Abstract 4131: Alternative splicing changes during the acquisition of anoikis resistance.

Abstract

Abstract Breast cancer is the most common cancer in women and the second leading cause of cancer-related death among women in the U.S. Metastases from the primary tumor are common and are the main cause of mortality in this population. Therefore, it is imperative to identify therapeutic molecules that target mechanisms specific to metastatic cells. One such mechanism to target is anoikis, a specialized form of programmed cell death that prevents epithelial cells shed from basement membranes from colonizing distant organs. Circulating tumor cells (CTCs) become anoikis-resistant, which is an essential early step in the development of distant metastases in many types of cancer including breast cancer. Recent studies have implicated RNA splicing dysregulation in a number of cancer phenotypes (e.g. oncogenesis). In these studies, we have developed anoikis-resistant (AnR) breast cancer cell lines, which grow unattached to hydrophilic surfaces. We then performed a preliminary intron / exon array screen comparing parental and AnR breast cancer cell lines. This approach identified a novel splice variant of Non-catalytic region of tyrosine kinase associated protein 1 (NckAP1), in which the 15-18 cassette is deleted. This splice variant is dysregulated in both AnR cells and in relevant samples from breast cancer patients. NckAP1, along with Nck and Ras-related C3 botulinum toxin substrate (Rac), are found in a complex with the actin-polymerization protein Wiskott Aldrich syndrome protein verprolin homologous 1 (WAVE1). After dissociation from this complex, WAVE1 is able to induce polymerization of actin during lamellipodia formation, and is thus a mediator of migration. Hence, splicing of NckAP1 may help mediate migratory capacity of breast cancer cells. These studies also suggest a major role for splicing regulation in metastasis. Citation Format: Quoc Huynh, Charles E. Chalfant, Margaret A. Park. Alternative splicing changes during the acquisition of anoikis resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4131. doi:10.1158/1538-7445.AM2013-4131