Reciprocal changes in the expression of transcription factors GATA-4 and GATA-6 accompany adrenocortical tumorigenesis in mice and humans

While certain genetic changes are frequently found in. adrenocortical carci noma cells, the molecular basis of adrenocortical tumorigenesis remains poo rly understood. Given that the transcription factors GATA-4 and GATA-6 have been implicated in gene expression and cellular differentiation in a varie ty of tissues, including endocrine organs such as testis, we have now exami ned their expression in the developing adrenal gland. as well as in adrenoc ortical cell lines and tumors from mice and humans. Northern blot analysis and in situ hybridization revealed abundant GATA-6 mRNA in the fetal and po stnatal adrenal cortex of the mouse. In contrast, little or no GATA-4 expre ssion was detected in adrenal tissue during normal development. In vivo sti mulation with ACTH or suppression with dexamethasone did not affect the exp ression of GATA-4 or GATA-6 in the murine adrenal gland. To assess whether changes in the expression of GATA-4 or GATA-6 accompany adrenocortical tumo rigenesis, we employed an established mouse model. When gonadectomized, inh ibin alpha/SV40 T-antigen transgenic mice develop adrenocortical tumors in a gonadotropin-dependent fashion. In striking contrast To the normal adrena l glands, GATA-6 mRNA was absent from adrenocortical tumors or tumor-derive d cell lines, while GATA-4 mRNA and protein were abundantly expressed in th e tumors and tumor cell lines. Analogous results were obtained with human t issue samples; GATA-4 expression was detected in human adrenocortical carci nomas but not in normal tissue, adenomas, or pheochromocytomas. Taken toget her these results suggest different roles for GATA-4 and GATA-6 in the adre nal gland, and implicate GATA-4 in adrenal tumorigenesis. Immunohistochemic al detection of GATA-4 may serve as a useful marker in the differential dia gnosis of human adrenal tumors.