Functional Profiling of FSH and Estradiol in Ovarian Granulosa Cell Tumors

Autor: Alejandra Cervera, Hugo M. Horlings, Noora Andersson, Mikko Anttonen, Ralf Bützow, Anniina Färkkilä, Marjut Pihlajoki, Markku Heikinheimo, Olli Carpén, Leila Unkila-Kallio, Johanna Tapper, Ursula Turpeinen, Ulla-Maija Haltia, Lotta Mäkinen, David B. Wilson
Přispěvatelé: HUS Children and Adolescents, HUS Gynecology and Obstetrics, Children's Hospital, Clinicum, Developmental and tumor biology research group, Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital Area, Research Program in Systems Oncology, Faculty of Medicine, Medicum, Doctoral Programme in Biomedicine, Sampsa Hautaniemi / Principal Investigator, Genome-Scale Biology (GSB) Research Program, Research Programs Unit, Department of Diagnostics and Therapeutics, HUSLAB, Department of Pathology, Precision Cancer Pathology, Olli Mikael Carpen / Principal Investigator, Helsinki One Health (HOH), University Management
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Journal of the Endocrine Society
ISSN: 2472-1972
Popis: Adult-type granulosa cell tumors (AGCTs) are sex-cord derived neoplasms with a propensity for late relapse. Hormonal modulators have been used empirically in the treatment of recurrent AGCT, albeit with limited success. To provide a more rigorous foundation for hormonal therapy in AGCT, we used a multimodal approach to characterize the expressions of key hormone biomarkers in 175 tumor specimens and 51 serum samples using RNA sequencing, immunohistochemistry, RNA in situ hybridization, quantitative PCR, and circulating biomarker analysis, and correlated these results with clinical data. We show that FSH receptor and estrogen receptor beta (ERβ) are highly expressed in the majority of AGCTs, whereas the expressions of estrogen receptor alpha (ERα) and G-protein coupled estrogen receptor 1 are less prominent. ERβ protein expression is further increased in recurrent tumors. Aromatase expression levels show high variability between tumors. None of the markers examined served as prognostic biomarkers for progression-free or overall survival. In functional experiments, we assessed the effects of FSH, estradiol (E2), and the aromatase inhibitor letrozole on AGCT cell viability using 2 in vitro models: KGN cells and primary cultures of AGCT cells. FSH increased cell viability in a subset of primary AGCT cells, whereas E2 had no effect on cell viability at physiological concentrations. Letrozole suppressed E2 production in AGCTs; however, it did not impact cell viability. We did not find preclinical evidence to support the clinical use of aromatase inhibitors in AGCT treatment, and thus randomized, prospective clinical studies are needed to clarify the role of hormonal treatments in AGCTs.
Databáze: OpenAIRE
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