Discovering novel mechanisms of taxane resistance in human breast cancer by whole-exome sequencing.

Abstract

Taxanes are important drugs used in the treatment of breast cancer; however, some cancer types are taxane-resistant. The aim of the present study was to investigate the underlying mechanisms of taxane resistance using whole-exome sequencing (WES). Six patients with breast cancer whose tumors responded well to anthracycline treatment but grew rapidly during neoadjuvant taxane-based chemotherapy, were included in the present study. WES of samples from these patients was carried out to identify somatic mutations of candidate genes thought to affect taxane resistance, and the candidate proteins were structurally modeled. The mRNA and protein expression levels of these candidate genes in other breast cancers treated with taxanes were also examined. Nine variants common to all six patients were identified and two of these [R552P in V-type proton ATPase catalytic subunit A (ATP6V1A) and T114P in apolipoprotein B MRNA editing enzyme catalytic subunit 3F (APOBEC3F)] were selected. The results also showed that, protein-structure visualization suggested that these mutations may cause structural changes. The Kaplan-Meier analyses revealed that higher APT6V1A and APOBEC3F expression levels were significantly associated with poorer disease-free survival (DFS) and overall survival. Moreover, multivariate analysis identified high ATP6V1A mRNA expression as an independent risk factor for poor DFS. Two specific mutations that might affect taxane resistance were identified. Thus, these results suggest that breast cancer patients receiving taxanes who have high ATP6V1A or APOBEC3F expression levels may have shorter survival.