Abstract 3298: Identifying a function for DHHC20 in breast cancer

Abstract

Abstract Triple negative breast cancer (TNBC) accounts for 15-20% of all cancers and is associated with a high propensity of metastasis, an increased risk of recurrence and a disproportionate number of deaths. Currently, therapeutic options are lacking in their ability to effectively treat TNBC; therefore, identification of novel, targetable signaling pathways is of great importance. Analysis of The Cancer Genome Atlas revealed that expression of the palmitoyl transferase DHHC20 is altered in breast cancer. DHHC20 is one of 23 protein palmitoyl transferases identified in mammalian cells, which catalyze the transfer of palmitate to cysteine residues of target proteins. Protein palmitoylation is critical in the trafficking, localization and function of various proteins and alterations in the expression and function of several DHHC palmitoyl transferases have been observed in cancer. Surprisingly, substrate specificity remains largely unknown and with the exception of a few palmitoylated proteins including Ras and the sex steroid receptors, the function of DHHC proteins in cancer has been largely unexplored. We utilized a TNBC cell culture model system to characterize the function of DHHC20 in breast cancer. Suppression of DHHC20 using short-hairpin RNA silencing resulted in several phenotypes consistent with a role for DHHC20 in tumor dormancy and progression. Specifically, knockdown of DHHC20 in MDA-MB231 cells increased the expression of CDK inhibitors p21 and p27, slowed cell division rates from every 24 hours to every 72 hours and increased the proportion of cells undergoing cellular senescence. Additionally, suppression of DHHC20 increased chemotaxis and enhanced mitogenic signaling through the Erk pathway under nutrient deprivation conditions. Finally, DHHC20 expression was dramatically reduced following 24hr of serum deprivation and loss of DHHC20 expression enhanced the survival of MDA-MB231 cells under low nutrient conditions. These findings suggest that DHHC20-mediated protein palmitoylation regulates important aspects of breast cancer progression including cell cycle control, mitogenic signaling responses and cell migration. The implication of these findings is that targeting the DHHC20 pathway may be of therapeutic interest for TNBC. Citation Format: Kristin B. Runkle, Samantha Terkowski, Ewa Stypulkowski, Eric Witze. Identifying a function for DHHC20 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 3298. doi:10.1158/1538-7445.AM2014-3298