DIRECT LUTEINIZING-HORMONE ACTION TRIGGERS ADRENOCORTICAL TUMORIGENESIS IN CASTRATED MICE TRANSGENIC FOR THE MURINE INHIBIN ALPHA-SUBUNIT PROMOTER SIMIAN-VIRUS-40 T-ANTIGEN FUSION GENE

Transgenic (TG) mice, expressing the Simian Virus 40 T-antigen (Tag) u nder a 6-kb fragment of the murine inhibin alpha-subunit promoter (inh alpha p), develop gonadal tumors of granulosa/theca or Leydig cell or igin. We showed previously that adrenocortical tumors develop if the T G mice are gonadectomized but never develop in intact animals. However , if functional gonadectomy was induced by GnRH antagonist treatment o r by cross-breeding the TG mice into the hypogonadotropic hpg genetic background, neither gonadal nor adrenal tumors appeared. Since the mos t obvious difference between the gonadectomized and GnRH-antagonist-tr eated or Tag/hpg double mutant mice is the elevated gonadotropin secre tion in the first group, we examined whether the adrenal tumorigenesis would be gonadotropin-dependent. Surprisingly, both the adrenal tumor s and a cell line (C alpha 1) derived from one of them expressed highl y functional LH receptors (LHR), as assessed by Northern hybridization , immunocytochemistry, ligand binding, and human CG (hCG)-stimulated c AMP and steroid production. No FSH receptor expression was found in th e adrenal tumors by RT-PCR. hCG treatment of the C alpha 1 cells stimu lated their proliferation, as measured by [H-3]thymidine incorporation . This effect was related to hCG-stimulated steroidogenesis since prog esterone, testosterone, and estradiol, at physiological concentrations , also stimulated the C alpha 1 cell proliferation. Different adrenoco rtical cells expressed initially LHR and Tag, whereas both were highly expressed in the tumor cells. In conclusion, the high level of functi onal LHR in the adrenal tumors indicates that this receptor can functi on as tumor promoter when ectopically expressed and stimulated by the ligand hormone.