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Cancer Res. 2015 Feb 15;75(4):720-31. doi: 10.1158/0008-5472.CAN-14-0652. Epub 2015 Feb 2.

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

Author information

1
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
3
Foundation PATH-Patients' Tumor Bank of Hope, Munich, Germany.
4
Institute of Pathology, University Hospital Cologne, Cologne, Germany.
5
Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
6
Molecular Biology of Breast Cancer, University Women's Clinic, Heidelberg, Germany.
7
Breast Cancer Group, Cardiff University, Cardiff, United Kingdom.
8
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
9
Gynecologic Oncology, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
10
Phenex Pharmaceuticals AG, Heidelberg, Germany.
11
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. peter.lichter@dkfz.de.

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.

PMID:
25643697
DOI:
10.1158/0008-5472.CAN-14-0652
[Indexed for MEDLINE]
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