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Estrogen-Related Receptor in Human Breast Carcinoma as a Potent Prognostic Factor

Departments of ¹ Pathology and ² Surgery, Tohoku University School of Medicine, Sendai, Japan; and ³ Department of Surgery, Tohoku Kosai Hospital, Sendai, Japan

Estrogen-related receptor (ERR) was identified as a gene related to estrogen receptor (ER) and belongs to a class of nuclear orphan receptors. ERR binds to estrogen responsive element(s) (ERE) and is considered to be involved in modulation of estrogenic actions. However, biological significance of ERR remains largely unknown. Therefore, we examined the expression of ERR in human breast carcinoma tissues using immunohistochemistry (n = 102) and real-time reverse transcription-PCR (n = 30). ERR immunoreactivity was detected in the nuclei of carcinoma cells in 55% of breast cancers examined, and relative immunoreactivity of ERR was significantly (P = 0.0041) associated with the mRNA level. Significant associations were detected between ER 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 ER and pS2 (P = 0.1415) in the ERR-positive cases (n = 56) or between ER and EBAG9/RCAS1 (P = 0.8271) in the ERR-negative group (n = 46). ERR 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 ERR possibly modulates the expression of ERE-containing estrogen-responsive genes, and ERR immunoreactivity is a potent prognostic factor in human breast carcinoma.

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