NEU DIFFERENTIATION FACTOR HEREGULIN MODULATES GROWTH AND DIFFERENTIATION OF HC11 MAMMARY EPITHELIAL-CELLS

The HC11 mouse mammary epithelial cell line has proven to be a valuabl e in vitro model to study the roles of peptide factors and hormones in volved in the growth and differentiation of mammary cells. Treatment o f HC11 cells with the lactogenic hormones, dexamethasone, insulin, and PRL (DIP), leads to cellular differentiation and production of the mi lk protein beta-casein. We have analyzed the effects of Neu differenti ation factor (NDF)/heregulin, a newly described activating ligand for erbB-2 and other members of the epidermal growth factor (EGF) receptor family, on cell growth and the expression of milk proteins in HC11 ce lls. In these cells, NDF induces tyrosine phosphorylation of erbB-2 an d erbB-3. Both NDF and EGF stimulate HC11 cell proliferation and promo te the responsiveness of HC11 cells to lactogenic hormones. NDF induce s the expression of a 22-kilodalton milk protein. This protein is up-r egulated by other factors, including dexamethasone, EGF, and basic fib roblast growth factor, and is controlled in a manner distinct from tha t of beta-casein. Like EGF, NDF inhibits the DIP-induced expression of beta-casein at the revel of transcription. The inhibition is due to t he negative effect of NDF on the activation of mammary gland factor (M GF/Stat5), a member of the Stat family of transcription factors, which is essential for beta-casein gene expression.