Estrogen-related receptor a in human breast carcinoma as a potent prognostic factor

Estrogen-related receptor alpha (ERRalpha) was identified as a gene related to estrogen receptor alpha (ERalpha) and belongs to a class of nuclear orphan receptors. ERRa binds to estrogen responsive element(s) (ERE) and is considered to be involved in modulation of estrogenic actions. However, biological significance of ERRa remains largely unknown. Therefore, we examined the expression of ERRa in human breast carcinoma tissues using immunohistochemistry (n = 102) and real-time reverse transcription-PCR (n = 30). ERRa immunoreactivity was detected in the nuclei of carcinoma cells in 55% of breast cancers examined, and relative immunoreactivity of ERRa was significantly (P = 0.0041) associated with the mRNA level. Significant associations were detected between ERa and ERE-containing estrogen-responsive genes, such as pS2 (P < 0.0001) and EBAG9/RCAS1 (P = 0.0214), in breast carcinoma tissues. However, no significant association was detected between ERa and pS2 (P = 0.1415) in the ERRalpha-positive cases (n = 56) or between ERa and EBAG9/RCAS1 (P = 0.8271) in the ERRalpha-negative group (n = 46). ERRa immunoreactivity was significantly associated with an increased risk of recurrence and adverse clinical outcome by both uni- (P = 0.0097 and P = 0.0053, respectively) and multi- (P = 0.0215 and P = 0.0118, respectively) variate analyses. A similar tendency was also detected in the group of breast cancer patients who received tamoxifen therapy after surgery. Results from our study suggest that ERRa possibly modulates the expression of ERE-containing estrogen-responsive genes, and ERRa immunoreactivity is a potent prognostic factor in human breast carcinoma.