The role of ABC transporter genes in breast cancer resistance

Background

Cellular multidrug resistance (MDR) to anticancer drugs remains one of the primary causes of suboptimal outcomes in cancer therapy. ATP-binding cassette (ABC) transporters belong to a family of transporter proteins that contribute to drug resistance via ATP-dependent drug efflux pumps. The aim of this study was to assess the role and clinical impact of ABCB1 and other ABC transporter genes in development of breast cancer MDR.

Material and Methods

Expression profile of ABC transporter genes (ABCB1, ABCC1, ABCC2 and ABCG2) was evaluated in 90 breast cancer patients. Gene expression was quantified in samples from tumor and non-tumor breast tissues by real-time PCR. In addition, seven ABCB1 polymorphisms (SNPs) were analyzed using Nanogen electronic microarrays and compared with High Resolution Melting Analysis. Determination of associations between: 1/ expression of ABC transporters, 2/ genetic variability and 3/ haplotype pattern of ABCB1 on one side and clinico-pathological features including survival of patients on the other side was performed.

Results

ABC transporters were expressed in majority of cases. Striking inter-individual variability in their expression was found. ABCB1 was down-regulated in 79.5% of all tumors, while opposite, i.e. up-regulation was observed for ABCC1 and ABCC2 expression. Similar expression profiles were found in patients treated by neoadjuvant and adjuvant chemotherapy. Patients with high ABCB1 expression treated with P-gp substrates anthracyclineor taxane-containing regimens had significantly shorter disease-free survival than those treated by other regimens (P = 0.031). In genetic variation studies, high frequencies of variant alleles in ABCB1 exon12 (C1236T, qT=38.3), exon21 (G2677T/A, qT=40.0) and exon26 (C3435T, qT=54.0) were observed. Individuals with variant alleles in exons12 and 26 had significantly lower ABCB1 expression in their tumors than patients with normal genotype. These two SNPs also correlated with estrogen receptor status of patients (P=0.011 and P=0.051 respectively).

Conclusions

ABCB1 SNPs may affect function of protein by influencing the expression level and modify breast cancer prognosis. Especially, SNPs in exons 12 and 26 influenced ABCB1 expression and seem to be good candidates for cancer validation studies. The observed association between ABCB1 SNPs and estrogen receptor status of patients warrants further research based on extended haplotype analysis. Moreover, expression of ABCB1 in tumor tissue may be considered as factor increasing the risk of failure of anthracycline or taxane-based chemotherapy.

This work was supported by grants IGA 9426-3 and GACR 305/07/P347.