EXPRESSION OF NUCLEAR XIAP REVEALS MOLECULAR SIGNATURES ASSOCIATED WITH MOST PROLIFERATIVE AND MIGRATORY FEATURES IN BREAST CANCER

INTRODUCTION AND OBJECTIVE: X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of apoptosis protein aberrantly expressed in cancer. XIAP performs its canonical antiapoptotic functions at the cytoplasm, but growing evidence implicate an unexplored role at the nucleus. Our group has demonstrated that nuclear XIAP is associated with unfavorable outcome in breast cancer patients as well as increased in vitro cell growth and chemoresistance. Here, we aimed to explore transcriptomic signatures associated with XIAP nuclear oncogenic functions in breast cancer. MATERIAL AND METHOD: MCF-7 human breast cancer-derived cells overexpressing XIAP variants: pEBB (empty vector), XIAPwildtype, XIAPH467A (cytoplasmic location) (lack of ubiquitin ligase activity; cytoplasmic location), XIAPΔRING (RING deletion; nuclear location) and XIAPNLS (Nuclear Localization Signal insertion; nuclear location) were compared by RNA microarray considering a ≥ 2- fold-change as criteria to define the differentially expressed genes (DEGs). Pathway analysis and related processes were obtained through gene enrichment analysis using MetaCoreTM and gene ontology (GO) dataset. The Venn diagram was produced using InteractiVenn. The STRING® database was used to construct a protein network. Interest genes were validated by qRT-PCR. RESULTS AND CONCLUSION: XIAPNLS overexpression induced a global repression in gene expression in comparison to XIAPwild type and XIAPΔRING. The most representative DEGs were involved in the regulation of cellular processes such as localization, transport, cell proliferation, migration, motility and protein phosphorylation. Following validation, MMP13, IGFPB6 and TFPI2 turned out to be the most differentially expressed in XIAPNLS in relation to XIAPΔRING, genes closely linked to cell proliferation and migration. Interestingly, MMP13 expression was found increased, and IGFBP6 and TFPI2 reduced in invasive breast cancer versus normal tissues. Notably, TFPI2 was also associated with favorable clinical outcome. Functional assays with candidate genes and XIAP nuclear interactomes are currently being performed and will help understand nuclear XIAP role in breast cancer aggressiveness.