Effect Of N-3 Polyunsaturated Fatty Acids On Risk Of Breast Cancer And The Underlying Mechanisms

N-3 polyunsaturated fatty acid(PUFA)refers to the polyunsaturated fatty acid containing two or more double bonds with the first double bond at the third carbon position at the methyl end of the carbon chain.In recent years,observational studies conducted in human suggested that n-3 PUFA has a protective effect on the development of many kinds of chronic diseases,such as hypertension,type 2 diabetes,cancer,non-alcoholic fatty liver and so on.However,the relationship between n-3 PUFA and breast cancer has always been controversial.Even though the experiments in animals and in vitro have shown that n-3 PUFA has a protective effect on breast cancer,epidemiological studies are inconsistent and there is a lack of strong evidence from the Chinese population.In the present study,we evalusted the relationship between n-3 PUFA and breast cancer by case-control studies in Chinese women,and further assessed the effect of maternal n-3 PUFA diet on breast cancer risk of female offspring in adulthood and the underlying mechanisms.The main findings are as follows:(])The results of case-control study in Chinese women showed that the contents of erythrocyte phospholipid fatty acids Cl8:3 n-3,C20:5 n-3 and total n-3 PUFA in breast cancer patient and benign tumor patients were both significantly lower than that in healthy people.Multivariable-adjusted logistic regression analysis showed that n-3 PUFA was negatively correlated with the incidence of breast cancer,indicating that low content of n-3 PUFA is a risk factor of breast cancer.(2)In a case-control study in Chinese women,we found that the content of metabolites such as erucic acid,choline,L-hydrowhey acid and stearate amide in malignant tumor tissues was significantly higher than that in benign tumor tissues,higher than in healthy mammary gland tissue,indicating that the disorder of phospholipid and lipid metabolism was a risk factor for breast cancer.(3)Animal study found that maternal exposure to n-3 PUFA diet during pregnancy and lactation has a protective effect on breast cancer risk of female offspring.Tumor incidence in offspring induced by 7,12-dimethylbenz[?]anthracene(DMBA)was lower in fish oil and flaxseed oil groups than safflower oil group.N-3 PUFA in fish oil and flaxseed oil groups also decreased the plasma concentrations of I7?-estradiol(E2),in both pregnant dams and offspring compared with safflower oil group.The offspring in fish and flaxseed oil groups showed delayed puberty onset,and their mammary glands contained decreased numbers of epithelial terminal end buds(TEBs,targets for malignant transformation)than offspring in safflower oil group.Reduced cell proliferation and increased apoptosis in offspring of fish oil and flaxseed oil groups were observed compared with offspring in safflower oil group.(4)Animal study indicated that the anti-cancer effect of maternal n-3 PUFAs was related to the regulation of IncRNA expression,which can further regulate the susceptibility of offspring to breast cancer.Transgenic fat-1 and wild-type C57BL/6J littermates were fed an n-6 PUFAs diet during pregnancy.Wild-genotype offspring of fat-1 mothers(fat-1 group)were compared with wild-genotype offspring of C57BL/6J mothers(control group)in breast cancer risk.Fat-1 group showed a significantly lower tumor incidence and smaller tumor volume compared with control group.N-3 PUFAs in fat-1 mothers changed the expression of long noncoding RNA(IncRNA,53 up-regulated and 45 down-regulated)in mammary gland of offspring.The IncRNA changes were associated with the changes of mRNA in multiple oncogenic signaling pathways,especially NF-?B,Jak-STAT and MAPK pathways.Expression of key protein in these pathways,namely p65,p60,STAT3,Jakl and p38 were significantly inhibited in fat-1 group.In conclusion,the present study suggested that n-3 PUFA was inversely associated with breast cancer in Chinese women.Maternal exposure to n-3 PUFA could decrease the breast cancer risk of female offspring,the mechanisms were involving the epigenetics,which decreased the expression of mRNA and protein in NF-?B,Jak-STAT and MAPK signaling pathways.