Cancer is a major cause of morbidity and mortality in our society. Like other malignancies, ovarian and testicular cancers arise through multiple genetic alterations. Using a knockout mouse model, we discovered that the inhibins, alpha:beta heterodimeric members of the transforming growth factor beta superfamily, are tumor suppressors with specificity for the gonads and adrenal cortex. In mice lacking alpha inhibin, neither inhibin A (alpha:betaA) nor inhibin B (alpha:betaB) is produced, and granulosa/Sertoli cell tumors of the ovaries and testis develop as early as 4 weeks of age with 100% penetrance. The ovarian tumors are often mixed tumors consisting of both granulosa cell and Sertoli cell components. Castration of male and female inhibin a knockout mice leads to a high incidence of sex steroidogenic adrenal cortical tumors (66 of 67 mice). Mice with gonadal or adrenal tumors are rapidly affected by a cancer wasting syndrome which mimics the cachexia syndromes associated with human cancer cases. Using a genetic approach to generate double mutant mice lacking both alpha inhibin and activin receptor type IIA (ActRIIA), we showed that tumor-produced activin directly signals through ActRIIA in the liver and stomach to cause this wasting syndrome. Using similar genetic approaches, we have shown the following: (1) Overexpression of the activin antagonist follistatin alleviates some of the cachexia-like symptoms caused by the circulating activins and slows the tumor development; (2) Absence of gonadotropins FSH and LH, prevents tumor development; (3) Lack of only FSH slows tumor development in both sexes, but mortality rates are sexually dimorphic (0% survival of females, 70% survival of males) demonstrating that FSH functions differentially in ovarian and testicular tumorigenesis; and (4) Absence of the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) speeds the process of gonadal tumorigenesis. The studies in this competitive renewal proposal will continue to define the inhibin signaling process and the mechanism of inhibin action in gonadal and adrenal function in vivo.
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