Changes in ErbB2 (her-2/neu), ErbB3, and ErbB4 during growth, differentiation, and apoptosis of normal rat mammary epithelial cells

Studies were undertaken to examine the natural role of ErbB2, ErbB3, and Er bB4 during the development of normal rat mammary epithelial cells (MECs) in vivo and in vitro. Immunohistochemical analysis demonstrated that mammary gland terminal end buds expressed abundant ErbB2 and ErbB4 but limited ErbB 3 in pubescent rats, whereas luminal epithelial cells in nulliparous rats e xpressed ErbB2, ErbB3, and/or ErbB4. During pregnancy, ductal epithelial ce lls and stromal cells expressed abundant ErbB3 but limited ErbB2. Although ErbB2 and ErbB3 were downregulated throughout lactation, both receptors wer e re-expressed during involution. In contrast, ErbB4 was downregulated thro ughout pregnancy, lactation, and involution. Immunoblotting and immunopreci pitation studies confirmed the developmental expression of ErbB2 and ErbB3 in the mammary gland and the co-localization of distinct ErbB receptors in the mammary gland of nulliparous rats. In agreement with our in vivo findin gs, primary culture studies demonstrated that ErbB2 and ErbB3 were expresse d in functionally immature, terminally differentiated and apoptotic MECs, a nd downregulated in functionally differentiated MECs. ErbB receptor signali ng was required for epithelial cell growth, functional differentiation, and morphogenesis of immature MECs, and the survival of terminally differentia ted MECs. Finally, ErbB4 expression did not interfere with functional diffe rentiation and apoptosis of normal MECs.