Alessandra Ciucci1, Gabriella Ferrandina1, Floriana Mascilini1, Flavia Filippetti1, Giovanni Scambia1, Gian Franco Zannoni1, Daniela Gallo2. 1. Department of Woman and Child Health, Fondazione Policlinico Universitario A. Gemelli IRCCS -Università Cattolica del Sacro Cuore, Rome, Italy. 2. Department of Woman and Child Health, Fondazione Policlinico Universitario A. Gemelli IRCCS -Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address: daniela.gallo@unicatt.it.
Abstract
OBJECTIVE: Adult granulosa cell tumor (AGCT) is a rare form of sex-cord stromal ovarian tumors. Due to their origin, AGCTs secrete estrogens, and thus, estrogen receptor (ER)-mediated signaling has been considered as a possible target for therapy. The aim of the present study was to get insights into estrogen receptor status and activity in AGCTs, as a strategy to provide molecular support for personalized hormonal treatments. METHODS: We evaluated by immunohistochemistry the expression of ERα, ERβ isoforms (i.e. ERβ1, ERβ2 and ERβ5), progesterone and androgen receptor (PR, AR) in 20 untreated AGCTs and 12 unmatched recurrent lesions. Thereafter, we visualized by immunofluorescence, the subcellular distribution of cytoplasmic receptors, and by the proximity ligation assays (PLA) we characterized in situ their ability to interact with other proteins involved in the apoptotic cascade. RESULTS: Primary AGCTs predominantly expressed ERβ isoforms, along with PR and AR, while only 30% of patients showed ERα expression. Recurrent tumors were associated with a decrease in AR levels. From mechanistic studies it emerges that ERβ2, and to a lesser extent ERβ1 and AR, are mitochondrial components in cancer cells and that ERβ2 can act as a binding partner of proteins involved in the apoptotic cascade, in turn potentially inhibiting apoptosis. CONCLUSIONS: As in other endocrine tumors, ERβ may play a role in the pathogenesis of AGCT; it is crucial to understand estrogen receptor-mediated pathways before planning hormonal treatment strategies in AGCT.
OBJECTIVE: Adult granulosa cell tumor (AGCT) is a rare form of sex-cord stromal ovarian tumors. Due to their origin, AGCTs secrete estrogens, and thus, estrogen receptor (ER)-mediated signaling has been considered as a possible target for therapy. The aim of the present study was to get insights into estrogen receptor status and activity in AGCTs, as a strategy to provide molecular support for personalized hormonal treatments. METHODS: We evaluated by immunohistochemistry the expression of ERα, ERβ isoforms (i.e. ERβ1, ERβ2 and ERβ5), progesterone and androgen receptor (PR, AR) in 20 untreated AGCTs and 12 unmatched recurrent lesions. Thereafter, we visualized by immunofluorescence, the subcellular distribution of cytoplasmic receptors, and by the proximity ligation assays (PLA) we characterized in situ their ability to interact with other proteins involved in the apoptotic cascade. RESULTS: Primary AGCTs predominantly expressed ERβ isoforms, along with PR and AR, while only 30% of patients showed ERα expression. Recurrent tumors were associated with a decrease in AR levels. From mechanistic studies it emerges that ERβ2, and to a lesser extent ERβ1 and AR, are mitochondrial components in cancer cells and that ERβ2 can act as a binding partner of proteins involved in the apoptotic cascade, in turn potentially inhibiting apoptosis. CONCLUSIONS: As in other endocrine tumors, ERβ may play a role in the pathogenesis of AGCT; it is crucial to understand estrogen receptor-mediated pathways before planning hormonal treatment strategies in AGCT.
Authors: Ulla-Maija Haltia; Marjut Pihlajoki; Noora Andersson; Lotta Mäkinen; Johanna Tapper; Alejandra Cervera; Hugo M Horlings; Ursula Turpeinen; Mikko Anttonen; Ralf Bützow; Leila Unkila-Kallio; Olli Carpén; David B Wilson; Markku Heikinheimo; Anniina Färkkilä Journal: J Endocr Soc Date: 2020-03-16
Authors: Joline F Roze; Hannah S van Meurs; Glen R Monroe; Wouter B Veldhuis; Luc R C W van Lonkhuijzen; Roel J Bennink; Jolijn W Groeneweg; Petronella O Witteveen; Geertruida N Jonges; Ronald P Zweemer; Arthur J A T Braat Journal: Oncotarget Date: 2021-03-30