PROSTATE, ADRENOCORTICAL, AND BROWN ADIPOSE TUMORS IN FETAL GLOBIN T-ANTIGEN TRANSGENIC MICE

Targeted oncogenesis in transgenic mice has unexpectedly produced pred ictable tissue-specific tumors. We previously showed that hybrid gene constructs of the human fetal G gamma- or mouse embryonic beta h1-glob in promoter linked to the viral simian virus 40 T antigen (G gamma/T a nd beta h1/T) expressed appropriately in embryonic erythroid tissue, w ith some unexpected expression elsewhere. Tumors arising in the G gamm a/T and beta h1/T transgenic mice were identified by histology, electr on microscopy, cell culture, and RNase protection analyses. In one G g amma/T transgenic line, males developed prostate tumors that showed mi xed neuroendocrine and epithelial cell features, whereas females devel oped adrenocortical tumors. In several other G gamma/T lines, brown ad ipose tumors, or hibernomas, developed in the subcutaneous interscapul ar neck and shoulder area, as well as internally in the periadrenal an d pericardial areas. Little or no expression of T antigen was detected in adult animals before visible tumor formation. In contrast, beta h1 /T transgenic mice developed only choroid plexus tumors. Transient tra nsfection assays in prostate and adrenocortical tumor-derived cell lin es showed that the G gamma-globin promoter is 7- to 10-fold more activ e than the beta h1-globin promoter. Activity of 5' G gamma-globin prom oter-deletion DNA plasmids was analyzed by transient transfection in a variety of human prostate cancer cell lines. The G gamma-globin promo ter region between -140 and -201 also showed high activity in the andr ogen-independent human prostate cancer cell lines DU-145 and PPC-1, bu t low activity in the androgen-responsive human prostate cell line LNC aP. We conclude that tumor formation in the G gamma/T transgenic lines apparently results from cryptic positive DNA cis elements active in p rostate and adrenocortical cells. Because G gamma-globin promoter acti vity is highest in embryonic tissue, tumors in adult transgenic mice m ay result from expression of T antigen in embryonic prostate, adrenal glands, and brown adipose tissue.