Nuclear Receptor Profiling of Ovarian Granulosa Cell Tumors

Abstract

Granulosa cell tumors of the ovary (GCT) represent ~5% of malignant ovarian tumors. The adult form is defined by a mutation in the FOXL2 gene. GCT exhibit many of the features of normal proliferating granulosa cells. We have profiled the expression of the 48 human nuclear receptors (NR) by quantitative RT-PCR in a panel of GCT and in two GCT-derived cell lines, COV434 and KGN. The highest level of expression is seen for COUP-TF2 with abundant expression of PPARγ, SF-1, and TR-α. Estrogen receptor (ER)-β is the most abundant of the steroid receptors with relatively high expression also of AR, ER-α, and PR. The concordance of expression for each NR across the tumors is remarkably high with same discordance between the cell lines and the tumors, particularly the COV434 line. No significant differences were observed with respect to tumor stage for NR expression. These findings provide a full profile of NR expression in GCT which will enable full characterization of their roles and potential as therapeutic targets.

The <i>FOXL2</i> Mutation (c.402C>G) in Adult-Type Ovarian Granulosa Cell Tumors of Three Japanese Patients: Clinical Report and Review of the Literature

“…The percentage of mutated tumors in the reviewed series was consistent with existing reports, ranging from 70.4% to 100% (mean, 91.9%). The FOXL2 mutation occurred in more than 90% of mutated tumors in all but two studies (Alexiadis et al 2011;D'Angelo et al 2011), in which FOXL2 mutation occurred in 70.4% and 85.7% of tumors. Excluding this study, the FOXL2 mutation occurred in 94.0% of AGCTs.…”

“…In humans, FOXL2 is expressed almost exclusively in ovarian tissue, in which it is involved in ovarian development (Cocquet et al 2002;Schmidt et al 2004). It has been reported that the somatic mutation in FOXL2 gene (c.402C>G) is present in more than 95% of ovarian AGCTs, but not in several other neoplasms (Schrader et al 2009;Shah et al 2009;Benayoun et al 2010;Jamieson et al 2010;Kim et al 2010a;Lee et al 2010;Al-Agha et al 2011;Alexiadis et al 2011;D'Angelo et al 2011;Gershon et al 2011;Hes et al 2011). Although the functional consequence of the missense mutation remain unclear, Benayoun et al (2013) reported that FOXL2 mutation induced genes that are associated with faster cell cycling and the downregulation of genes associated with cell death.…”

“…Eleven articles have reported patients of the somatic mutation in the FOXL2 gene (c.402C>G) among ovarian AGCTs (Schrader et al 2009;Shah et al 2009;Jamieson et al 2010;Kim et al 2010a, b;Lee et al 2010;Al-Agha et al 2011;Alexiadis et al 2011;D'Angelo et al 2011;Gershon et al 2011;Hes et al 2011). No article have identified the mutations other than the mutation of FOXL2 c.402C>G. Table 2 shows all of the patients in these articles, including our four patients, and shows the authors, number of patients studied for each series, number/percentage of mutated tumors, number/percentage of heterozygous mutated tumors, and number/percentage of primary tumors in each study.…”

Non-epithelial Ovarian Cancer: Elucidating Uncommon Gynaecological Malignancies

“…Hormonal therapy: Hormone treatment is a logical treatment for advanced GrCT, given their frequent oestrogen dependence and usually indolent course (51). Bone density monitoring is indicated for patients receiving aromatase inhibitors, as is the standard of care in breast cancer treatment.…”

In-depth Proteomic Characterization of Endogenous Nuclear Receptors in Mouse Liver

“…Because the expression pattern of NR genes in different tissues may suggest their relative functional importance in different tissues, expression profiling of NRs has greatly facilitated our understanding of the physiological functions of these receptors (12)(13)(14)(15)(16)(17)(18). The expression of the entire NR transcriptome was characterized by Mangelsdorf and colleagues; in their work, all 49 mouse NR mRNAs were measured via quantitative RT-PCR (QPCR) in 39 tissues (17).…”