The long term goal of this proposal is to establish the physiological role of the progesterone receptor (PR) in general mammalian development, particularly in the areas of male and female reproduction, behavior and breast cancer. The PR mediates the response to the steroid hormone, progesterone, through two intracellular receptor isoforms, PRA and PRB. The functional relevance in vivo of two forms of this receptor has yet to be established. The presence of PRs in non-reproductive tissues raises a number of questions regarding the potential role of these receptors in other areas of mammalian physiology besides reproduction. In particular, the functions of PRs in select tissues of the male, especially in the brain, has not yet been defined. The importance of progesterone and its receptor in normal mammary development and tumorigenesis is well established. Furthermore, accumulating evidence suggests that both progesterone and estrogen receptors provide common mediators through which hormone and non-hormone signaling pathways may converge to regulate the expression of a number of target genes that may, in turn, influence the oncogenic potential of the mammary gland. To study the role of the PR in an in vivo context, we propose to examine the phenotypic changes that will occur as a result of complete or selective ablation of the PR isoforms in the mouse. Our approach will be to generate mouse lines which are genetically incapable of expressing either one or both forms of the PR, using embryonic stem cell/gene targeting technologies. Collectively, these PR mutant mouse models will help to identify those functions in vivo which are associated with one or both forms of the PR. Furthermore, as well as confirming and extending the role of the PR in areas of mammalian physiology which have been long associated with progesterone action, these animals will serve to provide valuable information on the role of these receptors in newly discovered areas of progesterone physiology. Finally, analysis of the physiological effects of complete or selective loss of the PR isoforms on the normal development of the mammary gland and its susceptibility to carcinogen- induced mammary tumors, will help define the role of the PR in mammary gland tumorigenesis as well as its contribution to the refractory state of this organ to carcinogens when this tissue is exposed to an early treatment of estrogen and progesterone.