RAsGRP1 signals in breast development and cancer



 DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death in women. Nearly 12% of women in the U.S. will develop breast cancer over the course of their life and about 40,000 will die each year from the disease. The molecular and cellular origins of breast cancer are highly heterogeneous. Gene profiling has revealed at least five distinct subtypes. One such subtype is "Her2", which account for approximately 30% of all diagnosed breast cancers. Her2 breast cancers develop as a result of the overexpression or amplification of the epidermal growth factor receptor (EGFR) family protein Her2/EGFR2. Therefore, gaining better insight into EGFR signaling in the breast is critically important. EGFR signaling has been shown to play a key role in regulating mammary gland development. Evidence has emerged that shows inactivating mutations in EGFR lead to developmental defects. Further, augmented EGFR signals in multipotent progenitor cells drive specific branching effects and cell fate decisions. These developmental observations are also of relevance to breast cancer, since it is thought that the heterogeneity predominantly derives from distinct mammary epithelial cells (MECs) serving as the cell of origin. The Ras pathway is activated downstream of receptor tyrosine kinases, like EGFR. Ras signals are controlled in part by Ras activating proteins, including Ras guanyl-nucleotide releasing protein 1 (Rasgrp1). Work from our lab has shown that Ras signal intensity, as modulated by Rasgrp1, often acts to control the balance of proliferation and differentiation. Aberrant Rasgrp1 expression in lymphocytes leads to developmental delay and contributes to onset and progression of leukemia. Further, we have recently discovered Rasgrp1 acts paradoxically to limit EGFR-Ras signals within intestinal epithelial cells, resulting in enhanced proliferation and changes to intestinal progenitor cell differentiation when Rasgrp1 function is perturbed. How specific EGFR- RasGEF-Ras signals impact development of MEC lineages, cancer initiation and progression, and the specific role of Rasgrp1 herein remains unknown. Given the known importance of titrated EGFR-Ras signals during normal and malignant breast growth, I hypothesize that Rasgrp1 plays an important but unexplored role in mammary epithelial progenitor cell growth and differentiation by controlling the intensity of EGFR-Ras signals in these cells. To test our hypotheses, our lab has generated mouse models with ablated (Rasgrp1-/-) and impaired (Rasgrp1Anaef) Rasgrp1. We have also developed biochemical-, cell biological-, and in vivo- approaches to reveal molecular insights and have acquired critical preliminary data. I will characterize the expression of Rasgrp1 in MECs (Aim 1) and determine how distinct EGFR-Rasgrp1 signals impact MEC lineages during development (Aim 2). Lastly, I will investigate the role of EGFR-Rasgrp1 signaling in breast cancer (Aim 3). We anticipate that our studies will provide significant insights into how Rasgrp1 shapes the character of EGFR-Ras signals in MECs lineages during development and cancer.