Human Adrenal Androgens: Regulation of Biosynthesis and Role in Estrogen-Responsive Breast Cancer in a Mouse Model

Abstract

Abstract : These experiments investigate a mouse model for the biosynthesis of the human adrenal androgens (dehydroepiandrosterone, DHEA, and its sulfate, DHEAS) and the role of these steroids in human breast cancer growth. An androgen-dependent human breast cancer model was established in immunodeficient (scid) mice. Zona reticularis cells in the human adrenal cortex are responsible for adrenal androgen biosynthesis because of the suppressed expression of 3 beta-hydroxysteroid dehydrogenase (3beta-HSD) in these cells. A protein present in the non-DHEA-secreting zones of the cortex and absent from the zona reticularis which binds to a regulatory region of the type II 3 beta-HSD gene was partially purified. Human adrenocortical cells were transplanted into scid mice and were shown to replace the animals own adrenal function. Although zona reticularis cells were transplanted, DHEAS was not detected in mouse plasma. As an alternative to the use of human zona reticularis cells, clonal bovine adrenocortical cells were shown to be capable of forming tissue in scid mice that replaces the animals adrenal glands. This was shown both with normal clonal cells and with cells genetically modified by the insertion of marker genes. The ability to genetically modify the cells provides a means to test whether suppression of 3 beta-HSD by an antisense strategy can create a tissue with a very high rate of DHEA biosynthesis in the mouse transplant model.