Abstract B013: Neuregulin signaling in development and transformation of the luminal breast epithelium

Abstract

Abstract The goal of these studies is to determine how combined loss of ErbB3 and ErbB4 impact the normal and transformed luminal population of the breast epithelium. Although little is known regarding the role of ErbB3 in luminal breast cancers, and even less about ErbB4, we 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. Further, given that ErbB3 and ErbB4 are uniquely required within the luminal breast epithelium during phases of extreme physiological proliferation (i.e., puberty and pregnancy, respectively) it is likely that the neuregulin receptors drive cell growth and survival of breast cancers derived from the luminal breast epithelium. We hypothesize that elimination of NRG signaling by combined loss of ErbB3 and ErbB4 would prevent expansion of the mammary epithelium in response to physiological cues (i.e. pregnancy) and pathological cues (oncogene expression). 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 are generating mice that lack ErbB3 and ErbB4 in the alveolar mammary epithelium. We anticipate that combined gene targeting of ErbB3 and ErbB4 will cause a more pronounced lactational deficit. Citation Format: David B. Vaught, Donna Hicks, Rebecca Cook. Neuregulin signaling in development and transformation of the luminal breast epithelium. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B013.