Previous studies illustrated that some dietary components can influence cancer-related epigenetic mechanisms[28]. In this study, we discovered a series of valuable associations among dietary factors, HS3ST2 methylation, and BC. First, The dietary consumption of fruit, poultry, marine fish, milk, and pork and regular exercise was significantly associated with changes in the risk of BC.Second, low intake of fruits, poultry, marine fish, and milk and irregular exercise combined with HS3ST2 hypermethylation in PBL DNA significantly increased the risk of BC. Third, we found that canned meat consumption was correlated with HS3ST2 hypermethylation in tumor tissue, HS3ST2 hypermethylation in tumor tissue DNA was significantly correlated with the TNM stage, and HS3ST2 hypermethylation in PBL DNA was significantly correlated with a basal-like status.
The protective effect of fruit is linked to its high content of beneficial substances, which have antioxidant effects, thereby preventing the activation of many carcinogens, suppressing spontaneous mutations, and protecting cellular structures and DNA against oxidative damage generated by metabolic processes[29, 30].Fung et al.[31] studied 29 different fruits and vegetables and found that blueberries, strawberries, peaches, and nectarines were negatively associated with the risk of BC in postmenopausal women. In line with these findings, our study found that the weekly consumption of at least 500g of fruit significantly reduced the risk of BC (OR = 0.368, 95% CI = 0.163–0.833).
Poultry and marine fish contains polyunsaturated fatty acids (PUFAs), such as linoleic acid and linolenic acid. Jiang et al[32]. found that gamma-linoleic acid (GLA) can significantly increase the expression of nm-23 and cadherin. nm-23 is a metastasis suppressor gene, and cadherin is an intercellular connection molecule. The increased expression of nm-23 and cadherin suggests decreased tumor metastasis ability.In addition,Archana et al[18].found that HS3ST2 expression can increase cadherin expression in BC cells. GLA and HS3ST2 affect cadherin through different pathways and further regulate the progression of BC. Not only that, our results show that,the risk of BC was significantly reduced when intake of poultry(≥ 1 intake/week)/marine fish (≥ 1 intake/month) (OR = 0.554/0.384).The combined effect of almost no consumption poultry(< 1 intake/week)/marine fish (< 1 intake/month) and HS3ST2 hypermethylation increases the risk of BC (OR = 3.197/4.172), suggesting that women carrying HS3ST2 hypermethylation could benefit from higher poultry/marine fish intake. However, the mechanism of the correlation between HS3ST2 methylation and GLA needs further study.
Milk is rich in vitamin D and calcium, and the proportion of various mineral elements and trace elements is appropriate, permitting its easy absorption by the human body.And we found that milk intake (≥ 1 time/week) was associated with a reduced risk of BC (OR = 0.355, 95% CI = 0.181–0.696).1α,25(OH)2D3 is an important active form of vitamin D. Mintao et al[33].found 1α,25(OH)2D3 restrains stem cell like properties of ovarian cancer cells by enhancing vitamin D receptor and suppressing CD44,and Felipe et al[19].found HS3ST2 expression reduced the CD44 + phenotype associated with stem cells in MDA-MB-231 cell lines.Therefore, 1α,25(OH)2D3 may combine with HS3ST2 to play an anticancer role by inhibiting CD44 expression.Our study found combined effect of lower milk intake (< 1 time/week) and HS3ST2 hypermethylation increased the risk of BC by 6.072–fold versus that with milk intake ≥ 1 time/week and HS3ST2 hypomethylation (95% CI = 2.399–15.568). Thus, we suggest that individuals with HS3ST2 hypermethylation in PBL DNA maintain drink milk regularly state to prevent breast cancer.
Some studies found that high processed meat intake is associated with an increased risk of BC[34]. Processed meat contains high levels of amines, nitrates, and nitrites. All of these compounds are precursors of N-nitroso compounds, which are carcinogenic[35]. Animal experiments demonstrated that N-nitroso compounds can induce the expression of cyclin D1 and p21 in the rat mammary gland and promote tumorigenesis[36]. However, there has been no reported association between gene methylation in breast tumor tissue and processed meat consumption. In multivariate analysis, we found that the intake of canned meat was significantly correlated with the methylation level of HS3ST2 in BC tissues. This suggested that the consumption of processed meats such as canned meat might explain the changing methylation level of HS3ST2, thereby altering the functional expression of HS3ST2 in BC tissues. However, this conclusion must be confirmed in further in vitro studies.
Moreover, research has indicated that physical activity can help reduce the risk of BC in young women[37]. Estrogen, based on its own characteristics, can induce cell proliferation and promote the development of tumors, whereas physical exercise can reduce estrogen levels and the risk of BC[38]. Our study found that regular exercise reduced the risk of BC (OR = 0.410, 95% CI = 0.225–0.749). Compared with the combined exposure of regular exercise and HS3ST2 hypomethylation, a lack of exercise combined with HS3ST2 hypermethylation increased the risk of BC (OR = 4.149, 95% CI = 2.908–9.022). Therefore, we strongly recommend that women should increase their physical activity to prevent BC, especially those with exposure to high-risk dietary factors and HS3ST2 hypermethylation.
BC is a heterogeneous disease with a variety of clinicopathological features. Studies on the relationship between DNA methylation and clinicopathological features significantly increased our understanding of BC[40]. The TNM staging system is the most commonly used staging system for tumors at present. Higher stages indicate a higher degree of tumor progression[41].Different ER states represent different metastasis pattern and better survival of BC[42].Basal-like BC is characterized by high grade, presence of central necrotic or fibrotic zones, and lymphocytic infiltrate. Patients presenting with Basal-like BC have a poor prognosis and a short-term disease-free and overall survival[43]. The results of our study demonstrated that the methylation level of HS3ST2 in PBL DNA was significantly correlated with TNM stages II–IV (P = 0.034), and it is related to the ER-negative state and Basal-like in BC tissue, which may provide a direction for the study of BC progression, prognosis, and drug targets.
This study had some limitations. First, recall bias is impossible to completely avoid when collecting questionnaire data on diet. In addition, some data of diet were only collected as frequencies, and thus, the dose–response relationship was not further analyzed. Second, our results are only applicable to women in Northeast China, and larger studies in other populations are needed. Third, the conclusions of our study regarding the function of HS3ST2 hypermethylation need to be confirmed by further in vitro experiments.