ROLE OF ANDROGENS IN TESTICULAR-TUMOR DEVELOPMENT IN INHIBIN-DEFICIENT MICE

To understand gonadal tumor development, we have previously created a mouse model in which mice deficient in the inhibins develop gonadal se x cord-stromal tumors with essentially 100% penetrance. These tumors d evelop as early as 4 weeks of age and cause cancer cachexia-like sympt oms and subsequent death in the inhibin-deficient mice. Gonadectomized inhibin-deficient mice eventually develop adrenal cortical tumors wit h nearly 100% penetrance. These studies have identified inhibin as a n ovel secreted tumor suppressor protein with specificity for the gonads and adrenal glands. Sex steroids have been implicated to influence go nadal tumor development in humans and mice. To determine the role of a ndrogens in gonadal tumorigenesis in inhibin-deficient male mice, we h ave used a genetic intercross strategy, breeding inhibin alpha mutant mice with tfm (testicular feminization, a naturally occurring androgen receptor mutant) carrying females to eventually generate compound mut ant male mice that lack inhibins and carry the tfm mutation. These com pound mutant mice, like inhibin-deficient mice, continue to develop te sticular tumors and the accompanying cancer cachexia-like wasting synd rome. Consistent with these findings, elevated levels of activins A an d B secreted from the gonadal tumors are seen in the adult compound mu tant mice as well as the secondary pathological consequences of these high activin levels in the livers and glandular stomachs. However, in contrast to male mice lacking only inhibin, in which essentially 100% of the testicular tumors are hemorrhagic, 65% of the tumors in these c ompound mutant male mice are less hemorrhagic, and approximately 50% o f the compound mutants live longer than 17 weeks of age (95% of the ma le mice lacking only inhibin die by 12 weeks). These results suggest t hat androgens are not required for testicular tumor development in inh ibin-deficient mice, but may play a regulatory role in testicular tumo r progression.