Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.

Verena Thewes,Stefanie Heck,Robert I Nicholson,Ronald Simon,Barbara Burwinkel,Andreas Schneeweiss,Magdalena Schlotter,Ulrich Deuschle,Vladimir Benes,Tobias Anzeneder,Reinhard Büttner,Hans-Peter Sinn,Marc Zapatka,Guido Sauter,Peter Lichter,Petra Schroeter

doi:10.1158/0008-5472.can-14-0652

Abstract

Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer.

Highlights

The ligand-activated transcription factor estrogen receptor-a (ERa) is a key driver of the breast cancer phenotype in around 70% of patients [1]
ERa and estrogen-related receptor-a (ERRa) mRNA expression was analyzed in a cohort of 19 relapsed breast tumors, which emerged during or after completion of long-term adjuvant tamoxifen treatment
To assess the suitability of in vitro model systems for functional analyses, ERa and ERRa expression was studied in a tamoxifen(#TamR) and a fulvestrant (#FulvR)-resistant MCF-7 subline

Summary

Introduction

The ligand-activated transcription factor ERa is a key driver of the breast cancer phenotype in around 70% of patients [1]. Endocrine treatment modalities targeting ERa, such as the selective estrogen receptor modulator (SERM) tamoxifen or downregulator (SERD) fulvestrant (Fulv; SERM) constitute the basis for therapeutic intervention in ERa-positive tumors [2]. A compelling body of evidence suggests involvement of another nuclear hormone receptor, estrogen-related receptor-a (ERRa), in the pathogenesis of breast cancer. ERa and ERRa share only 33% homology in their ligand-binding domains, resulting in the insensitivity of ERRa to classical ERa ligands such as estrogen and tamoxifen [9,10,11]. Because of the lack of known natural ligands, ERRa is classified as orphan receptor, whereas its transcriptional activity can be abrogated by small-molecule inhibitors Because of the lack of known natural ligands, ERRa is classified as orphan receptor, whereas its transcriptional activity can be abrogated by small-molecule inhibitors (i.e., XCT790; ref. 12)

Methods

Results

Conclusion