Introduction
Breast cancer is recognized as the most common malignant tumour in women worldwide (1). One of the most common problems when treating breast cancer is drug resistance. This curable disease can be fatal if resistance to chemotherapy drugs develops, which leads to metastasis (2). The multidrug resistance 1 (MDR1) gene, a member of the ATP-binding cassette family, encodes a membrane-bound phosphoglycoprotein (P-gp) that acts as an ATP-dependent efflux pump, providing protection to normal cells against numerous substances, such as antibiotics, polysaccharides, organic cations and amino acids, and protection to the body against environmental toxins (3).
The human MDR1 gene mutation at exon 26, position 3435 (also known as C3435T) leads to decreased mRNA expression levels and P-gp activity (4). Although the C3435T mutation in exon 26 of the MDR1 gene is a silent mutation, this polymorphism affects the expression and function of P-gp in many ways (5), impacting susceptibility to cancer. When this gene mutation is overexpressed in breast cancer, it can cause cancer cells to become resistant to the drugs used for treatment (2), which leads to treatment failure.
In the past decade, the association between the MDR1 rs1045642 polymorphism and breast cancer in different populations has been studied; the association between the MDR1 rs1045642 polymorphism and breast cancer risk varies in different human populations (6). There are some previous studies on the association between MDR1 rs1045642 polymorphism and breast cancer risk. Such as, Cizmarikova et al (7), Gutierrez-Rubio et al (8), Abuhaliema et al (9) and Jaramillo-Rangel et al (10) performed studies on Slovak, Mexican, Jordanian and northern Mexican populations, respectively. Tatari et al (11), Henríquez-Hernández et al (12), Macias-Gomez et al (3), Ghafouri et al (13), Tazzite et al (14), Li et al (15) and Al-Eitan et al (16) studied Iranian, Spanish Canary Islands, Mexican, Kurdish, Moroccan, Chinese and Jordanian populations, respectively. Rubiś et al (17) reported that the association between MDR1 rs1045642 polymorphism and breast cancer risk in the Polish population. The results of several studies are inconsistent and inconclusive due to the limitations of individual studies. The inconsistent findings may also be due to limited sample size, single population, sample heterogeneity and differences in study methods.
To obtain a more precise estimation of the association between MDR1 rs1045642 polymorphism and breast cancer susceptibility, all published case-control studies with a cut-off date of August 2023 were collected for a meta-analysis and rational research methods and models were used to detail the role of the MDR1 rs1045642 polymorphism in ethnically diverse patients with breast cancer. The strengths of the present meta-analysis are that it is an update involving the large number of relatively comprehensive ethnicities with little sample heterogeneity.
Discussion
With the development of molecular biology, gene polymorphism analysis has been favoured by researchers (19) and gene polymorphisms are increasingly recognized as key risk factors for breast cancer (1). The present study performed a comprehensive meta-analysis of the association between MDR1 rs1045642 polymorphism and breast cancer to synthesize the basis of current relevant studies.
A genetic polymorphism of the MDR1 gene was first reported by Kioka et al (20) through in vitro studies of cancer cells. Subsequently, screening results for the entire MDR1 coding region have been reported (21). Similar meta-analyses have been performed to assess the association between the MDR1 rs1045642 polymorphism and breast cancer risk, but the results have varied. For example, Cizmarikova et al (7), Wang et al (6), Wang et al (22), Sharif et al (1), Abuhaliema et al (9) and Jaramillo-Rangel et al (10) reported an association between the MDR1 rs1045642 polymorphism and breast cancer. However, Taheri et al (23), Macias-Gomez et al (3), Tazzite et al (16), Li et al (15) and Totoń et al (24) reported that the MDR1 rs1045642 polymorphism was not associated with breast cancer. In the meta-analyses by Nordgard et al (25), George et al (26) and Sheng et al (4), there were biases in the digital entry of individual genotypes, which made their results less accurate. These data were cross-checked during the collection and analysis of the present meta-analysis. Sheng et al (4) reported that the MDR1 rs1045642 polymorphism may be associated with the risk of breast cancer in Caucasian but not in Asian populations; in contrast to the results of the present study, the authors reported that the genotype distribution of the Asian controls in their analysis was inconsistent with HWE. The present study performed a meta-analysis of 21 studies. The genotypic distribution of the remaining 19 controls was consistent with HWE, and the genotype distribution of the Asian control group was consistent with HWE. The data were reliable and the conclusion was more convincing.
When conducting subgroup analysis at the level of ethnicity, The study by Lu et al (27) showed that in Caucasians, the MDR1 rs1045642 polymorphism in the T allele contrast model and the TT genotype were associated with increased risk: (T vs. C, pooled OR=1.26; 95% CI: 1.04–1.52) and (TT vs. CC, OR=1.48; 95%CI: 1.04–2.11). The dominant model yielded statistically significant results (pooled OR=0.71; 95%CI: 0.52–0.96). The analysis of these models concluded that the MDR1 rs1045642 polymorphism increase breast cancer risk in additive and homozygous models, while decrease breast cancer risk in dominant models. Wang et al (21) reported that the MDR1 rs1045642 polymorphism increased the risk of breast cancer in the Caucasian population and was not associated with breast cancer in the Asian population. In the studies by Wang et al (22) and Sharif et al (1), the MDR1 rs1045642 polymorphism was associated with an increased risk of breast cancer in both the Asian and Caucasian populations. In the present meta-analysis that involved extraction and analysis of a large amount of validated data, 15 studies included were performed with Caucasian populations, 3 with Asian populations and 3 with mixed ethnicity populations. The HWE test results were consistent with HWE in 19 of 21 studies, with inconsistent HWE test results for two studies: The P-values for heterogeneity were reported to be P=0.013 and P=0.024 for Ozdemir et al (28) and Al-Eitan et al (16), respectively. A test result of P<0.05 indicated that the heterogeneity of the study was considered significant. In subgroup analyses, the MDR1 rs1045642 polymorphism was found to be notably associated with a higher risk of breast cancer in Asian populations in the recessive model (TT vs. CT + CC; OR=1.393; 95% CI, 1.143–1.698; P=0.001; I2<25%). The MDR1 C3435T polymorphism notably decreased the incidence of breast cancer in mixed populations (TT and CT + CC; OR=0.578; 95% CI, 0.390–0.856; P=0.006; I2<25%). In the analysis of the Caucasian population, among the four models, the homozygous model (TT vs. CC;OR=1.270; 95%CI: 0.929–1.737; P=0.134; I2>50%). In the additive model (T vs. C; OR=1.096; 95%CI: 0.933–1.287; P<0.265; I2>75%). In the recessive model (TT vs. TC + CC; OR=1.189; 95%CI: 0.953–1.484; P=0.125; I2>50%). In the heterozygous model (CT vs. CC; OR=0.997; 95%CI: 0.816–1.217; P=0.973; I2<75%). Our analysis shows that in the Caucasian population, the MDR1 rs1045642 polymorphism was not associated with breast cancer.
In conclusion, the present meta-analysis demonstrated that the MDR1 rs1045642 polymorphism was associated with breast cancer risk at the subgroup level; however, the results of the present meta-analysis were inconsistent with other studies. The MDR1 rs1045642 polymorphism in the recessive model was notably associated with an increased risk of breast cancer in Asian populations. In mixed populations, the MDR1 rs1045642 polymorphism was notably associated with a reduced risk of breast cancer. The MDR1 rs1045642 polymorphism was also notably associated with an increased tendency of breast cancer in Asian populations in both the homozygous and additive models. In mixed populations, the homozygous and additive models also showed that the MDR1 rs1045642 polymorphism was notably associated with a reduced breast cancer risk. In Caucasian populations, there was no notable association between the MDR1 rs1045642 polymorphism and breast cancer in all models.
In the present study, a screening of ethnicity and a subgroup analysis were performed. However, the limitations of the present study cannot be ignored. Firstly, the current meta-analysis requires a more comprehensive racial analysis. There were also multiple factors associated with the wide variation in the results of MDR1 rs1045642 polymorphism, including tissue used for the original analysis, sampling time and method, oestrogen receptor status, and sample size (3), that may have affected the accuracy of the association of MDR1 rs1045642 with breast cancer. To obtain precise results, studies of gene-environment and gene-gene interactions are essential (1), and interactions between different polymorphic sites of the same gene may regulate cancer risk (22). To obtain more complete and accurate results, studies with larger sample sizes, well-established ethnic groupings and more relevant functional studies are needed.