Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer
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 (...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
February 2, 2015
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| In: |
Cancer research
Year: 2015, Volume: 75, Issue: 4, Pages: 720-731 |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-14-0652 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/0008-5472.CAN-14-0652 Verlag, lizenzpflichtig, Volltext: https://cancerres.aacrjournals.org/content/75/4/720 
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| Author Notes: | Verena Thewes, Ronald Simon, Petra Schroeter, Magdalena Schlotter, Tobias Anzeneder, Reinhard Büttner, Vladimir Benes, Guido Sauter, Barbara Burwinkel, Robert I. Nicholson, Hans-Peter Sinn, Andreas Schneeweiss, Ulrich Deuschle, Marc Zapatka, Stefanie Heck, and Peter Lichter |
| Summary: | 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. Cancer Res; 75(4); 720-31. ©2015 AACR. |
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| Item Description: | Gesehen am 30.06.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-14-0652 |