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.