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 (XIAP^NLS-C-term) and investigated the oncogenic mechanisms associated with nuclear XIAP in breast cancer. Our results show that cells overexpressing XIAP^ΔRING (RING deletion) and XIAP^NLS-C-term exhibited XIAP nuclear localization more abundantly than XIAP^wild-type. Remarkably, overexpression of XIAP^NLS-C-term, but not XIAP^ΔRING, 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 XIAP^NLS-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.

避免细胞凋亡是癌症的标志之一。已知X连锁的凋亡蛋白抑制剂（XIAP）通过抑制胱天蛋白酶和泛素化靶蛋白来调节凋亡。XIAP主要在细胞质中发现，但最近的数据将核XIAP与乳腺癌的不良预后联系起来。在这里，我们生成了具有核定位信号（XIAP ^NLS-C-term）的XIAP突变体，并研究了与核XIAP相关的乳腺癌的致癌机制。我们的结果表明，过表达^XIAPΔRING（RING缺失）和XIAP ^{NLS-C-term的}细胞比XIAP^野生型更丰富地显示XIAP核定位。值得注意的是，XIAP ^NLS-C-term而不是XIAP的过表达^ΔRING赋予对阿霉素的抗性和增加的细胞增殖能力。有趣的是，Survivin和c-IAP1表达与XIAP致癌作用无关。但是，在XIAP ^NLS-C期过表达后，K63而不是K48链的NFκB表达和泛素化增加，表明核信号转导。一致地，多变量分析显示核素（而非细胞质）XIAP是激素受体阴性乳腺癌患者的独立预后因素。总而言之，我们的研究结果表明，核XIAP赋予不良结局以及RING相关的乳腺癌生长和化学耐药性。