Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer
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Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer. / Thewes, Verena; Simon, Ronald; Schroeter, Petra; Schlotter, Magdalena; Anzeneder, Tobias; Büttner, Reinhard; Benes, Vladimir; Sauter, Guido; Burwinkel, Barbara; Nicholson, Robert I; Sinn, Hans-Peter; Schneeweiss, Andreas; Deuschle, Ulrich; Zapatka, Marc; Heck, Stefanie; Lichter, Peter.
In: CANCER RES, Vol. 75, No. 4, 15.02.2015, p. 720-31.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer
AU - Thewes, Verena
AU - Simon, Ronald
AU - Schroeter, Petra
AU - Schlotter, Magdalena
AU - Anzeneder, Tobias
AU - Büttner, Reinhard
AU - Benes, Vladimir
AU - Sauter, Guido
AU - Burwinkel, Barbara
AU - Nicholson, Robert I
AU - Sinn, Hans-Peter
AU - Schneeweiss, Andreas
AU - Deuschle, Ulrich
AU - Zapatka, Marc
AU - Heck, Stefanie
AU - Lichter, Peter
N1 - ©2015 American Association for Cancer Research.
PY - 2015/2/15
Y1 - 2015/2/15
N2 - 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.
AB - 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.
U2 - 10.1158/0008-5472.CAN-14-0652
DO - 10.1158/0008-5472.CAN-14-0652
M3 - SCORING: Journal article
C2 - 25643697
VL - 75
SP - 720
EP - 731
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 4
ER -