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

• Verfasst von: Thewes, Verena [VerfasserIn]
• Verfasst von: Benes, Vladimir [VerfasserIn]
• Verfasst von: Burwinkel, Barbara [VerfasserIn]
• Verfasst von: Sinn, Peter [VerfasserIn]
• Verfasst von: Schneeweiss, Andreas [VerfasserIn]
• Titel: Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer
• Verf.angabe: 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
• E-Jahr: 2015
• Jahr: February 2, 2015
• Umfang: 13 S.
• Fussnoten: Gesehen am 30.06.2020
• Titel Quelle: Enthalten in: Cancer research
• Ort Quelle: Philadelphia, Pa. : AACR, 1916
• Jahr Quelle: 2015
• Band/Heft Quelle: 75(2015), 4, Seite 720-731
• ISSN Quelle: 1538-7445
• DOI: doi:10.1158/0008-5472.CAN-14-0652
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1702924076

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. Cancer Res; 75(4); 720-31. ©2015 AACR.