Prostate, adrenocortical, and brown adipose tumors in fetal globin/T antigen transgenic mice.
Targeted oncogenesis in transgenic mice has unexpectedly produced predictable tissue-specific tumors. We previously showed that hybrid gene constructs of the human fetal G gamma- or mouse embryonic beta h1-globin promoter linked to the viral simian virus 40 T antigen (G gamma/T and beta h1/T) expressed appropriately in embryonic erythroid tissue, with some unexpected expression elsewhere. Tumors arising in the G gamma/T and beta h1/T transgenic mice were identified by histology, electron microscopy, cell culture, and RNase protection analyses. In one G gamma/T transgenic line, males developed prostate tumors that showed mixed neuroendocrine and epithelial cell features, whereas females developed adrenocortical tumors. In several other G gamma/T lines, brown adipose tumors, or hibernomas, developed in the subcutaneous interscapular neck and shoulder area, as well as internally in the periadrenal and 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 transfection assays in prostate and adrenocortical tumor-derived cell lines showed that the G gamma-globin promoter is 7-to 10-fold more active than the beta h1-globin promoter. Activity of 5' G gamma-globin promoter-deletion DNA plasmids was analyzed by transient transfection in a variety of human prostate cancer cell lines. The G gamma-globin promoter region between -140 and -201 also showed high activity in the androgen-independent human prostate cancer cell lines DU-145 and PPC-1, but low activity in the androgen-responsive human prostate cell line LNCaP. We conclude that tumor formation in the G gamma/T transgenic lines apparently results from cryptic positive DNA cis elements active in prostate and adrenocortical cells. Because G gamma-globin promoter activity is highest in embryonic tissue, tumors in adult transgenic mice may result from expression of T antigen in embryonic prostate, adrenal glands, and brown adipose tissue.
Perez-Stable
C
C
Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Miami, Florida, USA.
Altman
N H
NH
Brown
J
J
Harbison
M
M
Cray
C
C
Roos
B A
BA
D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology; D000728:Androgens / Q000502:physiology; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics*; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics*; D008067:Lipoma / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012313:RNA / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000728:Androgens; D000957:Antigens, Viral, Tumor; D004273:DNA, Neoplasm; D012313:RNA; D005319:Fetal Hemoglobin