Abstract
Aims & Background:
Breast cancer is the most common cancer in women across the world. The toxic elements, arsenic (As), cadmium (Cd) and nickel (Ni), are generally associated with increased risk of many cancers and each of them has been designated as a group 1 human carcinogen. Several studies have been reported a relationship between toxic elements concentration in individuals with Breast Cancer and a critical role of these levels in the pathogenesis of Breast Cancer. The present study was conducted to estimate this probability by using meta-analysis method.
Method and martial: We searched several databases including PubMed, Scopus, Google scholar and Web of Science to identify case-control studies addressing relationship between toxic elements with Breast Cancer. A total of 15 reports published from different country from 1984- 2015 were included in this study. In this meta-analysis, data synthesis was performed using the random effects model. I² statistics were calculated to examine heterogeneity. To investigate the relationship between years of study and sample size meta-regression was used. The information was analyzed by R and STATA Ver 12.2.
Results: In this study due to non-uniform measurement methods of toxic elements, the concentration of this element was measured in various subgroups (1: plasma, 2: breast tissue 3: scalp hair and nail and 4: general) in both cases and controls. There was significance statistical difference between scalp hair and toenail Cd statuses between controls and breast cancer patient; whereas there was no significance statistical difference between plasma and breast tissues Cd concentration between case and controls; and the overall Integration of data from the three groups, there were significant difference between Cd status; mean difference: 2.45 [95% CI: 1.40-3.50; P=0.000]. There was significance statistical difference between all subgroups Ni statuses between controls and patient; and, the overall, there were significant difference between Ni status; mean difference: 2.33 [95% CI: 1.26-3.39; P=0.000]. There was no significance statistical difference between all subgroups As statuses between controls and breast cancer patient, and the overall, there were no significant difference between Ni status; mean difference: 0.52 [95% CI: -0.12-1.16; P=0.114].
Conclusion: In conclusion, this meta-analysis based random effect model supports a direct and positive association between cadmium and nickel concentration and breast cancer risk. Therefore, the cadmium and nickel concentration can be control in the sources of food, medicine, etc.
Keywords: Breast Cancer, toxic elements, arsenic (As), cadmium (Cd), nickel (Ni); plasma Concentration, breast tissue Concentration, Meta-analysis
background
Breast cancer remains a leading cause of morbidity and mortality in women worldwide. It incidence is on the rise and is still the most common malignancy among women; BC also contributes to a substantial proportion of the global cancer burden [1- 4].
Cancer incidence is usually related to risk factors which range from behavioral, genetic, occupational, nutritional and other. For breast cancer many risk factors were reported, namely gender, age, genetic risk factor, family history, personal history, abnormal breast biopsy, breast radiation and menstrual periods [5]. Although the incidence of breast cancer increases with age [6], certain lifestyle and environmental factors play an important role on breast cancer risk [7]. Such risk factors include the genetic background and environmental factors. For example, women who have inherited mutations in the BRCA1 or BRCA2 genes have substantially elevated risks of breast cancer [8]. Environmental factors also play a decisive role in breast carcinogenesis together with life-long dietary habits [7]. More evidence underlines that external factors are involved in the development of breast cancer: nutrition (obesity and alcohol consumption), smoking, and exposure to carcinogens (e.g., metal compounds) [7].Multiple studies underline the connection between the exposure to metals or metal compounds and breast cancer risk [9]. Among non-genetic factors, toxic metals are considered to be contributory causes for a variety of cancers [10–13].
The toxic elements, arsenic (As), cadmium (Cd) and nickel (Ni), are generally associated with increased risk of many cancers and each of them has been designated as a group 1 human carcinogen by the International Agency for Research on Cancer and the US National Toxicology Program [14]. It is reported that inorganic As has been found to induce chromosomal aberrations and sister chromatid exchange [15]. As induces carcinogenetic effects via a wide range of cellular changes including alterations in cell differentiation and proliferation[16]. Cells exposed to As have also been shown to increase cellular tyrosine phosphorylation, which is related to the aberrant cell signaling and uncontrolled cell growth associated with cancer development [17,18].
Exposure to cadmium (Cd) and other heavy metals is a well-known risk factor for cancer, and the effect of Cd on estrogen receptor levels and estrogen-induced responses in human breast can¬cer cells has been studied. Cadmium and other heavy metals inhibit enzyme function, DNA synthesis and repair [19]. Occupational and environmental pollution with Cd results mainly from mining, metallurgical industry (or when soldering with Ag–Cd solder), manufacture of Ni–Cd batteries, pigments, and plastic stabilizers. The toxic effects of Cd often stem from interference with various Zn mediated metabolic processes [14].
The Ni compounds can display tumor promoting capability via a number of mechanisms including inhibition of intercellular communication [20], immortalization of fibroblasts and epithelial cells [21], production of DNA-protein cross-links, oxidative damage, as well as inhibition of nucleotide excision repair [22] and an increase in DNA methylation leading to inactivation of gene expression [23].
Some studies show higher levels of toxic elements in cancer patients, while others report different levels of these elements or different levels of elements excretion in relationship with different types of tumor. So far no sure evidence has been reached in favour of any of the formulated hypothesis and in order to Authenticating studies performing a meta-analysis seems to be necessary.
Method and material:
Search strategies
A database was built for toxic elements in individuals with Breast Cancer from 1984- 2015 using PubMed,Web of Science, Google scholar Medline, Embase, the Cochrane Library and Scopus databases. The search was restricted to original articles published in English that present the a relationship between toxic elements concentration in individuals with Breast Cancer. The following keywords from Medical Subject Headings or titles or abstracts were used with the help of Boolean operators (and, or): Breast Cancer, toxic elements, arsenic (As), cadmium (Cd) , nickel (Ni), plasma concentration, breast tissue concentration, Scalp Hair concentration, toenail concentration and their combination. We also searched bibliographies of retrieved articles for additional references. The titles from the search results were examined closely and determined to be suitable for potential inclusion into the study. In addition, the references from selected articles were examined as a further search tool. Relevant trials noted in the reference lists of each selected article were also evaluated for inclusion. All papers which keywords were present in their titles or abstracts were used in the initial list and other unrelated articles were eliminated.
Inclusion and exclusion criteria
Eligible studies included epidemiologic manuscripts were analyzed As, Cd and Ni levels in Breast Cancer patients by measuring this element concentration in any of the following biological sample specimens: blood/ serum, breast tissue, Scalp Hair and nails. The selection of articles for review was completed based on 3 stages: titles, abstracts, and full texts. When necessary, authors were contacted for additional information. Studies were excluded if they presented insufficient data; if they were not epidemiologic studies; if they were not case-control studies. Review articles, congress abstracts, studies reported in languages other than English or Persian, meta-analyses or systematic reviews, and duplicate publication of the same study, were also excluded.
Data Extraction
For all studies, the following data were extracted: first author, year of publication, location, sample size, As, Cd and Ni concentration in patient and healthy individual, Mean difference, As, Cd and Ni screening method and sample specimens. (Figure 1-study flowchart). Abstracts and full articles were reviewed independently by two of the authors, and if results were discordant, papers were reviewed jointly until the differences were resolved.
Statistical analysis:
Studies were combined based on the sample size, mean and standard deviation. The difference between the average variance of the normal distribution was calculated using the formula of two integrated variance. To assess heterogeneity of the studies Cochran test and the I2 index was used. Due to significant heterogeneity in the studies, random effects model was used. To examine publication bias Begg Plot and regressions method were used. P-value less than 5% (P< 0.05) was considered as a significant heterogeneity test. Sensitivity analyses were pre-specified. Statistical analyses were performed using STATA version 12.
Results:
Our initial search strategy yielded 73 potential articles for inclusion. In a secondary screening, 27 of them were excluded based on title and abstract evaluation, and 46 were retained for detailed full-text evaluation. We excluded another 31 articles (8 review article, 12 lack of enough information, 11 Duplicate). After detailed analysis of selected articles, 15 case- control studies with 2,274 individual (1235 patient with breast cancer and 1039 healthy individual) fulfilled the inclusion criteria for the meta-analysis ( Figure 1). The standard unit for measuring Cd, Ni and As concentrations in some articles was microgram per liter [μg/L] and in some of them was microgram per gram [μg/g]. However, all studies were analyzed in terms of micrograms per liter .The characteristics of the 15 trials included in this meta-analysis are summarized in Table 1, including quality scores.
Cd, Ni and As concentrations were measured in three groups 1: plasma, 2: breast tissue and 3: scalp hair and toenail. In this study due to non-uniform measurement methods of toxic elements concentration, the levels of these elements in various subgroups in both cases and controls were measured.
In two studies, cadmium status was based on analysis of plasma and in two studies breast tissues was the sample specimen used, whereas in the remaining six, scalp hair was the sample specimen used. Also in one study, toenail cadmium status was used. There was significance statistical difference between scalp hair and toenail Cd statuses between controls and breast cancer patient; mean difference: 3.64 [95% CI: 2.08-5.21; P=0.00], whereas there was no significance statistical difference between plasma Cd concentration between cancerous patient and healthy controls; 1.29 [95% CI: -2.15 to 4.72; P=0.463]. Also, there was no significance statistical difference between breast tissues Cd concentration between cancerous patient and healthy controls; -0.00 [95% CI: -0.79 to 0.79; P=0.999], and by using a random effects model, the overall Integration of data from the three groups , there were significant difference between Cd status; mean difference: 2.45 [95% CI: 1.40-3.50; P=0.000]. Figure 2 show the results of meta-analysis for each study and for studies combination based on random effects model. These charts are given based on years of research and the author's name.
In one study, nickel status was based on analysis of plasma and in six studies breast tissues was the sample specimen used, whereas in the remaining five, scalp hair was the sample specimen used. There was significance statistical difference between all subgroups Ni statuses between controls and breast cancer patient; mean difference 1: plasma: 7.59 [95% CI: 5.37-9.81; P=0.00], 2: breast tissue 0.96 [95% CI: 0.54-1.38; P=0.00], 3: scalp hair and toenail 3.25 [95% CI: 0.67-5.83; P=0.014] and by using a random effects model, the overall Integration of data from the three groups , there were significant difference between Ni status; mean difference: 2.33 [95% CI: 1.26-3.39; P=0.000]. Figure 3 show the results of meta-analysis for each study and for studies combination based on random effects model.
In one study, arsenic status was based on analysis of plasma and in four studies, arsenic status was based on analysis of breast tissues, whereas in the remaining four, scalp hair was the sample specimen used. Also in two studies, toenail arsenic status was used.
There was no significance statistical difference between all subgroups As statuses between controls and breast cancer patient; mean difference 1: plasma: 0.38 [95% CI: -0.43-1.19; P=0.358], 2: breast tissue 0.03 [95% CI: -0.68-0.75; P=0.928], 3: scalp hair and toenail 0.87 [95% CI: -0.12-1.85; P=0.084] and by using a random effects model, the overall Integration of data from the three groups , there were no significant difference between As status; mean difference: 0.52 [95% CI: -0.12-1.16; P=0.114]. Figure 4 show the results of meta-analysis for each study and for studies combination based on random effects model.
Publication bias:
Publication bias was detected by drawing Beggs funnel plot in the meta-analysis. This diagram shows that there is a publication bias (cp=0.01); this means that it is possible that studies with the negative results have not been published (Figure 4).
there is no significant publication bias (p=0.00); this means, both of the tests (positive and negative results) have been published. (Figure 4)
Discussion
However with the increased usage in certain industrial processes such as smelting and electroplating, heavy metals have emerged as an environmental contaminant of growing concern. These heavy metals tend to accumulate in the body— a phenomenon called bioaccumulation [38]. Bioaccumulation of heavy metals in soft tissues interferes with normal physiological functions. Generally, these heavy metals exert their toxic effects by forming complexes with organic compounds. When heavy metals bind to nitrogen-, oxygen- or sulfur-containing groups on enzymes, for example, they disrupt proper protein folding and thus can inactivate enzymes that function in key metabolic processes [39]. Increased exposure to heavy metals is associated with impaired mitochondrial function, oxidative stress, DNA damage, deregulated cell growth and cell death [40].
In the present meta-analysis, the relationship between cadmium levels and breast cancer was examined. Combining the results from 11 epidemiologic studies (Fig. 2), indication that high levels of Cd were positively associated with risk of subsequent breast cancer (P=0.000). Recent clinical studies revealed that high concentrations of Cd were found in breast cancer patients [41], which was significantly higher than in normal controls [42]. In some of studied, a marginally significant association is also observed between cadmium levels and breast cancer risk [14,19,26,28,43]. A population based case-control sample of women living in Long Island also found a similar association [44]. Similar to these studies, the Long Island study estimated that approximately 35 % of breast cancer in the U.S. may be attributed to cadmium exposure. Since the case–control studies were conducted in breast cancer patients, the studies do not clearly establish whether cadmium is associated with the risk of developing breast cancer or is a consequence of the disease. A recent population based prospective cohort study shows that long term dietary intake of cadmium is associated with an increased risk of breast cancer in postmenopausal women [45] suggesting a causal effect of cadmium in the development of the disease. Although these studies suggest a correlation between Cd exposure and incidence of breast cancer, they fail to determine whether Cd is a major source for the etiology of breast cancer.
In the present study, the relationship between nickel levels and breast cancer was examined. Combining the results from 12 epidemiologic studies (Fig. 3), indication that high levels of Ni were positively associated with risk of subsequent breast cancer (P=0.000). Metals, such as nickel are essential metals required in trace amounts. Essential metals play an important role in metabolism and respiration, in membrane integrity and permeability, and in cell proliferation and death [46-47] where alterations in their concentration may result in disease or toxicity [47-49]. For example, essential metals at low concentrations function as components of enzymes but at high concentrations can inhibit enzyme activity [48].
Certain cadmium, nickel, and even arsenic compounds have been deemed carcinogenic by the IARC since the late 1970’s and 1980’s [41, 50, 51]. Our results demonstrated, high levels of Cd and Ni were positively associated with risk of breast cancer. This result is similar to a review conducted by Aquino et al, in this study relationship between Cd, Ni and As and cancer was examined. They found that most studies analyzed the effects of acute heavy metal exposure on breast cancer development and progression [52]. Aquino et al [52] concluded that chronic exposure to cadmium and nickel at concentrations well below WHO limits is still dangerous due to bioaccumulation and the peculiarly high affinity for specific proteins like the estrogen receptors. Recent studies have suggested that cadmium and nickel can function as endocrine disruptors by mimicking the action of estrogens. As a result, these metals are often referred to as metalloestrogens [53–55]. Byrne et al [56] in a review study demonstrated that, metalloestrogens such as cadmium and nickel include metal/metalloid anions and bivalent cations. Because metalloestrogens activate the estrogen receptor in the absence of estradiol, exposure to these metals may increase the risk of developing breast cancer.On the other hand, since estrogen itself plays an important role in the development and progression of the disease, the ability of metalloestrogens to bind to and activate the estrogen receptors suggests that these compounds may also contribute to the development of breast cancer [55, 57]. In support of this hypothesis, environmental exposure to many of the metalloestrogens is widespread and has increased significantly over the last 50 to 60 years. Many of the metalloestrogens also have a long biological half life (e.g., cadmium has a half life of 10 to 30 years) and accumulate in the body and in the breast [56]. There is also credible experimental evidence that cadmium activates ERα in vitro and in vivo as well as increasing epidemiological evidence linking cadmium to breast cancer [56]. It is hypothesized that metal-induced estrogen receptor activation is a crucial step in the carcinogenic process [58]. In addition, Cd has been shown to induce various pro-survival and cell cycle regulatory genes. These results suggesting that even low dose and acute exposure to Cd can bring about DNA damage in normal breast cancer cells [53]. Although there is evidence linking exposure to the metal with breast cancer, the role of cadmium, nickel and other metalloestrogens as causative agents in the etiology of the disease remains to be established.
In the present meta-analysis, the relationship between arsenic levels and breast cancer was examined. Combining the results from 11 epidemiologic studies (Fig. 4), indication that there were no associated between levels of As with risk of breast cancer (P=0.114).Some of studied indicated that the levels of As, were higher in samples of cancerous patients with related to healthy referents [14,28,30], whereas there were no significance statistical difference between As statuses between controls and breast cancer patient in most of included study in this meta- analysis [19,26,29,32,34,36,37]. Even sketchier is the evidence linking arsenic to breast cancer. Although an Australian case study conducted by Hinwood et al. reported that 40% of the cancers caused by arsenic-contaminated drinking water were breast cancers [59, 60], in vivo and in vitro studies indicate that arsenic disrupts estrogen receptor (ER) function and actually suppresses estrogen signaling pathway [61,62], findings that, in a review of Aquino et al, effectively argue against arsenic as a potential metalloestrogen [52]. The As induced cancer is the subject of much conjecture, various modes of action have been proposed for As carcinogenicity including its ability to alter DNA methylation patterns, act as a cocarcinogen, induce cell death and proliferation, inhibit DNA repair, and induce genetic damage [63]. The association between As exposure and different types of the cancer has been reported [64]. There are numerous epidemiological studies in humans that have demonstrated the carcinogenic effects of As from drinking water and incidence of different cancers [14]. Nonetheless, A large body of evidence indicates that arsenic compounds induce cell death in breast cancer cells and the induction of this effect is a possible endorsement for the treatment of breast cancer. For example, sodium arsenite mimics the effects of estradiol and induces cell proliferation in the estrogen-responsive breast cancer cell line MCF-7 while the S-phase recruitment was increased [65]. Interestingly, regarding the cell proliferation, a paradox effect was observed: lower concentrations (<5 μM) of sodium arsenite induced cell proliferation while higher concentrations (>5 μM) or longer treatment periods induced apoptosis [66].In addition, As also influences the enzymes participating in the folate cycle [66]. Liu et al. [67] and Wang et al. [68] showed that after 24 h exposure to As2O3 (0.01–1 μM) cell proliferation significantly increased and a progression from the G1 to S/G2 phases occurred in the nontumorigenic MCF10A breast epithelial cell line. Some effects are possibly due to a reduced plasma clearance, an enhanced tumor uptake, and an induction of tumor cell apoptosis [69].
Exposure of humans to these metals occurs primarily through dietary sources of food and water, air, cigarette smoke, and occupational exposure and can lead to significant accumulation in the body [56].
Limitations
The limitations and weaknesses of the current study were largely related to the methodology of the reviewed studies. One of the limitation in our study is no age group was analyzed, a recently published study by Julin et al. indicated a correlation between dietary cadmium exposure and breast cancer risk in postmenopausal women [45]. Thus, until more comprehensive analyses are carried out, it is not clear that exposure to cadmium or nickel during certain critical developmental periods increases breast cancer risk. Others of weaknesses are as follows:
1. Lack of a uniform method of measurement for the variances.
2. Selection of women referring to the health centers compared to a random selection.
3. Lack of information about nutrition and lifestyle of the participants.
4. Various kinds of screening methods and lack of a uniform standard unit for measuring zinc concentrations in different articles.
5. One significant limitation was the lack of access to some relevant studies.
Conclusion
There is sufficient evidence to warrant great concern over the increasing emission of heavy metals like cadmium and nickel into the environment. Acute exposures aside, the data suggest that even minimal levels of cadmium and nickel are potentially hazardous and could negatively impact the health of thousands of people. In conclusion, this meta-analysis based random effect model supports a direct and positive association between cadmium and nickel concentration and breast cancer risk. Overall, environmental contaminants of these metals have emerged as possible high risk factors for cancer due to their increased usage in various industrial processes and widespread proliferation in food sources. Therefore, the cadmium and nickel concentration can be control in the sources of food, medicine, etc. In summary, the results of this study can be used in clinical trials and randomized clinical trials for the prevention of breast cancer through by controlling the levels of cadmium and nickel in diet. At the end, smoking, obesity, alcohol, inactivity, and stress are other relevant risk factors for breast cancer.
Funding:
There is no benefits in any form have been or will be received from a commercial party related
directly or indirectly to the subject of this article.
Acknowledgement
We would like to acknowledge the Students Researches Committee of the Ilam University of Medical Sciences for financially supports of this project.