Associations between dietary intake of zinc and selenium and breast cancer: findings from a NHANES cross-sectional study

Introduction

The International Agency for Research on Cancer (IARC) has recently published the most up-to-date information on the global burden of cancer in 2020. Notably, breast cancer has now surpassed lung cancer (2.2 million cases) as the leading type of cancer worldwide, constituting 11.7% of all newly diagnosed cancer patients (1). Clinically, although surgery, chemoradiotherapy and targeted therapy have improved treatment outcomes, the prognosis of breast cancer remains poor (2). Notably, 30–60% of malignancies are closely linked to dietary variables. Diet and lifestyle factors are important predictors of cancer risk in developed countries (3,4). To date, the correlation between mineral or nutrient intake and the occurrence of various malignant tumors, such as colorectal (5), prostate (6), and lung cancer (7), has been comprehensively investigated.

Minerals such as zinc, selenium, and carotenoids have varying effects on the progression of malignancy. Currently, there is a renewed focus on investigating the connection between dietary variables and the risk of malignancy (8-10). Nevertheless, the available evidence regarding the association between dietary intake and malignancies remains limited and equivocal. For example, Wu et al. (11) reported significant differences in serum concentrations of Se, Zn, Cd, Ni, Mn, Fe, Cr, Mg, Al and Cu, as well as Cu/Zn, Cu/Fe, Cu/Se, Cu/Cd and Cu/Cr in patients with breast cancer and normal controls. However, in a case-control study by Piccinini et al. (12), measurements of Se, Zn, and Cu were taken in the plasma and hair of patients diagnosed with breast and lung cancers. The findings revealed a notable decrease in Se levels in hair, a marginal reduction in Se levels in plasma, and no discernible variance in Zn and Cu levels. Furthermore, previous studies have only examined individual dietary factors, disregarding the intricate and varied nature of dietary variables. Consequently, the findings regarding the correlation between dietary intake and malignancies have been limited in perspective. Generally, adjustments to one dietary profile result in corresponding modifications to other dietary profiles. Instead, focusing on food groups or dietary patterns avoids the covariation of dietary variables and avoids finding chance associations due to the analysis of multiple nutrients as exposures (13). Therefore, by considering multiple dietary factors, it is possible to gain a comprehensive understanding of the association between minerals and the disease process.

Furthermore, it is uncertain whether significant deficiencies in zinc, selenium, or carotenoids are associated with breast cancer (14-17), and it is also unknown whether these minerals influence breast cancer through other mediators, which needs clarification using data from large-scale population-based surveys. The National Health and Nutrition Examination Survey (NHANES) was designed as a continuous survey with the goal of monitoring the health and nutritional status of noninstitutionalized U.S. citizens. To our knowledge, this research is the first to thoroughly examine the associations between minerals intake and breast cancer using NHANES data. Briefly, the objective of this research was to investigate the associations between minerals intake and breast cancer in a representative cohort of Americans. We present this article in accordance with the STROBE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-83/rc).

Methods

Study population

The data for this research was obtained from the NHANES (https://www.cdc.gov/nchs/nhanes/) public data files spanning 1999 to 2020. The exclusion criteria for our research were as follows: (I) individuals under the age of 20; (II) individuals with missing data on breast cancer, zinc, selenium, or carotenoids; (III) individuals lacking data on variables such as poverty income ratio (PIR) and body mass index (BMI). Out of 59,149 participants in NHANES between 1999 and 2020, 25,244 participants were eligible for analysis (Figure 1). The data represent the U.S. civilian population and are nationally representative. All the participants in the NHANES dataset provided informed consent, and the data collection protocol was approved by the NCHS Ethics Review Board. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Figure 1 The entire process of this study is illustrated. GGT, gamma glutamyl transferase.

Exposure assessment

Zinc, selenium, and carotenoids were the primary exposure factors in this study (17). The interviewers collected data on the intake of three nutrients by conducting two consecutive 24-hour dietary surveys. This was done to assess the overall dietary intake using the combined reference in NHANES. Participants were interviewed at home and then underwent various clinical and laboratory tests at a mobile examination center (MEC). The first interview was conducted in person at the MEC and the second interview was completed over the phone 3 to 10 days later. Dietary intake was determined using the average of two dietary recalls (if available), or a single dietary recall. We selected these three nutrients from the NHANES dietary questionnaire because of their potential association with breast cancer: zinc (mg), selenium (µg), and carotenoids (µg).

Breast cancer data

The primary outcome of this study was breast cancer. In the “Medical Conditions” section of the NHANES questionnaires, we gathered information on the health conditions and medical histories of individuals, including the diagnosis of breast cancer (18). Participants were asked the following questions: “Have you ever been told by a doctor or other health professional that you had cancer or a malignancy of any kind?” And then followed by, “What type of cancer was it?” Age at diagnosis was also collected with the question: “How old were you when breast cancer was first diagnosed?” The data mentioned above were only reported for women who have been diagnosed with breast cancer.

Mediation analysis

Mediation analysis was employed to explore and quantify the extent to which the associations between zinc and selenium levels and breast cancer are influenced by potential mediators. Specifically, we utilized bootstrap-mediated effects modeling (19), a robust statistical method that relies on repeated resampling of the dataset to estimate the direct and indirect effects, along with their confidence intervals (CIs). Bootstrapping does not require distributional assumptions, which helps to avoid issues associated with the coefficient product test violating these assumptions. Moreover, since this method does not depend on standard errors, it circumvents inconsistencies arising from different standard error formulas. Simulation studies have demonstrated that, compared to other mediation testing methods, bootstrapping offers higher statistical power. Thus, bootstrapping is currently considered one of the most reliable methods for testing mediation effects. We quantified the extent to which the associations between zinc and selenium and breast cancer were influenced by mediators using the calculus of variations. The potential mediator of zinc in this study was total bilirubin (20-22). Additionally, uric acid (23-25), GGT (26,27), and total bilirubin (20) were identified as possible mediators for selenium.

Covariate assessment

Participants’ demographic characteristics, socioeconomic characteristics, health factors, and comorbidities were selected as covariates for statistical analysis (28-30). Age and race were all included as demographic factors. Socioeconomic and health factors included the family PIR, educational level, marital status and BMI. Specifically, PIR was calculated by dividing family income by the poverty guidelines for a specific survey year as a proxy for socioeconomic status. Additionally, data on characteristics related to medical comorbidities such as diabetes and cardiovascular disease (CVD) were gathered. Interpolation was used to handle the missing data.

Statistical analysis

The t-test or rank-sum test was used to analyze quantitative data, while the χ² test was used to examine variations in cohort characteristics across groups defined by categorical variables. Multifactor logistic regression was used to determine associations between exposure factors and breast cancer in preliminary analyses. Three models were developed to assess associations between dietary intake of zinc and selenium and breast cancer by using logistic regression model or linear regression. The three models are as follows: Model 1: adjusted for age and race; Model 2: adjusted as in model 1 plus PIR, BMI, education level, marital status; Model 3: adjusted as in model 2 plus diabetes and CVD. Mediation analysis was used to ascertain the possible mediating influence of the intermediary variable on the relationship between the exposure factor and the outcome variable (31). To examine the interaction between age, diabetes, CVD, and zinc and selenium intake on breast cancer. If the P value for interaction was less than 0.05, it was considered a significant interaction; if the P for interaction more than 0.05, it means that the difference in the effect between the different subgroups may be due to random error, and there is no significant interaction. Finally, all data analyses were conducted using R.3.5.2 (http://www.R-project.org). Sample sizes were determined using available data, and no ex-ante sample size calculations were conducted. The P value of less than 0.05 was considered statistically significant.

Results

Basic characteristics of study population

The analysis included a total of 25,244 NHANES participants, of whom 410 (1.62%) had diagnosed breast cancer at the time of data collection (Table 1). The mean age was 46.1 years overall, and 66 years in the breast cancer group, indicating that breast cancer cases were significantly older than those without breast cancer (P<0.001). The majority of participants were overweight or obese, with only 28.14% having a BMI under 25 kg/m², and no difference between breast cancer status groups (P=0.91).

Regarding race, 47.05% of the total sample and 68.05% of breast cancer cases were non-Hispanic White individuals. Specifically, breast cancer was significantly lower in non-Hispanic Black individuals (13.90% vs. 19.40% overall), Mexican Americans (8.78% vs. 18.29% overall) and other racial groups (9.27% vs. 15.52% overall) (all P<0.001). Moreover, there was no difference in socioeconomic status as assessed by the poverty-income ratio between the breast cancer groups (P=0.60). However, variations in marital status were observed: breast cancer participants had lower rates of being married/cohabiting (54.15% vs. 61.86% overall) and higher rates of being widowed/divorced/separated (42.20% vs. 20.76% overall) (P<0.001). At the same time, there was no difference in education level distribution between breast cancer status groups (P=0.85).

In terms of comorbidities, the breast cancer group exhibited a notably higher prevalence of diabetes (2.60% vs. 97.40%, P<0.001) and CVD (3.07% vs. 96.93%, P<0.001). Additionally, average zinc levels were found to be lower in participants with breast cancer compared to those without (10.2 vs. 12.0 mg, P=0.001). Similarly, mean selenium intake was significantly lower in the breast cancer group compared to the non-breast cancer group (95.7 vs. 114.4 µg, P<0.001). Nonetheless, no significant difference in mean carotenoid levels emerged (P=0.33).

In summary, the study suggests breast cancer participants were older, had lower zinc and selenium levels, higher rates of comorbid diabetes and CVD, and differed in marital status compared to the rest of the study population. Furthermore, racial differences in breast cancer prevalence were also apparent. These descriptive findings highlight important variables to consider as potential confounders or effect modifiers in subsequent analytic models.

Associations of zinc and selenium with breast cancer

To determine the associations between zinc and selenium and breast cancer. The initial logistic regression model, which included only basic demographic factors, revealed a negative association between both zinc and selenium and breast cancer (Table 2, Model 1). As expected, for every unit increase in zinc, the fully adjusted odds ratio (OR) was 0.05 (95% CI: 0.00–0.30, P=0.01). When examined by quartile, compared to the lowest zinc quartile (Q1), the ORs were 0.58 (95% CI: 0.41–0.83, P=0.003) for Q3 and 0.32 (95% CI: 0.19–0.54, P<0.001) for the highest quartile (Q4). These results indicate a dose-response association, with a negative association between both zinc and breast cancer.

Similarly, for each unit increase in selenium, the OR for breast cancer was 0.40 (95% CI: 0.29–0.55, P<0.001). Taking Q1 as a reference, the OR was 0.49 (95% CI: 0.33–0.74, P<0.001) for Q3 and 0.34 (95% CI: 0.22–0.51, P<0.001) for Q4. Again, this indicates a significant inverse dose-response association between selenium and breast cancer.

Meanwhile, expanding the models to include other PIR, BMI, education level and marital status (Table 2, Model 2) led to slight attenuation of the zinc and selenium association effect sizes, but statistical significance at P<0.05 was retained. In the fully adjusted model, the ORs per 1 unit increase were 0.07 (95% CI: 0.00–5.62, P=0.23) for zinc and 0.70 (95% CI: 0.51–0.97, P=0.03) for selenium. Comparing extreme quartiles, ORs were 0.50 (95% CI: 0.28–0.88, P=0.02) for Q4 versus Q1 for zinc and 0.69 (95% CI: 0.43–1.09, P=0.11) for Q4 versus Q1 selenium.

Additional control for diabetes and CVD comorbidities (Table 2, Model 3) further attenuated the associations. Consistently, the statistical significance (P<0.05) was remained for each unit increase in selenium (OR, 0.66; 95% CI: 0.47–0.93; P=0.02) as well as for Q4 versus Q1 for zinc (OR, 0.48; 95% CI: 0.27–0.86; P=0.01). In addition, these models demonstrate independent, dose-dependent negative associations between zinc, selenium status and breast cancer after careful adjustment for potential demographic, socioeconomic, and health-related confounders.

Moreover, the stratified analyses provided more detailed insight into specific subgroup trends (Table 3). For both zinc and selenium models, stronger protective associations were observed among women without baseline diabetes or CVD. These results suggest that the benefits of higher zinc and selenium levels were less apparent in the context of significant comorbidity burden. Alternatively, these interactions may have reflected existing perturbations in micronutrient homeostasis arising from diabetes, CVD or their treatment. Additionally, a significant age-effect modification was observed for zinc (P_interaction=0.07)—associations were stronger in women aged over 40 compared to younger women. No significant age-related interactions for selenium were observed. It is possible that these age-specific differences may be related to variations in menopause status, hormonal factors, or duration of micronutrient imbalance between younger and older women.

In summary, strong evidence from logistic regression analyses confirmed that insufficient zinc and selenium levels were independently inversely associated with breast cancer within this nationally-representative survey population. Moreover, the associations persisted after careful adjustment for confounders and appear stronger among women without baseline chronic diseases. Furthermore, the dose-response patterns were also evident, with lower odds of breast cancer seen with increasing zinc and selenium intake.

Mediation analysis of zinc and selenium with breast cancer

In order to examine the potential mediating role of bilirubin levels, our study conducted in a comprehensive mediation analysis to investigate the association between zinc and breast cancer. After adjusting for covariates such as age, race, and BMI, the mediation analysis of zinc, total bilirubin, and breast cancer was shown in Figure 2A. In the treatment group (high-zinc), zinc had a protective effect on breast cancer, with a total effect of −0.0013 (95% CI: −0.0042 to 0.0033, P<0.001), of which the average direct effect (ADE) was 0.0017 (95% CI: −0.0027 to 0.0054, P<0.001). The average causal mediation effect (ACME) of zinc in reducing breast cancer via bilirubin was −0.0029 (95% CI: −0.0032 to −0.0026, P<0.001). In conclusion, all of these results indicated that bilirubin may have played a role in mediating the previously established protective link between zinc levels and breast cancer. Particularly, the total effect represents the overall association without distinguishing between indirect and direct relationships.

Figure 2 Mediation analysis zinc/selenium and prevalence of breast cancer. (A) Mediation analysis of total bilirubin on the interaction between zinc and prevalence of breast cancer. (B-D) represent the mediation analysis of total bilirubin, uric acid, and GGT, respectively, on the interaction between selenium and the prevalence of breast cancer. Total effect = ACME + ADE. ACME, average causal mediation effect; ADE, average direct effect; GGT, gamma glutamyl transferase.

Additionally, several mediation models were constructed to evaluate if various biomarkers mediate the inverse association between selenium and breast cancer. Firstly, analysis with bilirubin as the mediator found significant ACMEs among both selenium-rich and deficient groups, indicating mediation effects. Specifically, in the low selenium group, ACME was −0.00145 (95% CI: −0.00207 to 0.00, P<0.001) mediating 12.99% of the total effect, while in the high selenium group, ACME was −0.00099 (95% CI: −0.00145 to 0.00, P<0.001) mediating 8.92% of the total effect. The average mediated effect was −0.00122 (95% CI: −0.00176 to 0.00, P<0.001) across all participants, explaining 10.95% of the overall association between selenium and breast cancer odds. Significant ADEs persisted in both low and high selenium groups after partitioning the total effect, confirming that direct protective associations also exist (Figure 2B).

Thereafter, uric acid was also tested as a potential mediator. Similar to the bilirubin analysis, significant ACME values were obtained (−0.00125 for the low selenium group and −0.000853 for the high selenium group), with a greater proportion of mediation (11.90% and 7.87% respectively). The direct effects remained statistically significant (Figure 2C). Finally, when GGT was modeled as a mediator, results were consistent with uric acid. Significant ACMEs were found in both low (−0.00125) and high (−0.000853) selenium groups explaining 11.90% and 7.87% of the total effects respectively. Meanwhile, the ADEs remained significant, consistent with a partial mediation model (Figure 2D).

In summary, mediation analysis provides new insight into indirect biological pathways that may help explain the inverse zinc and selenium-breast cancer associations revealed previously. Approximately 10% of this relationship appears to be mediated through circulating bilirubin, uric acid and GGT levels. These biomarkers have known antioxidant, anti-inflammatory and anti-carcinogenic properties which may be upregulated in states of higher selenium status. However, the significant direct effects persisting after mediation analysis also support potential alternate pathways related to DNA repair processes, immune surveillance, epigenetic modulation and inhibition of tumor proliferation and vascularization through which selenium could protect against breast cancer development. Further research into these specific mechanisms is warranted alongside validation in longitudinal datasets.

Discussion

Worldwide, breast cancer is the primary cause of cancer-related fatalities in women, and numerous factors increase the likelihood of developing breast cancer (1). Currently, lifestyle modifications are being used to enhance the prevention of breast cancer and enhance the prognosis (3). Nevertheless, the associations between minerals and tumors have not been thoroughly investigated, and the association between diet and breast cancer remains uncertain. Our study showed that breast cancer patients were significantly older than non-breast cancer patients and that the prevalence of breast cancer was related to race.

In addition, married/cohabiting individuals have a lower risk of breast cancer relative to widowed/divorced/separated individuals. In terms of comorbidities, the prevalence of diabetes and CVD was significantly higher in the breast cancer group. Furthermore, we performed stratified analyses for age, diabetes, and CVD to assess whether there was an interaction between these variables and found that age had a significant effect on zinc, which we speculate may be related to menopausal status, hormonal factors, or the duration of micronutrient imbalances in the body. Also of note, increased zinc and selenium were found to be associated with reduced breast cancer, and bilirubin, uric acid, and GGT were identified as mediators of the selenium-breast cancer link.

The significance of zinc and selenium has been extensively shown before. Generous studies have shown that zinc and selenium are involved in cell cycle activities, zinc is involved in the process of cell division, while selenium is also associated with cell growth and apoptosis (32-34). This also explains that disruption of the cell cycle is a major feature of cancer development and that the role of zinc and selenium in cell cycle regulation is closely linked to growth and reproduction of tumors. Moreover, low zinc levels may increase immune dysfunction and promote the growth and development of tumors (32,35). Additionally, previous studies have linked zinc to the development and progression of malignant tumors, such as rectal, stomach and breast cancers (14). Besides, zinc imbalance also affects head and neck cancer (36). Li et al. (37) found that zinc transport and zinc homeostasis have significant implications in the advancement of cancer, particularly in pancreatic cancer and breast cancer. Indeed, in this study, our conclusions from the large cross-sectional database NHANES also support previous works.

Currently, the results of epidemiological research on the association between selenium and breast cancer remain inconclusive. A large study of 145,033 postmenopausal women aged 50–79 examined the relationship between selenium and breast cancer, but selenium intake is not associated with incident breast cancer in the United States (15). Another study organized by Harris et al. (16) showed that a low selenium intake of 24.7 µg/day in a Swedish mammography cohort of 3,146 women with invasive breast cancer. Selenium intake before breast cancer diagnosis may increase diagnostic-specific and overall survival. Our study supports that selenium intake is negatively associated with breast cancer, which is consistent with the findings of Harris.

Further, we performed mediation analyses to assess whether several micronutrients intake modulate the association between zinc and selenium and the odds of breast cancer. It is noteworthy that the ACME of bilirubin was significant through mediation analyses of zinc and breast cancer effectiveness, suggesting that bilirubin mediates the previously observed protective association between zinc status and breast cancer. Another mediation analysis explained that approximately 10% of the inverse association of selenium with breast cancer was mediated through circulating bilirubin, uric acid, and GGT levels. This also suggests that zinc and selenium may reduce the risk of breast cancer through other pathways, such as DNA repair processes, immune surveillance, epigenetic regulation, and potential alternative pathways related to inhibition of tumor proliferation and vascularization.

Numerous investigations have shown the significant impact of oxidative stress and lipid peroxidation on breast cancer. In recent years it has been reported that zinc directly hinders the creation of O₂⁻ by blocking the NADPH oxidase complex responsible for its generation. Additionally, it indirectly stimulates the development of metallothionein, which acts as a scavenger for free radicals. Also for selenium, in the form of selenoproteins (particularly selenocysteine), directly facilitates the reduction of H₂O₂ and other peroxides by catalysis (38). Therefore, the roles of zinc and selenium in mitigating oxidative stress and lipid peroxidation may have a positive impact on preventing or slowing the development of tumors.

GGT is an enzyme located in the cell membrane, primarily involved in the transfer and degradation of glutamate and is widely recognized as a conventional liver biomarker (39). Simultaneously, it is associated with intracellular redox processes, potentially leading to cellular damage and oxidative stress (40). In such scenarios, zinc and selenium may competitively bind with other metal ions within the cell, thereby reducing metal-catalyzed oxidative reactions. Additionally, they may participate in the synthesis of antioxidant enzymes such as glutathione peroxidase (GPx). These reactions are likely to contribute to alleviating oxidative stress resulting from GGT-mediated redox processes, aiding in the protection of cells from damage.

In conclusion, this study adds weight to the hypothesis aiming to understand the associations between trace elements and breast cancer in women. We have also proposed the hypothesis that some substances, such as bilirubin and uric acid, may enhance selenium-zinc superoxide dismutase activity through their antioxidant properties, thereby increasing intracellular zinc bioavailability. Bilirubin may also increase the protective effect of selenium by affecting the metabolism of zinc and selenium in the human body. Our work seems promising in exploring the relationship between malignant tumors, including breast cancer, and antioxidants in micronutrients. Nevertheless, little is known about the specific mechanisms via which micronutrients interact with immunosurveillance, DNA repair processes, epigenetic control, and other processes in cancer.

In addition, our research is not without its flaws and restrictions. To begin, these findings come from a cross-sectional study, rather than a prospective cohort design, and thus do not accurately describe causality. Furthermore, we used a 24-hour dietary recall to assess nutrient intake, conducted through telephone interviews. However, this method may be prone to recall bias and has certain limitations that could affect the reliability of the conclusions drawn. Hence, further investigation is necessary, preferably via randomized controlled trials as well as extensive prospective and interventional investigations.

Conclusions

This cross-sectional analysis of NHANES data provides valuable population-based evidence supporting protective linear associations between dietary intake of zinc and selenium and breast cancer in women. Inverse associations remain significant after careful adjustment for potential demographic, socioeconomic and health confounders. Exploration of biological mediating pathways reveals a mediating role for bilirubin in the zinc-breast cancer linkage, in addition to meaningful indirect roles for bilirubin, uric acid, and GGT in explaining approximately 10% of the selenium-breast cancer linkage.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-83/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-83/prf

Funding: This research was supported by the Natural Science Foundation Program of Shandong Province (grant No. ZR2023MG071).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-83/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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