Inhibin-α knockout (Inha-/-) female mice develop sex cord-stromal
ovarian cancer with complete penetrance and previous studies demonstrate that the
pituitary gonadotropins (FSH and LH) are influential modifiers of
granulosa cell tumor development and progression in
inhibin-deficient females. Recent studies have demonstrated that Inha-/- ovarian follicles develop precociously to the early
antral stage in prepubertal mice without any increase in serum FSH. These studies suggest that in the absence of
inhibins, granulosa cells differentiate abnormally and thus at sexual maturity may undergo an abnormal response to
gonadotropin signaling contributing to
tumor development. To test this hypothesis, we stimulated immature wild-type and Inha-/- female mice with
gonadotropin analogs prior to
tumor formation and subsequently examined
gonadotropin-induced ovarian follicle development as well as preovulatory and
human chorionic gonadotropin-induced gene expression changes in granulosa cells. We find that at 3 wk of age,
inhibin-deficient ovaries do not show further
antral development or undergo cumulus expansion. In addition, there are widespread alterations in the transcriptome of
gonadotropin-treated Inha-/- granulosa cells, with significant changes in genes involved in extracellular matrix and cell-cell communication. These data indicate the
gonadotropins initiate an improper program of cell differentiation prior to
tumor formation in the absence of
inhibins.