THE C EBP-BETA TRANSCRIPTION FACTOR REGULATES EPITHELIAL-CELL PROLIFERATION AND DIFFERENTIATION IN THE MAMMARY-GLAND/

Studies of C/EBP beta-deficient mice have demonstrated a pivotal role for this transcription factor in hematopoiesis, adipogenesis, and ovar ian function. Here we show that C/EBP beta is also essential for norma l development and function of the mammary gland. Ductal morphogenesis in virgin C/EBP beta-deficient mice was disrupted, with ducts displayi ng reduced growth and branching. To distinguish whether the effect of C/EBP beta deficiency on mammary epithelium is indirect or cell autono mous, we performed ovarian and mammary gland transplants. Transplants of wild-type ovaries into mutant females partially restored ductal mor phogenesis during puberty but failed to support mammopoiesis during pr egnancy. At term, mutant mice harboring wild-type ovaries exhibited re duced alveolar proliferation and impaired epithelial cell differentiat ion, including a complete absence of milk protein expression. Mammary gland transplant experiments demonstrated that development of C/EBP be ta-deficient epithelium was defective within a wild-type stroma and ho st background. Cell proliferation during pregnancy was reduced and dif ferentiation, as measured by the activity of milk protein genes, was i nhibited. However, wild-type epithelium developed in a C/EBP beta-defi cient stroma. Thus, C/EBP beta plays an essential, cell autonomous rol e in the proliferation and differentiation of mammary secretory epithe lial cells and is required for the activation of milk protein genes.