Non-coding polymorphisms in nucleotide binding domain 1 in ABCC1 gene associate with transcript level and survival of patients with breast cancer

Abstract

Objectives: ATP-Binding Cassette (ABC) transporters may cause treatment failure by transporting of anticancer drugs outside of the tumor cells. Multidrug resistance-associated protein 1 coded by the ABCC1 gene has recently been suggested as a potential prognostic marker in breast cancer patients. This study aimed to explore tagged haplotype covering nucleotide binding domain 1 of ABCC1 in relation with corresponding transcript levels in tissues and clinical phenotype of breast cancer patients.

Methods: The distribution of twelve ABCC1 polymorphisms was assessed by direct sequencing in peripheral blood DNA (n = 540).

Results: Tumors from carriers of the wild type genotype in rs35623 or rs35628 exhibited significantly lower levels of ABCC1 transcript than those from carriers of the minor allele (p = 0.003 and p = 0.004, respectively). The ABCC1 transcript levels significantly increased in the order CT-GT>CC-GT>CC-GG for the predicted rs35626-rs4148351 diplotype. Chemotherapy-treated patients carrying the T allele in rs4148353 had longer disease-free survival than those with the GG genotype (p = 0.043). On the other hand, hormonal therapy-treated patients with the AA genotype in rs35628 had significantly longer disease-free survival than carriers of the G allele (p = 0.012).

Conclusions: Taken together, our study shows that genetic variability in the nucleotide binding domain 1 has a significant impact on the ABCC1 transcript level in the target tissue and may modify survival of breast cancer patients.

Figure 1. Schematic representation of functional domains of ABCC1.

Figure depicts functional domains of ABCC1 protein (A) and important structural motifs within NBD1 (B). Data modified from NCBI’s Conserved Domain Database (CDD) .

Figure 2. Haplotype analysis of ABCC1 SNPs.

Figure indicates linkage disequilibrium plot (A) and three blocks comprising of SNP diplotypes (B) predicted from experimental data obtained in the present study. The likelihood of linkage of two tested SNPs increases from white to red color (A). Population frequency of diplotypes and connections from one diplotype block to the next one are shown (B). Analysis was performed by HaploView v4.2 program.

Figure 3. Significant associations between transcript levels and polymorphisms in ABCC1.

All SNPs and frequent diplotypes were analyzed but to retain concise style only significant associations are reported.

Figure 4. Significant associations between DFS of patients with breast carcinoma and SNPs in ABCC1.

Kaplan-Meier survival curves for patients treated by chemotherapy (A) and hormonal therapy (B) were analyzed by Breslow test. In part A, dashed line represents DFS of patients with the GG genotype in rs4148353, while solid line indicates that of patients with the T allele. In part B, dashed line represents DFS of patients with the G allele in rs35628 and solid line DFS of those with the AA genotype. All SNPs have been analyzed but to retain concise style only significant associations are reported.