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Significance of combined analysis of PARP1 and EZH2 expression as potentially targetable biomarkers in breast cancer

Background PARP inhibitor (PARPi) is a new class of anticancer therapy and is currently used for the treatment of advanced BRCA-mutant breast cancer (BC). However, a significant number of patients with BRCA-deficient tumors do not respond well to PARPi treatment, and may develop resistance. So, it is important to know better the mechanisms of PARPi resistance to develop more efficient therapeutic approaches. Zeste-homolog 2 (EZH2), a member of the polycomb group of genes, affects PARPi sensitivity in BC. Patients and methods Using the immunohistochemistry technique, we investigated subcellular EZH2 and poly (ADP-ribose) polymerase-1 (PARP1) expression in 82 cases of BC including a subgroup (n=29) of triple-negative breast cancer (TNBC) and correlated their expression with clinicopathological parameters and patient’s outcome. Results High PARP1 was found in 70.7% of BC cases and high EZH2 was detected in 62.2% of cases. Combined overexpression of both PARP1 and EZH2 was found in 51.2% of cases. They were significantly associated with negative BRCA1 expression (P=0.033) and TNBC (P=0.026). In survival analysis, overexpression of both PARP1 and EZH2 was significantly associated with shorter recurrence-free survival and overall survival in all BC cases especially in BRCA1-negative and TNBC patients. They were also the only independent predictors for shorter recurrence-free survival (P=0.006, hazard ratio=1.75) in multivariate analysis. Conclusion Our findings prove that the combined high PARP1 and EZH2 expression was statistically associated with poor prognosis and survival outcome in early-stage BC, in particular BRCA1-negative and TNBC. Therefore, these results suggest that patients with high PARP1 and EZH2 expression may benefit from combining PARPi and EZH2 inhibitor therapy in BRCA1-negative BCs.