| First Author | Thewes V | Year | 2015 |
| Journal | Cancer Res | Volume | 75 |
| Issue | 4 | Pages | 720-31 |
| PubMed ID | 25643697 | Mgi Jnum | J:219959 |
| Mgi Id | MGI:5630024 | Doi | 10.1158/0008-5472.CAN-14-0652 |
| Citation | Thewes V, et al. (2015) Reprogramming of the ERRalpha and ERalpha target gene landscape triggers tamoxifen resistance in breast cancer. Cancer Res 75(4):720-31 |
| abstractText | Endocrine treatment regimens for breast cancer that target the estrogen receptor-alpha (ERalpha) 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 (ERRalpha) for ERalpha. To examine this hypothesis, we analyzed ERRalpha and ERalpha 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 ERalpha, ERRalpha, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERalpha and ERRalpha target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRalpha in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRalpha sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRalpha was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERalpha-positive cases. In addition, increased ERRalpha expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERalpha and ERRalpha cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRalpha as a candidate drug target to treat endocrine-resistant breast cancer. |
