Development, growth and function of the ovary are controlled by endocrine and paracrine signals. These may also influence the development of ovarian cancer. The aim of this study was to identify the key molecular markers of the unregulated growth and hormone synthesis seen in ovarian tumours, particularly in granulosa cell tumours (GCT). Genes used in this study were chosen on the basis of our understanding of growth and differentiation in the normal ovary. We sought to define the patterns of gene expression in a panel of epithelial and stromal ovarian tumours. Expression was determined by RT-PCR using gene-specific primers for the FSH receptor (FSHR); the FSH early response genes: regulatory subunit of protein kinase A (RII-beta), cyclin D2 (cycD2) and sgk; and late response markers: cyclooxygenase-2 (COX-2) and the LH receptor (LHR). The GCT had high expression of FSHR compared with normal ovaries and the other tumours. cycD2 and RII-beta and COX-2 genes were also highly expressed in the GCT. sgk and LHR expression was lower in all of the tumours than in normal ovaries. Serous cystadenocarcinomas also had an unexpectedly high expression of COX-2. Comparison of the gene expression profiles between each tumour group suggests a molecular phenotype for GCT that is similar to that reported for FSH stimulated pre-ovulatory granulosa cells.
Granulosa cell tumors of the ovary (GCT) express the inhibin subunit genes and secrete dimeric inhibin. Transgenic mice null for the alpha-inhibin gene develop GCT. It has been suggested that this apparent contradiction may be reconciled if the human GCT are resistant to the tumor-suppressive effects of inhibin. Inhibin receptors have recently been characterized as consisting of either betaglycan or p120 in association with the type II or type I activin receptor subunits (ActR), respectively. To test the hypothesis that GCT may exhibit loss of inhibin receptor expression we have examined the expression of the receptor subunits in a cohort of GCT and in mucinous and serous cystadenocarcinomas and normal ovary. Expression was determined by RT-PCR using gene-specific primers and probes combined with Southern blot analysis of the PCR products. The ActRI subunits and ActRIIA exhibited widespread albeit variable expression across tissues, with the highest levels in the serous tumors. ActRIIB expression was relatively low in the mucinous tumors and high in the GCT. Betaglycan expression was abundant, widespread, and variable across all tissues; highest mean levels occurred in the GCT and normal ovary. p120 expression was low or absent in all tissues except the GCT. Within the GCT there was parallel expression of the ActR subunits, betaglycan and p120; the levels, however, varied considerably between tumors. Expression of betaglycan and p120 in most GCT argues against the hypothesis, but does not exclude the possibility that low or absent expression of p120 might be significant in a subset of these tumors.
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