Mammary Gland Development Is Mediated by Both Stromal and Epithelial Progesterone Receptors

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Abstract
A combination of a knockout mouse model, tissue transplantation, and gene expression analysis has been used to investigate the role of steroid hor- mones in mammary gland development. Mouse mammary gland development was examined in progesterone receptor knockout (PRKO) mice us- ing reciprocal transplantation experiments to in- vestigate the effects of the stromal and epithelial PRs on ductal and lobuloalveolar development. The absence of PR in transplanted donor epithe- lium, but not in recipient stroma, prevented normal lobuloalveolar development in response to estro- gen (E) and progesterone (P) treatment. Con- versely, 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 development. Members of the Wnt growth factor family, Wnt-2 and Wnt-5B, were em- ployed as molecular markers of steroid hormone action in the mammary gland stroma and epithe- lium, respectively, to investigate the systemic ef- fects of E and P. Hormonal treatment of intact, ovariectomized, and PR2/2 mice and mice after transplantation of PR2/2 epithelium into wild type (PR1/1) stroma demonstrated that these two lo- cally acting growth factors are regulated by inde- pendent mechanisms. Wnt-2 is acutely repressed by E alone, while Wnt-5B gene expression is in- duced only after chronic treatment with both E and P. Wnt 5B appears to be one of the few molecular markers of P action in the mammary epithelium. This study suggests that the regulation of mam- mary gland development by steroid hormones is mediated by distinct effects of the stromal and epithelial PR and differential growth factor expres- sion. (Molecular Endocrinology 11: 801-811, 1997)

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