ESTROVARYTUMOUR

Investigating the Roles and Mechanisms of Action of Estrogens via Estrogen Receptor ß in Granulosa Cell Tumours of the Ovary

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 Obiettivo del progetto (Objective)

'Granulosa cell tumours (GCT) are a rare form of malignancy affecting women of all ages. Because GCT display a high propensity to recurrence and there is no efficient curative treatment beyond surgery, ~ 20% of adult patients die of the consequences of their tumour. However, despite the importance and insidiousness of GCT, very little is known of its molecular etiology. Although most GCT produce estrogens and strongly express estrogen receptor ß (ERß), the role of estrogens in GCT pathogenesis is currently unknown. Given the stimulatory effect of estrogens via ERß in the normal ovary on granulosa cell proliferation and survival, one can hypothesize that estrogens would exert similar actions in tumoral granulosa cells, thereby favouring GCT growth. Besides, estrogens stimulate cell metastasis in other cancers. The possibility that estrogens would exert a stimulatory role on GCT growth and metastasis is further suggested by my recent findings showing that, in tumoral granulosa cells, estrogens activate the phosphatidyl-inositol 3 kinase (PI3K) pathway by non-genomic actions. The PI3K pathway is frequently overactivated in human cancers to contribute to cell proliferation, survival and metastasis. This proposal, therefore, aims at 1) investigating the possibility that estrogens stimulate GCT growth and metastasis via ERß, and at 2) further understanding their underlying mechanisms of action, with a special emphasis on estrogens non-genomic mechanisms leading to the activation of the PI3K pathway. To address these goals, I will take advantage of the availability in the host laboratory of tumoral granulosa cell lines established from human GCT to carry out in vitro studies and to perform in vivo analyses with a xenograft mouse model. Overall, this proposal will provide important insights into the role of estrogens in GCT growth and progression and their molecular mechanisms with a special emphasis on novel modes of estrogens action through non-genomic mechanisms.'

Introduzione (Teaser)

Oestrogens play a tumour-promoting role in many gynaecological cancers. Based on this, a European study is addressing the impact of female sex hormones on granulosa cell tumour (GCT) formation and progression.