MEMBERS OF THE FATTY-ACID-BINDING PROTEIN FAMILY ARE DIFFERENTIATION FACTORS FOR THE MAMMARY-GLAND

Mammary gland development is controlled by systemic hormones and by gr owth factors that might complement or mediate hormonal action. Peptide s that locally signal growth cessation and stimulate differentiation o f the developing epithelium have not been described. Here, we report t hat recombinant and wild-type forms of mammary-derived growth inhibito r (MDGI) and heart-fatty acid binding protein (FABP), which belong to the FABP family, specifically inhibit growth of normal mouse mammary e pithelial cells (MEC), while growth of stromal cells is not suppressed . In mammary gland organ culture, inhibition of ductal growth is assoc iated with the appearance of bulbous alveolar end buds and formation o f fully developed lobuloalveolar structures. In parallel, MDGI stimula tes its own expression and promotes milk protein synthesis. Selective inhibition of endogenous MDGI expression in MEC by antisense phosphoro thioate oligonucleotides suppresses appearance of alveolar end buds an d lowers the beta-casein level in organ cultures. Furthermore, MDGI su ppresses the mitogenic effects of epidermal growth factor, and epiderm al growth factor antagonizes the activities of MDGI. Finally, the regu latory properties of MDGI can be fully mimicked by an 11-amino acid se quence, represented in the COOH terminus of MDGI and a subfamily of st ructurally related FABPs. This peptide does not bind fatty acids. To o ur knowledge, this is the first report about a growth inhibitor promot ing mammary gland differentiation.