Administration of Additional Phosphorylated Prolactin During Pregnancy Inhibits Mammary Ductal Branching and Promotes Premature Lobuloalveolus Development

Abstract

Abstract : Prolactin (PRL) is a hormone recognized as having both proliferative and differentiative activities in the mammary gland. Current theory proposes that it is the coexisting steroidal environment which dictates whether PRL is proliferative or differentiative. Preliminary data, presented as part of the initial proposal and established during year 1, however, suggested that it was the form of PRL released that dictated whether proliferation or differentiation would occur. By form of PRL we mean whether the PRL is released from the pituitary as an unmodified polypeptide or whether it is phosphorylated. To study this issue, we have produced recombinant, unmodified PRL (U-PRL) and a recombinant, molecular mimic of phosphorylated PRL, S179D PRL In the studies conducted during the first and second year, we have demonstrated that U-PRL promotes mammary growth, while Sl79D PRL inhibits growth and promotes differentiation. Further, we have demonstrated that these effects of U-PRL and S179D PRL are produced directly on the mammary gland. In addition, we have been able to show that U-PRL and S179D PRL exert these very different effects by changing the balance of signaling between the two major pathways in mammary epithelium. Thus U-PRL primarily uses the Jak 2-Stat 5a pathway, while Sl%9D PRL increases use of the MAP kinase pathway.