Drug development for ovarian hyper-stimulation and anti-cancer treatment: blocking of gonadotropin signaling for epiregulin and amphiregulin biosynthesis

Abstract

Gonadotropins play a crucial role in ovarian homeostasis and fertilization through the activation of the cAMP cascade. However, gonadotropin hyper-stimulation may be associated with higher risk for ovarian cancer development. It has been suggested, that high gonadotropin levels in peritoneal and ovarian cystic fluids of patients suffering from benign ovarian cysts, may lead to malignancy. Moreover, we have recently discovered that gonadotropin stimulation can activate the MAPK cascade in target cells. Using DNA microarray technology and RNA from human granulosa cells, we discovered that stimulation with saturating doses of gonadotropins dramatically elevates activity of genes coding for epiregulin and amphiregulin. These gene products can bind and activate the EGF receptor and ERBB4, which are associated with the development of various cancers such as ovarian, breast endometrial and other non-gynecological malignancies. Gonadotropin receptors are expressed not only in the gonads, but also in non-gonadal tissues and in cancer cells. The discovery that gonadotropins activate certain mitogenic signal transduction pathways, may serve as a guide for novel anti-cancer therapy by (1) specific interference at the receptor level to block the gonadotropic response, or arresting the receptor expression and (2) blocking downstream mitogenic signals generated by these hormones, like attenuation of the expression of epiregulin and amphiregulin that belong to the EGF family, using anti-sense and/or SiRNA techniques targeted to suppress their expression. Moreover, since amphiregulin and epiregulin act as mediators of luteinizing hormone (LH) action in the mammalian ovulatory follicles, regulation of the expression of these factors may open new possibilities in treatment of ovarian malfunction implicated with ovarian hyper-stimulation.