Abstract 2460: APC regulates COX-2 independent of Wnt signaling in breast cancer

Abstract

Abstract Breast cancer is the leading cause of cancer-related death in non-smoking women, and the most commonly diagnosed cancer in women. The Adenomatous Polyposis Coli (APC) tumor suppressor gene is mutated or silenced by hypermethylation in 18-70% of sporadic breast cancers depending on subtype; however, the molecular mechanisms downstream of APC loss in the breast remain largely unexplored. While inactivation of APC most commonly leads to increased signaling through the Wnt/β-catenin pathway, there are multiple, less-investigated functions of APC, including regulation of GSK3β-mediated signaling, proliferation, epithelial polarity, cytoskeletal organization, and DNA repair. Given that restoration of tumor suppressors is a hurdle in treating tumors arising from loss of gene function, it is critical to investigate and understand the downstream signaling pathways involved in tumorigenesis. Our laboratory is particularly interested in investigating the effect of APC loss or mutation in breast cancer, and the complex Wnt-independent signaling downstream of APC loss in the breast. We previously demonstrated that Apc mutation accelerates the mouse mammary tumor virus-Polyoma middle T antigen (MMTV-PyMT) transgenic model of breast tumorigenesis independently of Wnt/β-catenin signaling. Interestingly, focal adhesion kinase (FAK)/Src/JNK signaling was up-regulated and required for the enhanced proliferation and squamous phenotype mediated by Apc mutation. Despite the lack of Wnt/β-catenin pathway activation, Apc-mutant mammary tumor cell lines demonstrated enhanced expression of Cyclooxygenase-2 (COX-2) and production of prostaglandin E2 (PGE2), known to be important in triple-negative and inflammatory breast cancers, two aggressive breast cancer subtypes. While treatment with the Src inhibitor (PP2) decreases COX-2 protein expression, there is no effect on the level of phosphorylated JNK, indicating a non-linear signaling pathway. Consistent with this, treatment with an inhibitor of JNK (SP600125) has no effect on COX-2 expression. These data suggest that while Src activation downstream of Apc mutation enhances COX-2 in a Wnt-independent manner, the pathway does not travel through activation of JNK. Therefore, the mechanisms by which Apc mutation initiates this stream of events to enhance mammary tumorigenesis, and the contribution of COX-2 to the phenotypes acquired in Apc-mutant breast cancer remain unclear. Citation Format: Monica K. VanKlompenberg, Claire Bedalov, Jenifer R. Prosperi. APC regulates COX-2 independent of Wnt signaling in breast cancer. [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 2460. doi:10.1158/1538-7445.AM2014-2460