Regulation of mouse mammary gland development and tumorigenesis by the ERBB signaling network

The four ERBB receptors and their multiple polypeptide ligands are differen tially expressed during development of the mouse mammary gland. Profiles su ggest that ERBB1/EGF receptor (EGFR)(4) and ERBB2/Neu are required during d uctal morphogenesis, whereas the Neuregulin (NRG) receptors, ERBB3 and ERBB 4, are preferentially expressed through alveolar morphogenesis and lactatio n. Consistent with these profiles, recent gene knockouts established that E GFR and its ligand, Amphiregulin (AR), are essential for ductal morphogenes is in the adolescent mouse and likely provide the required epithelial-strom al signal. In contrast, the phenotypes of transgenic mice expressing domina nt negative ERBB2 and ERBB4 proteins suggest that these receptors different ially act to promote or maintain alveolar differentiation. This view of ERB B action provides a conceptual framework for future testing using more soph isticated conditional knockout models. New or existing transgenic mice are also being used to better understand the contributions of ERBB receptors an d ligands to mammary tumorigenesis, as well as to more closely mimic the hu man disease. Recent studies have focused on defining molecular events in ne oplastic progression, and in the case of ERBB2/Neu, the requirement for ERB B heterodimerization partners as well as the relative importance of gene am plification versus gene mutation. Collectively, these recent studies establ ish that normal development and homeostasis of the mammary,oland is critica lly dependent on regulated ERBB signaling. They also illustrate the value o f animal models in deciphering roles for the complex ERBB network in this d ynamic tissue.