A reappraisal of progesterone action in the mammary gland.

The ovarian hormones estrogen and progesterone and their respective receptors are essential for maintenance of postnatal developmental plasticity of the mammary gland and play a key role in mammary tumorigenesis. Mouse models in which expression of the progesterone receptors was genetically ablated have recently become available. Studies of these models have demonstrated that progesterone is specifically required for pregnancy associated ductal proliferation and lobuloalveolar differentiation of the mammary epithelium, but not for immediate postpubertal ductal morphogenesis. Use of these mice in combination with mammary gland transplantation indicates that developmental regulation by progesterone appears to occur through a paracrine mechanism in which progesterone receptor (PR) positive cells represent a subset of non-proliferating epithelial cells that are capable of directing proliferation and/or differentiation of neighboring receptor negative cells. The hierarchical organization of these receptors in the epithelium and their segregation from proliferating cells is a conserved feature in rodent and human mammary tissue. The identification of paracrine mediators of the progesterone response is now an imminent goal as is the delineation of the individual contributions of the two PR isoforms using similar approaches.