Estrogen-related receptor γ modulates cell proliferation and estrogen signaling in breast cancer

Breast cancer is primarily a hormone-dependent tumor that can be regulated by status of steroid hormones including estrogen and progesterone. Estrogen-related receptors (ERRs) are orphan nuclear receptors most closely related to estrogen receptor (ER) and much attention has been recently paid to the functions of ERRs in breast cancer in terms of the interactions with ER. In the present study, we investigated the expression of ERR gamma in human invasive breast cancers by immunohistochemical analysis (n =110) obtained by radical mastectomy. Nuclear immunoreactivity of ERR gamma was detected in 87 cases (79%) and tended to correlate with the lymph node status. No significant associations were observed with other clinicopathological characteristics, including the expression levels of both estrogen and progesterone receptors. In MCF-7 breast cancer cells, we demonstrated that ERR gamma mRNA was up-regulated dose-dependently by estrogen, and that this up-regulation of ERR gamma mRNA by estrogen was abolished by ICI 182,780 treatment. We also demonstrated that exogenously transfected ERR gamma increased MCF-7 cell proliferation. Furthermore, ERR gamma enhanced estrogen response element (ERE)-driven transcription in MCF-7 cells. In 2931 cells, ERR gamma could also stimulate ERE-mediated transcription with or without ER alpha. These results suggest that ERR gamma plays an important role as a modulator of estrogen signaling in breast cancer cells. (C) 2010 Elsevier Ltd. All rights reserved.