Abstract 2040: Adenomatous polyposis coli mediated signaling, self renewal and differentiation of breast epithelial cells

Abstract

Abstract Breast cancer is the leading cause of cancer-related death in non-smoking women in the United States. Despite tremendous amounts of information about the etiology of breast cancer, many questions remain unanswered. It has been demonstrated that specific subtypes of breast cancer differ in their sensitivity to chemotherapeutic and targeted therapies. The oncogenic events and signaling pathways driving these tumor subtypes are distinct. This indicates that increased knowledge of the molecular events defining the unique subtypes will provide opportunities for novel therapeutic approaches tailored to fit the specific subtypes and will therefore lead to improvement in patient outcomes. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in 18-70% of sporadic breast cancers depending on subtype. Oncomine database analysis revealed reduced expression of APC in aggressive estrogen receptor (ER) negative breast cancers compared to ER-positive breast cancer or normal breast. Using the ApcMin/+ mouse model, we identified pre-neoplastic lesions in the breast and enhanced breast tumorigenesis in the presence of the Polyoma middle T antigen (PyMT) oncogene. Apc mutation changed the tumor histopathology from solid to squamous adenocarcinomas, resembling the highly aggressive human metaplastic breast cancer. In this model of mouse mammary tumorigenesis, these changes occurred independent of Wnt/b-catenin signaling and required activation of focal adhesion kinase (FAK)/Src signaling, with a subsequent increase in cyclooxygenase-2 (COX-2). The applicability of these signaling pathways to human breast cancer remains unclear. Using the epithelial cell reprogramming assay for growing normal breast epithelial cells, we have begun to characterize expression of cell surface markers to delineate subtypes of epithelial cells. We have also assessed APC expression and correlated APC expression with risk and well-established clinical markers, such as ErbB2. Future studies will modulate APC expression in specific compartments of breast epithelial hierarchy to accomplish our objectives of dissecting the molecular alterations specifically downstream of APC loss and its role in the self-renewal and differentiation of breast epithelial cells. Citation Format: Alyssa Lesko, Harikrishna Nakshatri, Manjushree Anjanappa, Poornima Bhat-Nakshatri, Jenifer Prosperi. Adenomatous polyposis coli mediated signaling, self renewal and differentiation of breast epithelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2040. doi:10.1158/1538-7445.AM2014-2040