MAMMARY-GLAND DEVELOPMENT IS MEDIATED BY BOTH STROMAL AND EPITHELIAL PROGESTERONE RECEPTORS

A combination of a knockout mouse model, tissue transplantation, and g ene expression analysis has been used to investigate the role of stero id hormones in mammary gland development. Mouse mammary gland developm ent was examined in progesterone receptor knockout (PRKO) mice using r eciprocal transplantation experiments to investigate the effects of th e stromal and epithelial PRs on ductal and lobuloalveolar development. The absence of PR in transplanted donor epithelium, but not in recipi ent stroma, prevented normal lobuloalveolar development in response to estrogen (E) and progesterone (P) treatment. Conversely, the presence of PR in the transplanted donor epithelium, but not in the recipient stroma, revealed that PR in the stroma may be necessary for ductal dev elopment. Members of the Wnt growth factor family, Wnt-2 and Wnt-5B, w ere employed as molecular markers of steroid hormone action in the mam mary gland stroma and epithelium, respectively, to investigate the sys temic effects of E and P. Hormonal treatment of intact, ovariectomized , and PR-/- mice and mice after transplantation of PR-/- epithelium in to wild type (PR+/+) stroma demonstrated that these two locally acting growth factors are regulated by independent mechanisms. Wnt-2 is acut ely repressed by E alone, while Wnt-5B gene expression is induced only after chronic treatment with both E and P. Wnt 5B appears to be one o f the few molecular markers of P action in the mammary epithelium. Thi s study suggests that the regulation of mammary gland development by s teroid hormones is mediated by distinct effects of the stromal and epi thelial PR and differential growth factor expression.