Abstract : Studies have shown that ErbB3 and ErbB4 (the neuregulin receptors) are required for growth and survival of the two major luminal mammary epithelial cell types, the ductal luminal mammary epithelium, and the milk-producing alveolar mammary epithelium. However, as both ErbB3 and ErbB4 are capable of binding to neuregulins and heterodimerizing with other ErbB family members, there is evidence that ErbB4 may compensate for loss of ErbB3, and vice versa making it likely that the neuregulin receptors drive cell growth and survival of breast cancers derived from the luminal breast epithelium. Our early studies demonstrate loss of ErbB3 expansion of the alveolar epithelium during pregnancy, decreased expression of genes encoding milk proteins, and decreased milk delivery to nursing pups. This is similar to what is seen in ErbB4-deficient mammary glands. We are currently studying the ErbB3-dependnet molecular mechanisms required for expansion of the alveolar epithelium during pregnancy, and have generated mice that lack ErbB3 and ErbB4 in the alveolar mammary epithelium for specific analysis of neuregulin loss in mammary morphogenesis, lactational differentiation, and breast cancer development.