Abstract 4405: Over-expression of PARP is associated with an aggressive phenotype and can be synergistically targeted using combination of PARP and XIAP inhibitors in breast cancer

Abstract

Abstract Breast cancer is the most common cancer in females and despite improvement in treatment modality with the introduction of hormonal targeted therapy, these cancers still remains a major cause of morbidity and mortality in females. Poly ADP ribose polymerase (PARP) is an enzyme which plays a critical role for repairing single-strand breaks. The main function of PARP1 is dependent upon cellular stress responses and directs cells towards DNA repair based on the strength of the stress stimulus. PARP has been found to be over-expressed in various tumors including ovarian cancer; breast cancer and lung cancer, however, its role in the pathogenesis of breast cancer of Middle Eastern origin have not been completely elucidated. Therefore, we examined the expression of PARP in a large cohort of more than 1000 breast cancer by IHC in a tissue microarray format and found PARP was over expressed in 44.7% (451/1008) and was found to be significantly associated with aggressive markers such as Triple negative phenotype, high grade tumors, large tumor size, stage 4 disease and had a poor 5 year overall survival of 72.6 months as compared to 85.4 months (p = 0.0005). Interestingly PARP expression was also found to be significantly associated with aggressive molecular markers such as activated AKT, XIAP and proliferative marker; ki67. Next, in vitro effect of inactivation of PARP was evaluated using a PARP inhibitor; olaparib on a panel of BC cell lines. Olaparib treatment alone did not affect the cell viability and apoptosis at doses up to 10μM concentration. However, when BC cells were treated with sub-optimal dose of Olaparib (1μM) and Embelin (XIAP inhibitor)(5μM) in combination for 48 hours, there was appreciable inhibition of cell viability via induction of apoptosis. Combination of Olaparib and Embelin induced apoptosis via activation and cleavage of caspases-9, -3 and PARP in BC cells. These studies highlight the importance of targeting PARP in combination with either small molecular inhibitors or chemotherapeutic agents in BC can improve the management and survival of this aggressive disease. Citation Format: Maqbool Ahmed, Azhar R. Hussain, Shaham Beg, Saravanan Thangavel, Rafia Begum, Dahish Ajarim, Fouad Al-Dayel, Abdul Khalid Siraj K. Siraj, Khawla S. Al-kuraya. Over-expression of PARP is associated with an aggressive phenotype and can be synergistically targeted using combination of PARP and XIAP inhibitors in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4405.