Abstract 4786: Cellular localization of PRMT5 correlates with poor recurrent free survival in triple-negative breast cancer (TNBC) (2015)

Abstract PURPOSE: TNBC is an aggressive disease with limited effective targeted therapies. Protein arginine methyltransferase 5 (PRMT5) is an enzyme that symmetrically methylates arginine residues of both histone and non-histone proteins that regulate cellular growth and drive malignant transformation. PRMT5 is an oncogenic marker for aggressive cancers with limited treatment options like glioblastoma multiforme (GBM) and mantle cell lymphoma (MCL) and PRMT5 knockdown has been shown to improve survival in a preclinical model of GBM. The expression profile of PRMT5 in TNBC has not been previously evaluated. METHODS: We obtained a clinical database of TNBC patients that correlates to tissue samples collected after resection of the original breast tumor (n = 106). Tissue microarrays (TMA) were stained for PRMT5 and graded based on level of cytoplasmic and nuclear staining. The association of PRMT5 expression with patient overall survival (OS) and recurrent free survival (RFS) was analyzed using a log-rank test. Multivariate COX regression model was used to evaluate PRMT expression level as independent predictor of OS and RFS with histopathologic factors such as lymph node involvement and tumor size. RESULTS: High cytoplasmic levels of PRMT5 in TNBC correlated with improvement in RFS (p = 0.043, CI 0.218-0.976), while showing no correlation with OS. High levels of nuclear PRTM5 did not show a significant correlation with OS or RFS. Patients with tumors showing high nuclear and low cytoplasmic levels of PRMT5 had the worst OS and RFS (p&lt;0.05). When accounting for stage, lymph node status, and nuclear or cytoplasmic PRMT5 levels, higher stages predicted worse RFS with stage 3 being the worst (p&lt;0.01). Having high PRMT5 in the cytoplasm alone was associated with an improved RFS trend (p = 0.08), but TNBC with low cytoplasmic PRMT5 and high nuclear PRMT5 levels was significant for predicting worse RFS (p = 0.005). Most TNBC with high cytoplasmic levels of PRMT5 were Stage 2 (65%) and most TNBC with low nuclear levels of PRMT5 were also Stage 2 (64%). In stage 3 cancers, 55% had low cytoplasmic levels of PRMT5 while 44% had high nuclear levels of PRMT5. The levels of PRMT5 in the cytoplasm or nucleus were no different depending on the presence or absence of positive lymph nodes at the time of diagnosis. CONCLUSIONS: PRMT5 is variably expressed in TNBC and the cellular location of PRMT5 correlates with RFS and OS. Having association between tumors with low cytoplasmic and high nuclear levels with significantly worse RFS implies that high cytoplasmic PRMT5 may have a protective effect. These results prompt further investigation into the biologic role of PRMT5 in TNBC and whether it can serve as a potential therapeutic target. Citation Format: Elaine P. Alexander, Christian T. Earl, Xiaokui Mo, Konstantin Shilo, Robert A. Baiocchi, Maryam B. Lustberg. Cellular localization of PRMT5 correlates with poor recurrent free survival in triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4786. doi:10.1158/1538-7445.AM2015-4786