Thewes, Verena, Simon, Ronald, Schroeter, Petra, Schlotter, Magdalena, Anzeneder, Tobias, Buettner, Reinhard, Benes, Vladimir, Sauter, Guido, Burwinkel, Barbara, Nicholson, Robert I., Sinn, Hans-Peter ORCID: 0000-0003-2836-6699, Schneeweiss, Andreas, Deuschle, Ulrich, Zapatka, Marc ORCID: 0000-0001-8287-5967, Heck, Stefanie and Lichter, Peter (2015). Reprogramming of the ERR alpha and ER alpha Target Gene Landscape Triggers Tamoxifen Resistance in Breast Cancer. Cancer Res., 75 (4). S. 720 - 732. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

Endocrine treatment regimens for breast cancer that target the estrogen receptor-alpha (ER alpha) 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-alpha (ERR alpha) for ER alpha. To examine this hypothesis, we analyzed ERR alpha and ER alpha 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 ER alpha, ERR alpha, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ER alpha and ERR alpha target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERR alpha in tamoxifen-and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERR alpha sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n - 1041), increased expression of ERR alpha was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ER alpha-positive cases. In addition, increased ERR alpha expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ER alpha and ERR alpha cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERR alpha as a candidate drug target to treat endocrine-resistant breast cancer. (C)2015 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Thewes, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simon, RonaldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeter, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlotter, MagdalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anzeneder, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benes, VladimirUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sauter, GuidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burwinkel, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nicholson, Robert I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sinn, Hans-PeterUNSPECIFIEDorcid.org/0000-0003-2836-6699UNSPECIFIED
Schneeweiss, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deuschle, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zapatka, MarcUNSPECIFIEDorcid.org/0000-0001-8287-5967UNSPECIFIED
Heck, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lichter, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-407588
DOI: 10.1158/0008-5472.CAN-14-0652
Journal or Publication Title: Cancer Res.
Volume: 75
Number: 4
Page Range: S. 720 - 732
Date: 2015
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1538-7445
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ESTROGEN-RELATED-RECEPTOR; LIGAND-BINDING DOMAIN; TRANSCRIPTIONAL ACTIVITIES; ENDOCRINE RESISTANCE; GROWTH; EXPRESSION; CELLS; BIOMARKERS; PATHWAY; IDENTIFICATIONMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/40758

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