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
