A polymorphism C3435T of the MDR-1 gene associated with smoking or high body mass index increases the risk of sporadic breast cancer in women

Abstract

Abstract. The human multidrug resistance gene 1 (MDR-1) encodes a plasma membrane P-glycoprotein (P-gp) that functions as the transmembrane efflux pump for various structurally unrelated anticancer agents and toxins. Polymorphisms in the MDR-1 gene may have an impact on the expression and function of P-gp, thereby influencing the susceptibility to various diseases, including cancer. We investigated the incidence of C3435T polymorphisms at exon 26 in the MDR-1 gene in 92 women with breast cancer and potential association of altered genotypes with smoking and high body mass index in cancer development among patients. The MDR-1 C3435T allelotype and genotype analysis revealed a high incidence (75.0%) of polymorph alteration in the MDR-1 gene. The frequencies of homozygous T/T, heterozygous C/T and homozygous C/C genotypes were 25.0, 50.0 and 25.0%, respectively. The risk of breast carcinoma in patients with MDR-1 polymorphism was significantly associated with the higher body mass index, where women with BMI >30 kg/m 2 and C allele in genotype had a higher risk of disease compared to patients with lower amounts of body fat tissue (p=0.0439). The risk was highest for the homozygous carriers of C allele with BMI >30 kg/m 2 compared to patients with BMI 25.1-30 or ≤25 kg/m 2 (OR 3.65, 95% CI 0.94-14.20; or OR 2.50, 95% CI 0.55-11.41), respectively. Consistent with the results of genotyping and BMI analyses, smoking patients harboring the C/T or C/C genotype had an increased risk of cancer (OR 1.28, OR 1.58,, respectively) when exposed to carcinogens in tobacco smoke, although it was not statistically significant. Our findings suggest that the MDR-1 C3435T polymorphism occurs in high incidence among women with breast carcinoma where C allele carriers have increased risk of developing cancer when exposed to toxic substances. Our observations are the first that indicate this polymorphism as a modulator of health to be associated with an increased risk of breast cancer.

Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: A case-control study

“…Functional polymorphism C3435T in the MDR1 gene alters the detoxification protective function of Pgp in breast tissue cells exposed to environmental carcinogens in tobacco smoke. This SNP occurs in high incidence among women with breast carcinoma where C allele carriers have increased risk of developing cancer when exposed to toxic substances (35). No significant differences were observed in genotype and allelic frequencies between this publication and the present study.…”

“…The results varied in level of statistical significance and role of genotype consequence. Whereas the T/T form was in majority associated with higher risk of disease origin, the carriers of C/C genotype were supposed to have a worse prognosis (35). We did not observe significant differences in this gene polymorphism between patients with breast cancer compared with controls.…”

“…No significant differences were observed in genotype and allele frequencies between case and control groups, and no breast cancer risk factor was observed related to these polymorphisms. A statistical association was seen between p53 codon 72 gene polymorphism and family history of breast cancer in both groups, as well as between MDR1 C3435T gene polymorphism and smoking habits in cases (35). We introduced new data that could help to characterize the Canary population.…”

“…C3435T polymorphism in the MDR1 gene may limit the local detoxification activity in breast tissue and be a risk factor for cancer development and behaviour (35). Different studies have been associated this polymorphism in MDR1 gene with smoking, high body mass index and risk of BC (35,36).…”

Influence of Genotype and Haplotype of MDR1 (C3435T, G2677A/T, C1236T) on the Incidence of Breast Cancer - a Case-Control Study in Jordan

“…Zubor et al (2007), reported that, among patients in Slovak Republic, those carrying CC genotype of C3435T had increased risk of breast cancer. In a study by Macias-Gomez et al (2014) conducted among Mexicans the prevalence of the TT genotype was 8% for patients with fibrocystic changes (FCC), 13% for infiltrating ductal breast cancer (IDBC) and 24% for control samples.…”