Estrogen-Related Receptor a Is Critical for the Growth of Estrogen Receptor-Negative Breast Cancer

Expression of estrogen-related receptor alpha (ERR(x) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of this orphan nuclear receptor in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ER(alpha) and ERR alpha initially suggested that these receptors may have similar transcriptional targets. Using the well-characterized ER alpha-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ER alpha-ERR alpha. cross-talk using an unbiased microarray approach. In addition to generating a host of novel ERR alpha. target genes, this study yielded the surprising result that most ERR alpha-regulated genes are unrelated to estrogen signaling. The relatively small number of genes regulated by both ER alpha and ERRa led us to expand our study to the more aggressive and less clinically treatable ER alpha-negative class of breast cancers. In this setting, we found that ERR alpha expression is required for the basal level of expression of many known and novel ERR alpha target genes. Introduction of a small interfering RNA directed to ERR alpha into the highly aggressive breast carcinoma MDA-MB-231 cell line dramatically reduced the migratory potential of these cells. Although stable knockdown of ERR alpha expression in MDA-MB-231 cells had no effect on in vitro cell proliferation, a significant reduction of tumor growth rate was observed when these cells were implanted as xenografts. Our results confirm a role for ERR alpha in breast cancer growth and highlight it as a potential therapeutic target for estrogen receptor-negative breast cancer. [Cancer Res 2008;68(21):8805-12]