical for mibolerone-induced ER-beta up-regulation in breast cancer cells. This occurs through an increased recruitment of AR to the ARE site within the ER-beta promoter region, along with an enhanced occupancy of RNA polymerase II. Finally, silencing of ER-beta gene expression by RNA interference is able to partially reverse the effects of mibolerone on cell proliferation, p21 and cyclin D1 expression.

Conclusions

Collectively, these data provide evidence for a novel mechanism by which activated AR, through an up-regulation of ER-beta gene expression, inhibits breast cancer cell growth.
Appendix
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Metadata
Title
Estrogen receptor beta as a novel target of androgen receptor action in breast cancer cell lines
Authors
Pietro Rizza
Ines Barone
Domenico Zito
Francesca Giordano
Marilena Lanzino
Francesca De Amicis
Loredana Mauro
Diego Sisci
Stefania Catalano
Karin Dahlman Wright
Jan-ake Gustafsson
Sebastiano Andò
Publication date
01-02-2014
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2014
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3619

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