Expression of nuclear XIAP associates with cell growth and drug resistance and confers poor prognosis in breast cancer.

Evasion from apoptosis is one of the hallmarks of cancer. X-linked inhibitor of apoptosis protein (XIAP) is known to modulate apoptosis by inhibiting caspases and ubiquitinating target proteins. XIAP is mainly found at the cytoplasm, but recent data link nuclear XIAP to poor prognosis in breast cancer. Here, we generated a mutant form of XIAP with a nuclear localization signal (XIAPNLS-C-term) and investigated the oncogenic mechanisms associated with nuclear XIAP in breast cancer. Our results show that cells overexpressing XIAPΔRING (RING deletion) and XIAPNLS-C-term exhibited XIAP nuclear localization more abundantly than XIAPwild-type. Remarkably, overexpression of XIAPNLS-C-term, but not XIAPΔRING, conferred resistance to doxorubicin and increased cellular proliferative capacity. Interestingly, Survivin and c-IAP1 expression were not associated with XIAP oncogenic effects. However, NFκB expression and ubiquitination of K63, but not K48 chains, were increased following XIAPNLS-C-term overexpression, pointing to nuclear signaling transduction. Consistently, multivariate analysis revealed nuclear, but not cytoplasmic XIAP, as an independent prognostic factor in hormone receptor-negative breast cancer patients. Altogether, our findings suggest that nuclear XIAP confers poor outcome and RING-associated breast cancer growth and chemoresistance.