Endoplasmic reticulum stress inhibits AR expression via the PERK/eIF2\u03b1/ATF4 pathway in luminal androgen receptor triple-negative breast cancer and prostate cancer

Yongqing Cai,Xiaoping Yu,Xiangru Zheng,Ying Zhao,Moustapha Hassan,Wenjun Li,Hongfang Zeng,Xiaoli Li,Bo Chen,Duanfang Zhou,Weiying Zhou

doi:10.1038/s41523-021-00370-1

Abstract

Androgen receptor (AR) is an important prognostic marker and therapeutic target in luminal androgen receptor triple-negative breast cancer (LAR TNBC) and prostate cancer (PCa). Endoplasmic reticulum (ER) stress may activate the unfolded protein response (UPR) to regulate associated protein expression and is closely related to tumor growth and drug resistance. The effect of ER stress on AR expression and signaling remains unclear. Here, we focused on the regulation and underlying mechanism of AR expression induced by ER stress in LAR TNBC and PCa. Western blotting and quantitative RT-PCR results showed that AR expression was markedly decreased under ER stress induced by thapsigargin and brefeldin A, and this effect was dependent on PERK/eIF2α/ATF4 signaling activation. Chromatin immunoprecipitation-PCR and luciferase reporter gene analysis results showed that ATF4 bound to the AR promoter regions to inhibit its activity. Moreover, ATF4 overexpression inhibited tumor proliferation and AR expression both in vitro and in vivo. Collectively, these results demonstrated that ER stress could decrease AR mRNA and protein levels via PERK/eIF2α/ATF4 signaling in LAR TNBC and PCa. Targeting the UPR may be a treatment strategy for AR-dependent TNBC and PCa.

Highlights

The androgen receptor (AR) is a nuclear receptor that functions as a transcription factor activated by the steroid hormone androgen
Some studies have shown that AR is highly expressed in up to 70–90% of all breast cancer types, including as much as 30% of triple-negative breast cancers (TNBC) that are deficient in the expression of estrogen receptor α (ERα), progesterone receptor (PR) and HER2
We demonstrated that Endoplasmic reticulum (ER) stress decreased AR expression at the transcriptional level via PERK/eIF2α/ ATF4 signaling in luminal androgen receptor (LAR) TNBC and prostate cancer (PCa)

Summary

INTRODUCTION

The androgen receptor (AR) is a nuclear receptor that functions as a transcription factor activated by the steroid hormone androgen. The UPR is initiated through the activation of three ER-resident sensors: inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6), and protein kinase R (PKR)-like ER kinase (PERK)[14,15]. These signaling pathways clear misfolded proteins and restore ER homeostasis by weakening protein translation and transcription to relieve ER load, upregulating the expression of genes that are involved in increasing ER protein folding capacity (e.g., BiP), and activating the ERassociated degradation pathway if the protein cannot be refolded correctly[16,17].

RESULTS

Li et al 3

DISCUSSION

Findings

METHODS