Developing a Mammary Gland is a Stat Affair

The mammary gland is a recent acquisition on the phylogenetic scale of organ evolution and is characterized by an unparalleled regenerative capacity. With each pregnancy an expanded lobulo-alveolar compartment rises on the ductal compartment and differentiates to secrete large amounts of milk during lactation. After weaning of the young the entire alveolar compartment undergoes apoptosis and is remodeled to return to a virgin-like state. Evolution recruited old hands from existing signaling pathways to guide and accomplish the extraordinary task of repeatedly building and destroying this highly specialized tissue. Seventy years ago it was known that the presence of estrogen, progesterone, and prolactin (PRL)(3) was essential for ductal and alveolar development. The recent ability to generate mice from which genes have been deleted by homologous recombination has made it possible to gain molecular insight into the signaling pathways used by these hormones to effect mammary differentiation. In the cast of characters progesterone and PRL are on center stage. After binding to its receptor, PRL activates the JAK-STAT pathway leading to transcription of genes which induce alveolar proliferation and differentiation. In vivo experiments have shown that JAK-Stat signaling is mandatory for adult mammary gland development and lactation. Two Stat molecules, Stat3 and Stat5, appear to have opposite functions and their relative activity may serve to control developmental cycles of mammary tissue. While Stat5 activity has been linked to alveolar proliferation and function, Stat3 activity correlates with the loss of alveolar function, cell death and the initiation of mammary tissue remodeling.