Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer

Kafka, Ariane; Sauer, Georg; Jaeger, Christoph; Grundmann, R; Zeillinger, Robert; Deissler, Helmut

doi:10.3892/ijo.22.5.1117

Cited by 58 publications

(63 citation statements)

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“…In contrast, an independent study reported lower MDR1 expression, significantly decreased overall AML-survival, and a high probability of relapse in patients with the MDR1 3435CC genotype compared to those with the 3435TT genotype (64). Consistent with this study, the 3435C genotype was also associated with resistance to preoperative chemotherapy in locally advanced breast cancer (65) The importance of P-glycoprotein in the disposition of drugs used in antiretroviral therapy has led to investigation of MDR1 genetic variation in HIV populations. Though the T-129C, G2677T/A, and C3453T polymorphisms do not influence the risk of HIV infection per se (66), the C3435T polymorphism was found to predict immune recovery after initiation of antiretroviral treatment.…”

Section: Impact Of Mdr1 Genetic Variation On Disease Coursesupporting

confidence: 65%

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

2004

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The multidrug resistance (MDR1) gene product P-glycoprotein is a membrane protein that functions as an ATP-dependent efflux pump, transporting exogenous and endogenous substrates from the inside of cells to the outside. Physiological expression of P-glycoprotein in tissues with excretory or protective function is a major determinant of drug disposition and provides a cellular defense mechanism against potentially harmful compounds. Therefore, P-glycoprotein has significant impact on therapeutic efficacy and toxicity as it plays a key role in absorption of oral medications from the intestinal tract, excretion into bile and urine, and distribution into protected tissues such as the brain and testes. There is increasing interest in the possible role of genetic variation in MDR1 in drug therapy. Numerous genetic polymorphisms in MDR1 have been described, some of which have been shown to determine Pglycoprotein expression levels and substrate transport. Furthermore, some of these polymorphisms have an impact on pharmacokinetic and pharmacodynamic profiles of drug substrates and directly influence outcome and prognosis of certain diseases. This review will focus on the impact of genetic variation in MDR1 on expression and function of P-glycoprotein and the implications of this variation for drug therapy and disease risk.

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Section: Impact Of Mdr1 Genetic Variation On Disease Coursesupporting

confidence: 65%

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

2004

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“…Homozygous mutant 3435TT in exon 26 was associated with higher plasma levels of digoxin and lower P-gp expression compared to wild type 3435CC [9]. Lower expression of P-gp in 3435TT carriers gives better prediction for treatment response to palliative chemotherapy in woman with breast cancer [39]. Simon et al [40] reported that patients with acute myocardial infarction that are on clopidogrel and are carrying 3435T mutant variant have more than five times greater rate for development of adverse events than wild type carriers.…”

Section: Discussionmentioning

confidence: 99%

Genotype Variability and Haplotype Profile of Abcb1 (Mdr1) Gene Polymorphisms in Macedonian Population

Naumovska

Nestorovska

Sterjev

et al. 2014

Prilozi

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The aim of this study was to evaluate the most common ABCB1 (MDR1, P-glycoprotein) polymorphisms in the population of R. Macedonia and compare the allele and haplotype frequencies with the global geographic data reported from different ethnic populations. The total of 107 healthy Macedonian individuals from the general population was included. Genotypes for the ABCB1 for three polymorphisms C1236T [rs1128503], G2677A/T [rs2032582] and C3435T [rs1045642] were analyzed by Real-Time PCR. Obtained allele frequencies for these three SNPs were similar to those observed in other European Caucasians. The detected genotype frequencies were 33.6% for 1236CC, 44.9% for 1236CT and 21.5% for 1236TT in exon 12; 32.7%, 44.9% and 22.4% for 2677GG, 2677GT and 2677GT consecutively in exon 21; and 25.2% for 3435CC, 52.3% for 3435CT and 22.5% for 3435TT in exon 26.Strong LD was observed in our study among all = 0.859, r 2 = 0.711). Eight different haplotypes were identified and the most prominent was the CGC haplotype (45.3%). Our study was the first to have documented the distribution of ABCB1 alleles, genotypes and haplotypes in the population of R. Macedonia. The obtained results can help in the prediction of different response to the drugs that are P-glycoprotein substrates. Additionally, in the era of individualized medicine the determination of the P-glycoprotein genotype might be a good predictive marker for determination of the subpopulations with higher risk to certain diseases.

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“…In addition to the known association between increased expression of this glycoprotein in tumor cells and the phenomenon of multidrug resistance against antineoplastic agents (28) are reports on the relationship between MDR-1 genotype and susceptibility to cancer (29)(30)(31), based on the fact that some of the polymorphic variants of the MDR-1 gene, including C3435T at exon 26, have been shown to affect the expression and function of Pglycoprotein (32,33). Of great importance is also the finding that polymorphism C3435T of the MDR-1 gene can predict response to preoperative chemotherapy in locally advanced breast cancer (34). Considering all these observations together we hypothesize that C3435T polymorphism in the MDR-1 gene may limit the local detoxification activity in breast tissue and be a risk factor for cancer development and behavior.…”

Section: Introductionmentioning

confidence: 99%

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

Žúbor

Lasabová²,

Hatok³

et al. 2007

Oncol Rep

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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.

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Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer

Cited by 58 publications

References 0 publications

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

Genotype Variability and Haplotype Profile of Abcb1 (Mdr1) Gene Polymorphisms in Macedonian Population

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

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