Mitochondrial estrogen receptor β2 drives antiapoptotic pathways in advanced serous ovarian cancer

We previously showed an unfavorable prognostic role of the cytoplasmic estrogen receptor beta 2 (cER beta 2) in serous ovarian cancer. Here we aimed to investigate molecular determinants in cell survival function of cER beta 2 in this malignant disease. We used immunohistochemistry to evaluate differences in apoptosis (quantified by the expression of cleaved caspase-3) and cell proliferation (quantified by the expression of Ki-67) in 56 advanced serous ovarian cancer cases, stratified according to the absence or presence of estrogen receptor beta 2 (ER beta 2) protein in the cytoplasmic compartment (31 cER beta 2- and 25 cER beta 2+ cases, respectively). Thereafter, by immunofluorescence, we visualized the subcellular distribution of ER beta 2, and by the proximity ligation assays, we characterized in situ its ability to interact with other proteins specifically involved in the apoptosis cascade. Finally, we assessed cytochrome c expression by immunohistochemistry. We demonstrated that, although not affecting tumor proliferation, cytoplasmic ER beta 2 expression was indeed associated to a lower apoptotic rate in ovarian cancer cases. Then, we proved that cER beta 2 is targeted to mitochondria where it interacts as a binding partner with BAD (B-cell lymphoma [Bcl] 2-associated death promoter). This interaction, precluding the Bcl-xL (B-cell lymphoma extra large)/BAD heterodimer formation, inhibited Bax (Bcl-2-like protein 4) oligomerization, the release of cytochrome c, and ultimately apoptosis. In conclusion, we provide in vivo mechanistic evidence for an antiapoptotic function of mitochondrial ER beta 2, a finding supporting the value of its cytoplasmic expression as an unfavorable prognostic biomarker for serous ovarian cancer. (C) 2015 Elsevier Inc. All rights reserved.