Introduction

Cancer is a heterogeneous disease that affects individuals worldwide. The International Agency for Research on Cancer (IARC) expected, for 2018, 18.1 million new cases and 9.6 million deaths by neoplasia. Female breast cancer is in the second place in the ranking of causes of death by cancer, with 11.6% of all deaths in the world, followed by prostate tumors (7.1% of cases) [1]. According to the National Cancer Institute (INCA), in Brazil, there were be about 60 thousand new cases of breast cancer for the biennium 2018–2019. Regardless of non-melanoma skin tumors, the breast cancer is the most incident in the Brazilian Southern, resulting in an estimated risk of 73.07 cases per 100,000 women [2].

Similar to other types of malignant tumors, the development of breast carcinoma is complex, environmental variables such as lifestyle and intrinsic characteristics of the patient also influence the development and evolution of this malignant disease, such as age [3, 4], hormone factors [5], menopause [6], smoking [7], exposure to ionizing radiation [8], and overweight [9]. Hence, it is important to understand these elements to determine the diagnosis and prognosis of patients.

Most cancers are associated with external risk factors. Therefore, a wide of substances are constantly interacting with the body by several routes, and they need to be eliminated securely to avoid any kind of injury to its DNA. Likewise, there is a complex system formed by phase I detoxification enzymes, components of the P450 cytochrome system [10], and by phase II detoxification enzymes, that includes the glutathione S-transferases (GSTs) [11] and the N-acetyltransferases (NATs) [12]. All this system is responsible for metabolizing environmental and xenobiotic factors that can be potentially associated with the increased carcinogenesis [11].

The GSTs represent a superfamily of cytosolic, mitochondrial and microsomal enzymes, which are involved in the metabolism of xenobiotic compounds and their reactive products, preventing the oxidative stress [11, 13]. This superfamily is divided into Alpha, Mu, Omega, Pi, Sigma, Theta and Zeta classes, according to its structural, chemical and physical characteristics. Their N-terminal residue interacts with the thiol group of the glutathione peptide in its reduced form (γ-l-glutamyl- l-cysteine-glycine, GSH), providing the conjugation of compounds to be excreted, including carcinogens, drugs and metabolism products [14, 15].

Genetic polymorphisms can lead to variations in the activity of the enzymes, resulting in combinations ranging from partial to complete deletions, which can result even in a null phenotype [16, 17]. The glutathione transferase mu 1 (GSTM1) and glutathione transferase theta 1 (GSTT1) genes belong to the mu and theta classes, respectively. They present null polymorphic variants by complete deletion also called null genotypes that result in a complete absence of the enzyme function in both cases, GSTM1- null and GSTT1- null genotypes [18].

As already stated by researchers these polymorphisms are associated with the development of several diseases, such as uterine leiomyoma [19], hypertension [20], psoriasis [21], prostate carcinoma [22] and chronic myeloid leukemia [23], among others. Studies also showed that genetic polymorphisms of this system may act as predictors of susceptibility to some types of cancer, such as lung [24], colorectal [25], breast [26] and cervical [27]. However, few studies have discussed the clinical meaning of such variants, as well its correlation with the parameters that are determinant of poor prognosis. Thus, results in the correlation with breast cancer have been controversial because some of them found a significant association and others showed a risk association. Therefore, this study aimed to systematically review and evaluate studies regarding the occurrence of polymorphisms in the GST system in patients with breast cancer. The current study also aimed to investigate if there are correlation between the presence/absence of the genetic variants and the susceptibility, as well as between determinants of pathology’s prognosis (Fig. 1).

Fig. 1
figure 1

Identification process of eligible studies. VHL: Virtual health library

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Materials and methods

Review protocol

The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol, adapted from Moher et al. [28].

Literature search

PubMed and the regional portal of the Virtual Health Library (VHL) were used to perform the searches (the last search was conducted on April 15th, 2020). The descriptors applied were "glutathione transferase" and "breast cancer" and "genetic polymorphism". Then, some filters were selected: Portuguese and English language, type of document (article), published between 2013 and 2020. Additionally, complete readings of literature reviews and systematic reviews with similar subjects were performed. The studies were pre-selected by reading their titles and abstracts and separated for further analysis and extraction of data.

Inclusion and exclusion criteria

Inclusion criteria:

  1. 1.

    Case–control studies and case studies;

  2. 2.

    The aim of the studies: study the influence of GSTT1 and/or GSTM1 polymorphisms on breast cancer;

  3. 3.

    Studies with complete data and statistical results.

Exclusion criteria:

  1. 1.

    Review studies, meta-analyses, case reports, comments or clinical tests;

  2. 2.

    Other types of cancer or hematological malignancies;

  3. 3.

    Studies containing incomplete data or duplicate data.

Biases

The possible biases of the eligible studies were analyzed according to the limitations of each study, such as sample size, statistics of the results and the parameters involved.

Results

Eligible studies

The VHL database search resulted 769 articles. After the filters’ refining 139 articles were found, and after the analysis of the titles and abstracts, 26 articles were selected. In PubMed database, 244 articles were found and, after selecting the filters, 67 articles remained, of which 35 were selected for a full reading. Other articles from literature review readings were not included, because these articles did not attend the inclusion criteria or were already included. Thus, 21 articles were included in this review.

Characteristics of the studies

From the studies included in the systematic analysis, 13 are case–control studies [25, 29,30,31,32,33,34,35,36,37,38,39,40], and 8 are cohort studies [41,42,43,44,45,46,47,48]. Most studies (28.6%) are from China, followed by Mexico (19.0%). The sample size ranged from 49 to 1109 (6747 cases). Table 1 summarizes the main results found by the included studies for GSTT1 and GSTM1 polymorphisms, and their correlation with the development of breast cancer and/or response to treatment.

Table 1 Summary of the main results found by the studies analyzed concerning the GSTT1 and GSTM1 polymorphisms and their correlation with clinicopathological parameters that determine the prognosis of the disease
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Discussion

We performed a review to evaluate the association between GSTM1 and GSTT1 polymorphisms (combined or not) on breast cancer risk and response to treatment, including 6747 breast cancer patients.

Polymorphic variants of GSTs influence the effectiveness of detoxification of the cytotoxins from drugs or carcinogens, and it can increase the susceptibility to cancer development. Several studies discussed the influence of GSTT1 and GSTM1 deletion polymorphisms in some malignancies such as acute myeloid leukemia [49], lung cancer [50] and hepatocellular carcinoma [51]. However, the role of these polymorphisms is not clear towards the susceptibility to breast cancer development, as well as their correlation with the factors that determine the prognosis of this disease.

The simultaneous deletion of GSTM1 and GSTT1 has been associated with a higher risk of developing breast cancer, which increases when it is correlated with exposure to environmental factors such as pesticides, as demonstrated by Sohail et al. (2013) in a case–control study conducted in 200 Pakistani women. Besides, the authors reported an association between these GST variants and a higher risk of developing breast cancer in women who smoke or have a positive family history for the disease [32]. Another article published by the group of Garcia-Martinez and collaborators (2017) observed an association of susceptibility to the development of breast cancer in Mexican women with a deletion in GSTM1, in a case–control study with 1882 women [36]. In other studies, significant results were obtained concerning the deletion of GSTM1, suggesting that it would be associated with a higher risk of developing breast cancer [30, 31, 39, 47]. In a study performed in the population of Cyprus, it was concluded that the null variant for GSTT1 was positively associated with the development of breast cancer, in relation to the wild variant, according to a study of 2286 women [25].

Breast tumor can be divided into grades I, II and III, according to the differentiation of the carcinoma cells into well differentiated, moderately differentiated and less differentiated, respectively. This parameter is considered a significant prognostic factor, considering that the less differentiated the tumor cells are, less similar to the normal breast cells [52, 53]. Brazilian researchers showed that the deletion of GSTT1 was positively associated with increased risk of disease recurrence, as well as deleted GSTM1 was correlated with a worse prognosis of patients because a higher percentage of patients with histopathologic grade III tumors was observed in the presence of this polymorphism [41].

GSTM1 active genotype can influence breast cancer progression, preventing the evolution of the disease in non-chemotherapy patients, observed a Chinese cohort study with 714 participants [48]. On the other hand, individuals carrying the null genotype for GSTT1 and/or GSTM1 may have a better response to treatment with chemotherapy. According to an Indian cohort study, when null GSTM1 genotype was evaluated combined with the Ile/Val GSTP1 genotype (another GST family polymorphism), an association was found with the presence of a response to neoadjuvant chemotherapy [44]. It was also found an association of the null genotype of GSTM1 as a protective factor in relation to the response to chemotherapy in patients with breast cancer who had high plasma levels of glucose [29]. A similar association was described in a study conducted in 262 women in the Chinese population, and showed a better response to chemotherapy among patients with null GSTM1 genotype [42]. In contrast, Wang and Huang (2015) demonstrated that the null GSTM1 genotype was more associated with a worse response to chemotherapy and lower survival [46].

Some limitations were identified by the authors in the analyzed studies. Tulsyan et al. (2013) highlighted the fact that they did not analyze variants in the genes that regulate the detoxification phase I, as well as the sample size used [44]. Another study performed by Yuan et al. (2015) stated that the disagreements found in the literature about polymorphisms of the GSTs family may be attributed to the different ethnic groups analyzed, as to the sample universe used [41]. We agree that there should be one more exclusion criteria concerning ethnicity, but few studies would be included in the review if we limited our search based on this. It has been indicated that neither phenotypic characteristics nor self-declaration replaces genetic ancestry, therefore we cannot use ethnicity as a parameter. Also, there is the possibility of biases in some correlations, such as in the assessment of exposure to environmental factors such as pesticides, that the bias can occur because exposure is verbally reported by patients, without the application of a structured quantitative instrument [39].

Conclusions

It is clear that most studies reveal a risk association between the deletion of GSTM1 and/or GSTT1 and the development and/or prognosis of breast cancer. In addition, it should be noted that these results of risk association were found in large part in the populations of the Americas and Europe, followed by Asians. Regarding the response to treatment, protective associations were found in the presence of GSTM1 deletion. However, due to the inconclusive results of many studies, further analysis in this area is required.