Abstract 3789: The alternatively spliced PRMT1 isoform PRMT1v2 promotes breast cancer cell survival and invasiveness.

Abstract

Abstract Breast cancer is the leading cause of cancer-related deaths in women. Despite intensive treatment to overcome this disease, recurrence is common and often incurable due to the highly aggressive nature of the recurrent tumour. Protein arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs) and plays an important role in many cellular processes. Aberrant PRMT expression has been observed in several common cancer types, however their precise contribution to the cell transformation process and cancer progression is not well understood. Previously, we reported that the PRMT1 gene generates several alternatively spliced isoforms and our initial biochemical characterization of these isoforms revealed that they exhibit distinct substrate specificity and sub-cellular localization. Here we have focused on the PRMT1v2 isoform, which is the only predominantly cytoplasmic isoform and has increased relative expression in breast cancer cell lines and tumours. Specific depletion of PRMT1v2 using RNA interference caused a significant decrease in breast cancer cell survival due to an induction of apoptosis. Furthermore, depletion of PRMT1v2 in MDA-MB-231, an aggressive breast cancer cell line, resulted in significantly decreased cell invasion. Alternatively, PRMT1v2 overexpression in a non-aggressive breast cancer cell line, MCF7, was sufficient to enhance their invasiveness. This novel activity is specific to PRMT1v2, as overexpression of other isoforms did not enhance invasion. It also requires both proper subcellular localization and methylase activity. Consistent with an invasive phenotype, PRMT1v2 overexpression caused altered cell morphology and reduced cell-cell adhesion. Finally, we observed a significant reduction in β-catenin protein levels, a critical cell-cell adhesion protein, and show that this reduction is pivotal to PRMT1v2-enhanced cell invasion. Our study underscores the importance of characterizing the distinct functional differences between PRMT1 isoforms. Overall, we demonstrate a specific role for PRMT1v2 in promoting breast cancer cell survival and invasion, and propose that it may represent a promising therapeutic target. *RMB is a Postdoctoral Fellow of the Canadian Institute of Health Research Citation Format: Robert Mitchell Baldwin, Alan Morettin, Genevieve Paris, Isabelle Goulet, Jocelyn Cote. The alternatively spliced PRMT1 isoform PRMT1v2 promotes breast cancer cell survival and invasiveness. [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 3789. doi:10.1158/1538-7445.AM2013-3789