Understanding the role of Apoptosis Inhibitor 5 (Api5) in breast cancer

Abstract

The balance between cell death and cell division is essential for the maintenance of homeostasis in multicellular organisms. Apoptosis, or programmed cell death, plays a vital role in the maintenance of this homeostasis and therefore, is a tightly regulated process. Deregulation of apoptosis can lead to cancer. Apoptosis inhibitor 5 (Api5) is an inhibitor of apoptosis. The molecular mechanism underlying the activation and regulation of Api5 is yet to be thoroughly explored. Api5 has been reported to be associated with several cancers, including ovarian, bladder, and lung cancers. Studies suggest that Api5 can be used as a biomarker for ovarian and bladder cancers. However, the role of Api5 in breast cancer, which reports the highest number of deaths due to cancer, remains unclear. My project focuses on investigating the role of Api5 in breast cancer. In vitro overexpression studies using 3D breast acinar cultures demonstrated that overexpression of Api5 resulted in the transformation of non-tumorigenic breast epithelial cells with increased proliferation and various phenotypic changes. Api5 knockdown affected the tumorigenic potential and associated phenotypes of breast cancer cells. Mechanistically Api5 was shown to activate FGF2 signalling, possibly leading to PDK1-Akt and ERK pathway activation. Interestingly Api5-FGF2 signalling activates PDK1-Akt/ cMYC axis during the early days of acinar morphogenesis, while activation of ERK signalling occurred during the later days. Together this led to elevated proliferation, migration, anchorage-independent growth, protein synthesis and reduced apoptosis, supporting the malignant growth of Api5 overexpressing cells. in silico studies using TCGA and GENT2 database demonstrated that elevated levels of Api5 transcript in breast cancers that was also associated with poor patient survival. This further correlated with histopathological analyses of tumour samples where higher expression of Api5 was observed in breast tumour tissue compared to the adjacent normal tissue, thus suggesting that elevated levels of Api5 might be associated with breast malignancy