Association Between One-carbon Metabolism-related Vitamins and Risk of Breast Cancer: A Systematic Review and Meta-analysis of Prospective Studies

Abstract

Epidemiologic studies focusing on the association between 1-carbon metabolism-related vitamins (ie, folate, vitamin B₆, vitamin B₂, vitamin B₁₂) and breast cancer risk have reported inconsistent findings. We conducted a systematic search of the reported data and performed a meta-analysis of prospective case-control and cohort studies to derive a more precise evaluation. The PubMed and EMBASE databases were searched to identify eligible studies. A total of 27 studies involving 49,707 cases and 1,274,060 individuals were included in the meta-analysis. The results indicated that a high intake of folate, vitamin B₆, and vitamin B₂ might decrease the risk of breast cancer. The corresponding pooled relative risks (RRs) for the highest intake compared with the lowest were 0.93 (95% confidence interval [CI], 0.88-0.99; P = .018), 0.94 (95% CI, 0.89-1.00; P = .037) and 0.90 (95% CI, 0.82-0.99; P = .026). No significant association between vitamin B₁₂ and breast cancer risk was found (RR, 0.99; 95% CI, 0.94-1.04; P = .604). Further study showed that folate and vitamin B₆ might decrease the risk of estrogen receptor-negative (ER⁻)/progesterone receptor-negative (PR⁻) breast cancer but not ER⁺/PR⁺ breast cancer. The dose–response meta-analysis indicated a significant linearity relationship between folate intake and a reduced risk of ER⁻/PR⁻ breast cancer. An increment of folate intake (100 μg/d) corresponded to a 7% deceased risk of ER⁻/PR⁻ breast cancer (RR, 0.93; 95% CI, 0.89-0.98; P = .007). In conclusion, a high intake of 1-carbon metabolism-related vitamins might contribute to the prevention of breast cancer, especially ER⁻/PR⁻ breast cancer.

Introduction

Breast cancer is the most commonly diagnosed malignancy and the leading cause of cancer-related death for women worldwide.^1,2 Despite the success of earlier diagnoses with mammography screening and recent advances in cancer treatment, breast cancer remains one of the most commonly occurring and deadly diseases in women, with a significantly increased incidence in developing countries resulting from the increased life expectancy, urbanization, and adoption of Western food and lifestyle.3, 4, 5 Dietary factors and nutritional status play important roles in breast carcinogenesis and cancer development. The concept of nutritional support as a part of a comprehensive cancer prevention and management program has increased in interest in the past 20 years. Epidemiologic studies have shown that a high intake of dietary fiber, vitamin D, vitamin A, omega-3 polyunsaturated fatty acids, and certain flavonoids, such as quercetin, catechin, and soy isoflavone, might reduce breast cancer risk.6, 7, 8, 9, 10, 11 These results highlight the potential benefits for breast cancer prevention through dietary modification.

B vitamins are essential, water-soluble micronutrients found naturally in green leafy vegetables, legumes, and organ meats such as liver. Some B vitamins, including folate, riboflavin, vitamin B₆, vitamin B₁₂, and choline, have been purported to influence carcinogenesis and development through their role in regulating 1-carbon metabolism. One-carbon metabolism comprises a complex network of biochemical pathways involving interactions among homocysteine, methionine, and B vitamins. Folate and betaine donate methyl groups to homocysteine to produce methionine, which is involved in DNA and RNA methylation, influencing gene stability and expression. Dysregulation of 1-carbon metabolism and DNA methylation has been assumed to promote carcinogenesis and progression.^12,13 The diet is a major source for key substrates and cofactors involved in 1-carbon metabolism. Therefore, it is important to determine the associations of 1-carbon metabolism-related vitamins with cancer risk. Many epidemiologic studies have evaluated the relationships between these B vitamins and various types of cancer, including breast cancer.14, 15, 16, 17, 18 However, studies that focused on the association between 1-carbon metabolism-related vitamins and breast cancer risk have reported inconsistent findings. Therefore, it is both interesting and necessary to provide a systematic review and meta-analysis for a precise assessment. Furthermore, in the past 2 years, many population-based studies, in particular, several large-scale prospective studies, focusing on the issue have been reported.19, 20, 21, 22, 23, 24 New and increased amounts of data in recent years have provided a chance to estimate the association of these vitamins with the risk of breast cancer.

Clinically, breast cancer is a heterogeneous disease. Different subtypes of breast cancer have different pathogenesis and risk factors.^4,25, 26, 27 Using gene expression profiling, breast cancer can be classified into subtypes by the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). These subtypes, including ER-positive (ER⁺), ER-negative (ER⁻), ER⁺/PR⁺, ER⁻/PR⁻, HER2⁺, HER2⁻, and ER⁻/PR⁻/HER2⁻, differ in prognosis and the factors that influence their occurrence. Thus, 1-carbon metabolism-related vitamins might exert different influence on the risk of different breast cancer subtypes. In the present study, we conducted a systematic search of the reported data and performed a meta-analysis to determine the association of the vitamins (ie, folate, vitamin B₆, B₁₂, B₂, and choline) with the risk of breast cancer subtypes. These results in our study have highlighted the potential benefits of dietary modification for breast cancer prevention.