Multi-Drug Resistance 1 Genetic Polymorphisms Gene Expression and Prediction of Chemotherapy Response in Breast Cancer Egyptian Patients

Abstract

Although anthracycline-based chemotherapy is a crucial treatment for breast cancer, its outcome is limited by the multidrug resistance MDR. Overexpression of P-glycoprotein (Pgp), a transmembrane active efflux transporter of various drugs and carcinogenic substrate, may result in MDR. The impact of MDR1 polymorphisms on MDR1 expression and risk of breast cancer, and whether it can alter chemotherapeutic agents response in breast cancer is unclear. The present work studied the relevance between MDR1 C3435T, C1236T, G2677T/A polymorphisms and MDR1 gene expression and susceptibility to breast carcinoma as well as sensitivity to anthracyinebased chemotherapy in Egyptian females with breast cancer (BC). We determined mRNA levels of MDR1 in breast tumor specimens (n=190) by real-time rt-PCR. Blood samples from BC female patients and healthy controls were obtained for genotyping. ARMS-PCR assay was used for detection of C3435T, C1236T and G2677T/A Polymorphisms. This study revealed that C3435 TT patients showed a significant decrease in MDR1 mRNA level compared with CC genotypes. No association was found between the MDR1 C1236T, G2677T/A polymorphisms and MDR1 mRNA expression. The frequency of C3435 TT genotype and T allele were significantly higher in BC patients compared to the controls (P < 0.05). C3435 TT and C3435 CT had odds ratio (p-value) 5.6 (<0.001) and 2.28 (0.01) for response to anthracycline-based chemotherapy, respectively, compared to CC genotype. No statistically significant differences were observed between patients and control regarding the allelic and genotypic frequencies of MDR1 C1236T, G2677T/A polymorphisms as well as no correlation was detected to the response rate to anthracycline-based chemotherapy. Our results suggested that C3435T, but not C1236T or G2677T/A, was associated with changes in MDR1 gene expression and hence alters the response after anthracyclin based chemotherapy.

Key words: Chemotherapy. Polymorphisms. Multidrug resistance. Breast cancer.