Abstract
Patients with aggressive breast cancer (BC) subtypes usually don’t have favorable prognosis despite the improvement in treatment modalities. These cancers still remain a major cause of morbidity and mortality in females. This has fostered a major effort to discover actionable molecular targets to treat these patients. Poly ADP ribose polymerase (PARP) is one of these molecular targets that are under comprehensive investigation for treatment of such tumors. However, its role in the pathogenesis of BC from Middle Eastern ethnicity has not yet been explored. Therefore, we examined the expression of PARP protein in a large cohort of over 1000 Middle Eastern BC cases by immunohistochemistry. Correlation with clinico-pathological parameters were performed. Nuclear PARP overexpression was observed in 44.7% of all BC cases and was significantly associated with aggressive clinico-pathological markers. Interestingly, nuclear PARP overexpression was an independent predictor of poor prognosis. PARP overexpression was also directly associated with XIAP overexpression, with PARP and XIAP co-expression in 15.8% (159/1008) of our cases. We showed that combined inhibition of PARP by olaparib and XIAP by embelin significantly and synergistically inhibited cell growth and induced apoptosis in BC cell lines. Finally, co-treatment of olaparib and embelin regressed BC xenograft tumor growth in nude mice. Our results revealed the role of PARP in Middle Eastern BC pathogenesis and prognosis. Furthermore, our data support the potential clinical development of combined inhibition of PARP and XIAP, which eventually could extend the utility of olaparib beyond BRCA deficient cancer.
Highlights
Breast cancer is a leading cause of morbidity and mortality in women worldwide
This is the first report on Poly ADP ribose polymerase (PARP) protein expression in a large cohort of primary Middle Eastern breast cancer (BC) by immunohistochemistry in a tissue microarray format
We show that high nuclear PARP expression was detectable in 44.7% of the examined cases. nPARP expression was, in general, correlated with more aggressive tumor characteristics
Summary
Breast cancer is a leading cause of morbidity and mortality in women worldwide. In Saudi Arabia, BC is the most common cancer among females, accounting for 28.7% of newly diagnosed female cancers and the incidence continues to increase every year [1]. X-linked inhibitor of apoptosis protein (XIAP) has been found to be a promising therapeutic molecular target in Middle Eastern BC and other cancers [21,22,23]. We were able to demonstrate the superiority and synergism of inhibition of PARP (using olaparib) and XIAP (using embelin) together over using single inhibitor alone This synergistic effect on cell proliferation, apoptosis and tumor growth is demonstrated both in vitro and in vivo.
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