Pregnancy-associated plasma protein (PAPP)-A expressed in the mammary gland controls epithelial cell proliferation and differentiation.

Lactation is an important event in all-mammalian species. To investigate the role of pregnancy-associated plasma protein (PAPP)-A in lactogenesis, we determined (i) PAPP-A expression in mouse mammary glands and (ii) the biological functions of PAPP-A in mammary epithelial cells. PAPP-A mRNA level was low during early mid pregnancy and increased during mid-late pregnancy, and then slightly decreased during lactation. Cell proliferation signals, but not differentiation, increased PAPP-A mRNA expression in HC11 mammary epithelial cells. Treatment of recombinant PAPP-A protein stimulated HC11 cell proliferation and suppressed the expression of β-casein mRNA, which is one of the milk proteins and cell differentiation marker. Surprisingly, in forcing expression experiment, PAPP-A increased β-casein mRNA expression. Our data suggest that PAPP-A has different roles on intracellular expressing and extracellular treatment to mammary epithelial cells. Taken together, in early pregnancy, circulating PAPP-A protein might be supplied from other organs and stimulates mammary gland growth. In contrast, during mid-late pregnancy, local PAPP-A expression begins and enhances cell differentiation within mammary epithelial cell.