Abstract 17: Xiap over-expression is a poor prognostic marker in breast cancer and can be targeted to induce efficient apoptosis
Authors: Azhar R. Hussain, Maqbool Ahmed, Rong Bu, Shaham Beg, Alanood M. Alrashed, Roxanne Melosantos, Dahish S. Ajarim, Shahab Uddin, Khawla S. AlKuraya
Journal: Cancer Research (2015)

Abstract Breast cancer is the most common cancer in females and is ranked only second to lung cancer in cancer-related deaths all over the world in women. Despite improvement in diagnosis and management of breast cancer, the survival rate of this disease for stage 4 disease is still only 22%. X-linked Inhibitor of Apoptosis (XIAP) is a member of the inhibitor of apoptosis family of proteins that has been shown to be over-expressed in a variety of cancers including breast cancer leading to an overall poor survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored. We therefore examined the expression of XIAP in a cohort of 964 breast cancer cases by immunohistochemistry and found that XIAP was over-expressed in 29.5% (284/964) of the cases and was found to be directly associated with clinical parameters such as tumor size (p = 0.0044), extra nodal extension (p = 0.0041) and poorly differentiated breast cancer (p&amp;lt;0.0001). In addition, XIAP over-expression was also significantly associated with activated AKT (p&amp;lt;0.0001), Ki-67 (p&amp;lt;0.0001) and PARP (p&amp;lt;0.0001). Finally, XIAP over-expression in our cohort of breast cancer was an independent poor prognostic marker in multivariate analysis. Next, we investigated inhibition of XIAP using a specific inhibitor; Embelin on a panel of breast cancer cell lines and found that Embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. In order to identify the exact pathway involved in XIAP inhibition, we treated breast cancer cells with different doses of Embelin and found that there was down-regulation of XIAP leading to activation of caspases-9, -3 and PARP. We also found that Embelin treatment caused cleavage of caspase-8 and truncation of Bid leading to activation of the mitochondrial apoptotic pathway and efficient apoptosis. Finally, as our clinical data demonstrated a significant association between XIAP over-expression and activation of AKT in breast cancer samples, we synergistically induced apoptosis in breast cancer cells using sub-optimal doses of Embelin and PI3-kinase inhibitor; LY294002. These data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and XIAP can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells. Citation Format: Azhar R. Hussain, Maqbool Ahmed, Rong Bu, Shaham Beg, Alanood M. Alrashed, Roxanne Melosantos, Dahish S. Ajarim, Shahab Uddin, Khawla S. AlKuraya. Xiap over-expression is a poor prognostic marker in breast cancer and can be targeted to induce efficient apoptosis. [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 17. doi:10.1158/1538-7445.AM2015-17