BRCA1 inhibits AR–mediated proliferation of breast cancer cells through the activation of SIRT1

Wenwen Zhang,Fang Yang,Xiaoxiang Guan,Jan Åke Gustafsson,Anders Strom,Yucai Wang,Yongmei Yin,Jiayan Luo

doi:10.1038/srep22034

Abstract

Breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor protein that functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. The androgen receptor (AR) is expressed in more than 70% of breast cancers and has been implicated in breast cancer pathogenesis. However, little is known about the role of BRCA1 in AR-mediated cell proliferation in human breast cancer. Here, we report that a high expression of AR in breast cancer patients was associated with shorter overall survival (OS) using a tissue microarray with 149 non-metastatic breast cancer patient samples. We reveal that overexpression of BRCA1 significantly inhibited expression of AR through activation of SIRT1 in breast cancer cells. Meanwhile, SIRT1 induction or treatment with a SIRT1 agonist, resveratrol, inhibits AR–stimulated proliferation. Importantly, this mechanism is manifested in breast cancer patient samples and TCGA database, which showed that low SIRT1 gene expression in tumor tissues compared with normal adjacent tissues predicts poor prognosis in patients with breast cancer. Taken together, our findings suggest that BRCA1 attenuates AR-stimulated proliferation of breast cancer cells via SIRT1 mediated pathway.

Highlights

IntroductionIt was previously suggested that androgen receptor (AR) could inhibit endogenous ERα transactivation in ERα -positive breast cancer[6]
We evaluated the role of BRCA1 in androgen receptor (AR)–mediated cell proliferation in human breast cancer tissues and cell lines
We report that a high expression of AR was associated with shorter overall survival (OS) in 149 non-metastatic breast cancer patients

Summary

Introduction

It was previously suggested that AR could inhibit endogenous ERα transactivation in ERα -positive breast cancer[6]. Elevated AR and reduced ERα mRNA were reported in tamoxifen-resistant tumors in vitro and in vivo[13]. AR overexpression rendered ERα -positive breast cancer cells resistant to the growth-inhibitory effects of tamoxifen, whereas treatment with the AR antagonist, bicalutamide, reversed this resistance[13]. We evaluated the role of BRCA1 in AR-mediated cell proliferation in human breast cancer tissues and cell lines. We found that AR serves as a downstream mediator of BRCA1 function in tumor suppression through the activation of SIRT1, and that resveratrol inhibited AR–stimulated proliferation by activating SIRT1. BRCA1–mediated SIRT1 activation was manifested in clinical breast cancer patients and TCGA database

Methods

Results

Conclusion