TY - JOUR
T1 - Functional profiling of FSH and estradiol in ovarian granulosa cell tumors
AU - Haltia, Ulla Maija
AU - Pihlajoki, Marjut
AU - Andersson, Noora
AU - Mäkinen, Lotta
AU - Tapper, Johanna
AU - Cervera, Alejandra
AU - Horlings, Hugo M.
AU - Turpeinen, Ursula
AU - Anttonen, Mikko
AU - Bützow, Ralf
AU - Unkila-Kallio, Leila
AU - Carpén, Olli
AU - Wilson, David B.
AU - Heikinheimo, Markku
AU - Färkkilä, Anniina
N1 - Publisher Copyright:
© Endocrine Society 2020.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Aromatase
KW - Estrogen receptor
KW - Granulosa cell tumor
KW - Hormonal treatment
UR - http://www.scopus.com/inward/record.url?scp=85101275882&partnerID=8YFLogxK
U2 - 10.1210/JENDSO/BVAA034
DO - 10.1210/JENDSO/BVAA034
M3 - Article
AN - SCOPUS:85101275882
SN - 2472-1972
VL - 4
SP - 1
EP - 20
JO - Journal of the Endocrine Society
JF - Journal of the Endocrine Society
IS - 4
ER -