Abstract
BackgroundBreast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women. Despite improvement in diagnosis, the survival rate of this disease has still not improved. X-linked Inhibitor of Apoptosis (XIAP) has been shown to be over-expressed in various cancers leading to poor overall survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored.MethodsWe examined the expression of XIAP in more than 1000 Middle Eastern breast cancer cases by immunohistochemistry. Apoptosis was measured by flow cytometry. Protein expression was determined by western blotting. Finally, in vivo studies were performed on nude mice following xenografting and treatment with inhibitors.ResultsXIAP was found to be over-expressed in 29.5% of cases and directly associated with clinical parameters such as tumor size, extra nodal extension, triple negative breast cancer and poorly differentiated breast cancer subtype. In addition, XIAP over-expression was also significantly associated with PI3-kinase pathway protein; p-AKT, proliferative marker; Ki-67 and anti-apoptotic marker; PARP. 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 and found that embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. Finally, breast cancer cells treated with combination of embelin and PI3-kinase inhibitor; LY294002 synergistically induced apoptosis and caused tumor growth regression in vivo.ConclusionThese data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells.
Highlights
Breast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women
Determination of X-linked Inhibitor of Apoptosis (XIAP) expression by IHC and correlation with clinical data and molecular markers To identify the role of XIAP in the pathogenesis of breast cancer, we analyzed expression of XIAP by IHC on a tissue microarray (TMA) format on a large cohort of BC samples collected at King Faisal Specialist Hospital and Research Centre (KFSHRC) from 1990 to 2011
XIAP over-expression led to a poor overall survival of 71.8% as compared to 82.8% (p = 0.0005) (Fig. 1b) and was found to be an independent poor prognostic marker in multivariate analysis (Additional file 2: Table S2)
Summary
Breast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women. In Saudi Arabia, breast cancer is the most common cancer in females as well as remains the major cause of morbidity and mortality within the female population [6] One reason behind this increase in morbidity and mortality in breast cancer could be the strong-association with many aggressive molecular markers that tend to cause increased proliferation of cancer cells and impart resistance to conventional chemotherapy [7, 8]. These aggressive markers include dysregulated proteins of the survival pathways [8] and proliferative markers [9] that tend to make the tumor resistant to conventional chemotherapy, grow rapidly and spread to surrounding tissues and distant organs. There is an urgent need for identifying molecular targets that are either overexpressed or constitutively activated in breast cancer that can be therapeutically targeted
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