Signaling by the sex steroids, estrogen and progesterone, through their cognate receptors, is essential for mammary gland morphogenesis. A central role for progesterone receptor (PR) in normal mammary development is established by the fact that in PR null mutant mice, which have estrogen receptor a (ERa), there is a severe inhibition in lobulo-alveolar growth, normally accompanying pregnancy and occurring in response to estrogen and progesterone. PR exists in two molecular forms (the 'A' and 'B' forms) whose actions can vary depending on cell and promoter context. Furthermore, PR-A can inhibit the activity of PR-B and both forms can inhibit the activity of estrogen receptor. At present, the precise role of PR and, in particular, the relative importance of the two isoforms in mediating either normal mammary development or carcinogenesis is unknown.

Our hypothesis is that both forms of PR are required for normal mammary development and an imbalance in the native ratio of PR-A and PR-B can lead to a perturbation in the cross-talk between ER, PR-A and PR-B. We believe that this, in turn, results in inappropriate ER and PR dependent gene expression leading to a derangement in epithelial cell replicative homeostasis and thereby triggering mammary carcinogenesis. Towards testing our hypothesis, we have created transgenic mice carrying an imbalance in the native ratio of 'A' to 'B' forms by over expressing either the 'A' or 'B' form (referred to as PR-A and PR-B transgenics). The mammary development in both these strains of transgenic mice are abnormal. In adult PR-A transgenics, there is extensive ductal growth and branching while in PR-B transgenics mammary growth is compromised. Furthermore, in PR-A transgenics, mammary glands exhibit dysplasias, suggesting increased propensity for tumorigenesis. These findings imply a perturbation in epithelial cell replicative homeostasis in the mammary glands of both PR-A and PR-B transgenics.

The present goals of our laboratory, therefore, are to identify the molecular mechanisms responsible for the altered growth patterns of mammary glands of PR-A and PR-B transgenics, determine if in these tissues there is a perturbation in the cross-talk between ER, PR-A and PR-B and to assess their tumorigenic potential in vivo.

The growth promoting effects of estrogen/ERa and progesterone/PR are believed to be mediated by growth factors that signal through the family of erbB receptors, such as C-neu/erbB2. Overexpression of C-neu results in mammary carcinomas in both humans and mice. Yet, as found by our laboratory in transgenic mice overexpressing C-Neu, ERa dependent ductal growth during puberty is compromised. This implies that, between puberty (6 weeks of age) and the onset of overt tumors (about 9 months of age), mammary epithelial cells overcome the growth restraint imposed at puberty, become immortalized, and give rise to preneoplasias and finally carcinomas. Accordingly, we are examining the mammary glands of C-neu transgenic mice at various ages and development, in order to identitfy the various stages of transformation. We believe that such studies can provide insights for arresting the generation of preoneoplasias and their progression to carcinomas.