Functional Profiling of FSH and Estradiol in Ovarian Granulosa Cell Tumors

Abstract

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.

FOXO1 mitigates the SMAD3/FOXL2C134W transcriptomic effect in a model of human adult granulosa cell tumor

“…In contrast to the rarer juvenile Granulosa Cell tumors, the bulk of granulosa cell tumors are the adult type (aGCT), which occur peri to post-menopausally [ 52 – 54 ]. Patients characteristically present elevated estrogen levels and postmenopausal bleeding [ 3 , 55 ]. Almost all aGCTs bear the unique somatic mutation FOXL2 C134W [ 56 ], which appears essential to the aGCT development [ 8 , 9 , 11 , 25 , 57 – 60 ].…”

FOXO1 mitigates the SMAD3/FOXL2C134WTranscriptomic Effect in a Model of Human Adult Granulosa Cell Tumor

“…In contrast to the rarer juvenile Granulosa Cell tumors, the bulk of granulosa cell tumors are the adult type (aGCT) which occur peri to post-menopausally [50][51][52]. Patients characteristically present elevated estrogen levels and postmenopausal bleeding [3,53]. Almost all aGCTs bear the unique somatic mutation FOXL2 C134W [54], which appears essential to the aGCT development [7,9,14,25,[55][56][57][58].…”

Estrogen disorders: Interpreting the abnormal regulation of aromatase in granulosa cells (Review)

“…A recent study designed and synthesized a novel aromatase inhibitor based on triazole and imidazole ( 113 ). However, the current inhibitors are mainly used in the treatment of breast cancer, albeit for other steroid-dependent diseases and female infertility, and there are a relatively few effective and specific drugs available ( 114 , 115 ), which indicates that the search for novel AIs and other effective drug targets is crucial.…”