Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Thewes, Verena UNSPECIFIED UNSPECIFIED UNSPECIFIED Simon, Ronald UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeter, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlotter, Magdalena UNSPECIFIED UNSPECIFIED UNSPECIFIED Anzeneder, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Benes, Vladimir UNSPECIFIED UNSPECIFIED UNSPECIFIED Sauter, Guido UNSPECIFIED UNSPECIFIED UNSPECIFIED Burwinkel, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Nicholson, Robert I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sinn, Hans-Peter UNSPECIFIED orcid.org/0000-0003-2836-6699 UNSPECIFIED Schneeweiss, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Deuschle, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Zapatka, Marc UNSPECIFIED orcid.org/0000-0001-8287-5967 UNSPECIFIED Heck, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Lichter, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-412478
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:	Keywords Language ESTROGEN-RELATED-RECEPTOR; LIGAND-BINDING DOMAIN; TRANSCRIPTIONAL ACTIVITIES; ENDOCRINE RESISTANCE; GROWTH; EXPRESSION; CELLS; BIOMARKERS; PATHWAY; IDENTIFICATION Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41247