Abstract 32: The role of Lrig1 signaling in mammary gland development and tumorigenesis

Abstract

Abstract Lrig1 is a transmembrane leucine-rich repeat protein and a negative regulator of oncogenic receptor tyrosine kinases (RTKs) such as the ErbB family members. The Sweeney lab recently demonstrated that under-expression of Lrig1 predicts poor prognosis in breast cancer. Breast cancer patients with high Lrig1 expression show significantly longer relapse-free survival, identifying Lrig1 as a new prognostic marker. Recently, Lrig1 was found to be a tumor suppressor in intestinal tissue. It was shown that Lrig1 null mice develop ErbB receptor-dependent duodenal adenomas. Based on Lrig1's function as a negative regulator of RTKs and its reported tumor suppressor activity in intestinal epithelium, we hypothesized that Lrig1 null mice would be susceptible to mammary tumorigenesis. To characterize the function of Lrig1 in the mammary gland, we compared mammary development in Lrig1 wild type (+/+) and null (-/-) mice at regular intervals from 4 to 12 weeks. Mice were screened for evidence of hyperplasia, pre-malignant lesions or tumors by whole mount analysis across age and the intensity of specific proteins was surveyed by western blot. Organotypic growth of the mammary epithelial cells from wild type and null mice was examined in three-dimensional cell culture to examine whether any phenotypes are inherent to the epithelium. Since Lrig1 has been defined as a stem cell marker in the intestine, its role in stem cell maintenance was determined by examining the impact of Lrig1 loss on mammary stem cells. Although these studies are ongoing, early results indicate an increase in the amount of Lrig1-target proteins by western blot in the Lrig1-/- mice as opposed to the Lrig1+/+ mice mammary gland tissue. Epithelium from Lrig1-/- mice present an exaggerated branching response when stimulated with TGFα in comparison to Lrig1+/+ epithelium. Our studies also indicate that Lrig1-/- mammary glands are enriched in stem cells when compared to Lrig1+/+ mammary glands. In addition, a number of proliferative lesions were encountered in the mammary gland whole mounts of the Lrig1-/- mice, but not that of the Lrig1+/+ mice, which strongly suggests that Lrig1 plays a growth suppressor role in the mammary gland. Citation Format: Catalina Simion, Qian J. Chen, Charles L. Wilkerson, Hanine Rafidi, Alexander D. Borowsky, Colleen Sweeney. The role of Lrig1 signaling in mammary gland development and tumorigenesis. [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 32. doi:10.1158/1538-7445.AM2015-32