Adrenocortical tumorigenesis in transgenic mice: the role of luteinizing hormone receptor and transcription factors GATA-4 and GATA-61

Abstract

Transgenic (TG) mice, bearing the Simian Virus 40 T-antigen (Tag) under a 6-kb fragment of the murine inhibin alpha-subunit promoter (inhalpha), develop gonadal tumors of granulosa or Leydig cell origin with 100% penetrance by the age of 5-7 months. When these TG mice were gonadectomized prepubertally, between 21-25 days of life, adrenal gland tumors were observed in each mouse by the age of 5-7 months. No adrenal tumors were detected in any intact TG, gonadectomized or intact or control non-TG littermates. The adrenocortical tumors appeared to originate from the X-zone of the adrenal cortex. If functional gonadectomy was induced by GnRH antagonist treatment or by cross-breeding of the TG mice into hypogonadotropic hpg genetic background, neither gonadal nor adrenal tumorigenesis appeared. This prompted a hypothesis that adrenal tumor development in inhalpha/Tag TG mice is related to elevated gonadotropin secretion, which is the most obvious difference between the surgical and functional gonadectomy models. The adrenal tumors and a cell line (Calpha1) derived from them, was found to express luteinizing hormone receptor (LHR), but no FSHR, and hCG treatment stimulated their proliferation. No FSHR was found in the adrenal glands. On the basis of this it was suggested that expression of the potent oncogene T-antigen, allow LH in adrenocortical cells to function as a tumor promoter, and induction of high level functional LHR expression in adrenal tumors. Given the induction of expression and regulation of the GATA-4 and GATA-6 zinc finger family of transcription factors in the gonads by gonadotropins, it was in our interest to explore their expression in the adrenals. We utilized the inalpha/Tag TG mouse model and pathological human adrenal samples to explore the role of GATA-4 and GATA-6 in adrenocortical tumorigenesis. Abundant GATA-6 mRNA expression was found in normal control adrenal cortex during mouse development, whereas GATA-4 mRNA was undetectable. In striking contrast to this, GATA-6 was absent from murine adrenocortical tumors, while GATA-4 mRNA expression was dramatically upregulated in the murine adrenal tumors as well as in human adrenocortical carcinomas. Taken together, these results suggest different roles for GATA-4 and GATA-6 in the adrenal gland, and implicate GATA-4 in adrenal LHR expression and tumorigenesis. Immunohistochemical detection of GATA-4 may serve as a useful marker in differential diagnosis of human adrenal tumors. In addition, the inhalpha/Tag TG model will be helpful for exploring the molecular mechanisms underlying adrenocortical tumorigenesis, ectopic LHR expression in adrenals and the GATA-4/LHR interaction that is related to adrenal tumorigenesis in TG mice.