Abstract 4196: Neuregulin signaling in development and transformation of the luminal breast epithelium

Abstract

Abstract ErbB3 and ErbB4 are members of the ErbB family of receptor tyrosine kinases (RTK) that can be activated by neuregulins (NRGs) and as a result are often referred to as the neuregulin receptors. The neuregulin receptors are required for growth and survival of the ductal and alveolar luminal epithelium. We have recently shown that ErbB3 is required for survival and growth of the ductal luminal epithelium and to maintain the balance of differentiated epithelial cell types in the mammary gland, which is consistent with the fact the ErbB3 expression is highest in the ductal luminal epithelium and in luminal progenitor populations of the mouse and human mammary glands. ErbB4, is also required for growth in the luminal mammary epithelium, but not within the ductal luminal population, rather in the alveolar luminal population. In addition to neuregulin receptor signaling in development, ErbB3 and ErbB4 expression has been found to be at the highest levels in luminal breast cancers compared to other molecular breast cancer subtypes. Furthermore, human luminal breast cancer cell lines also express higher levels of ErbB3 and ErbB4 than cell lines derived from other molecular breast cancer subtypes. Since both ErbB3 and ErbB4 are capable of binding to neuregulin ligands and heterodimerizing with other ErbB family members, there is evidence that ErbB4 may compensate for loss of ErbB3, and vice versa. Thus, our goal is to understand how combined loss of ErbB3 and ErbB4 impact the normal luminal cell populations and the transformed cell populations of the breast epithelium. We hypothesize that loss of ErbB3 and ErbB4 will decrease cellular growth and survival during development and in our mouse models of breast cancer. Early studies demonstrate conditional loss of ErbB3fl/fl and ErbB4fl/fl independently and in combination decrease pup weights compared to control mice and demonstrate reduced epithelium/alveolar cell expansion in whole mount and histology analysis. In addition, early analysis of ErbB3fl/fl, ErbB4fl/fl ErbB3fl/fl/ErbB4fl/fl crossed to the p110 inducible mouse model of breast cancer are trending to a delay in tumor onset. Molecular analysis demonstrates a reduction in Pi3K/Akt signaling and Jak/Stat signaling in ErbB3fl/fl and ErbB4fl/fl respectively, with ongoing studies currently underway to analyze signaling in ErbB3fl/fl/ErbB4fl/fl mice in development. Citation Format: David B. Vaught, Donna Hicks, Violeta Sanchez, Rebecca Cook. Neuregulin signaling in development and transformation of the luminal breast epithelium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4196. doi:10.1158/1538-7445.AM2015-4196