ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation

Signaling by members of the epidermal growth factor receptor family plays a n important role in breast development and breast cancer. Earlier work sugg ested that one of these receptors, ErbB4, is coupled to unique responses in this tissue. To determine the function of ErbB4 signaling in the normal mo use mammary gland, we inactivated ErbB4 signaling by expressing a COOH term inally deleted dominant-negative allele of ErbB4 (ErbB4 Delta IC) as a tran sgene in the mammary gland. Despite the expression of ErbB4 Delta IC from p uberty through later stages of mammary development, an ErbB4 Delta IC-speci fic phenotype was not observed until mid-lactation. At 12-d postpartum, lob uloalveoli expressing ErbB4 Delta IC protein were condensed and lacked norm al lumenal lactation products. In these lobuloalve-oli, beta-casein mRNA, d etected by in situ hybridization, was normal. However, whey acidic protein mRNA was reduced, and alpha-lactalbumin mRNA was undetectable. Stat5 expres sion was detected by immunohistochemistry in Erb4 Delta IC-expressing tissu e. However, Stat5 was not phosphorylated at Y694 and was, therefore, probab ly inactive. When expressed transiently in 293T cells, ErbB4 induced phosph orylation of Stat5. This phosphorylation required an intact Stat5 SH2 domai n. In summary, our results demonstrate that ErbB4 signaling is necessary fo r mammary terminal differentiation and Stat5 activation at mid-lactation.