Expression of X-Linked Inhibitor of Apoptosis Protein (XIAP) in Breast Cancer Is Associated with Shorter Survival and Resistance to Chemotherapy

Abstract

XIAP, the most potent inhibitor of cell death pathways, is linked to chemotherapy resistance and tumor aggressiveness. Currently, multiple XIAP-targeting agents are in clinical trials. However, the characterization of XIAP expression in relation to clinicopathological variables in large clinical series of breast cancer is lacking. We retrospectively analyzed non-metastatic, non-inflammatory, primary, invasive breast cancer samples for XIAP mRNA (n = 2341) and protein (n = 367) expression. XIAP expression was analyzed as a continuous value and correlated with clinicopathological variables. XIAP mRNA expression was heterogeneous across samples and significantly associated with younger patients' age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, HR+/HER2- status, and PAM50 luminal B subtype. Higher XIAP expression was associated with shorter DFS in uni- and multivariate analyses in 909 informative patients. Very similar correlations were observed at the protein level. This prognostic impact was significant in the HR+/HER2- but not in the TN subtype. Finally, XIAP mRNA expression was associated with lower pCR rate to anthracycline-based neoadjuvant chemotherapy in both uni- and multivariate analyses in 1203 informative patients. Higher XIAP expression in invasive breast cancer is independently associated with poorer prognosis and resistance to chemotherapy, suggesting the potential therapeutic benefit of targeting XIAP.

Keywords: HER2; TN; XIAP; anthracycline; apoptosis; cell death; luminal B; metastasis; pCR; proteomics; taxanes.

Figure 1

Distribution of XIAP mRNA and protein expression in breast cancer samples. (A) Histogram of distribution of XIAP mRNA expression levels (log2) across the 2341 clinical samples. The red line represents the density curve of distribution. (B) XIAP mRNA expression level (log2) reported as violin plot and box plot. (C) Histogram of distribution of XIAP protein expression levels (log2) across the 367 clinical samples. The red line represents the density curve of distribution. (D) XIAP protein expression level (log2) reported as a violin plot and box plot.

Figure 2

Shorter disease-free survival in high XIAP expression. (A) Kaplan–Meier DFS curve in 909 patients. (B) similar to (A), but according to high and low XIAP mRNA expression (the XIAP-low and XIAP-high groups were defined by the Cox model prediction). (C) Kaplan–Meier DFS curve in 347 patients. (D) similar to (A), but according to high and low XIAP protein expression.