title: Mitochondrial estrogen receptor β2 drives antiapoptotic pathways in advanced serous ovarian cancer.
abstract: We previously showed an unfavorable prognostic role of the cytoplasmic estrogen receptor β2 (cERβ2) in serous ovarian cancer. Here we aimed to investigate molecular determinants in cell survival function of cERβ2 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 β2 (ERβ2) protein in the cytoplasmic compartment (31 cERβ2- and 25 cERβ2+ cases, respectively). Thereafter, by immunofluorescence, we visualized the subcellular distribution of ERβ2, 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 ERβ2 expression was indeed associated to a lower apoptotic rate in ovarian cancer cases. Then, we proved that cERβ2 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 ERβ2, a finding supporting the value of its cytoplasmic expression as an unfavorable prognostic biomarker for serous ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, 8-00168, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ciucci
authors.affiliation: Department of Histopathology, Catholic University of the Sacred Heart, 8-00168, Rome, Italy.
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Zannoni
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, 8-00168, Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Travaglia
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, 8-00168, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, 8-00168, Rome, Italy. Electronic address: d.gallo@rm.unicatt.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gallo
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism / Q000473:pathology*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008928:Mitochondria / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D047629:Estrogen Receptor beta
keywords: ERβ2; ERβcx; Mitochondria; Ovarian carcinomas; Ovary