| Breast cancer is the most common malignancy among females and its incidence is increasing. Epidemiological investigations and studies reveal the close link between dietary nutritional factors and occurrence, development and prognosis of tumors. Different types of fatty acids have different effects on the risk of breast cancer, increasing attention has been paid to the complicated relationship between the intake of dietary fat and the risk of breast cancer.Polyunsaturated fatty acids (PUFA), which have more than two double bonds in the structure, are divided into n-3 and n-6 type according to the localization of the first double bond. PUFAs play an important role in many physiological processes and they are tightly associated with the risk of breast cancer. Studies suggest n-6 and n-3 PUFA have different effects on the occurrence, development of breast cancer. It is found that n-6 PUFA can stimulate the growth and development of tumors, whereas n-3 PUFA can inhibit the cells proliferation and exert a protective effect on tumors development. However, the molecular mechanisms are far from understood.Study demonstrated that the ratios of n-6 PUFA to n-3 PUFA, but not absolute concentration of these fatty acids in adipose tissue were to be strongly associated with the risk of breast cancer. a low ratio of n-6/n-3 PUFA was more desirable in reducing the risk of the chronic diseases such as tumors. Nevertheless, it still remains unclear on determinating an rational ratio of n-6/n-3 PUFA in the diet for preventing breast cancer. Hence, it is very important to explore the molecular mechanisms of different dietary fatty acids and n-6/n-3 PUFA ratios on breast cancer development, and is also helpful to prevent breast cancer through the dietary intervention.Estrogen and its associated signal transduction play a key role in the occurance of breast cancer. The level of estrogen is considered to be the key risk factor to the carcinogenesis. The level of estrogen in the body is due to the dynamic balance of synthesis and metabolism. The synthesis of estrogen are involved with many enzymes and mostly determined by the expression and activities of some rate-limiting enzymes such as 17α-hydroxylase (CYP17) and aromatizing enzyme (CYP19).As we know, the essential reason of carcinogenesis is the mutation or abnormal expression of oncogenes or anti-oncogenes. BRCA1 and p53 are two important anti-oncogenes which play significant role in the occurrence and development of breast cancer. We presume that different ratio of n-6/n-3 PUFA in the diet could have different effects on the risk of breast cancer and these effects may be achieved by the way of regulating the level of estrogen and its signal transduction, moreover related with influence on mutation or abnormal expression of oncogenes or anti-oncogenes.Based on analysis above, combined with the daily dietary characteristics, this study was designed to investigate the effects and molecular mechanism of different n-6/n-3 PUFA ratios on occurrence and progression of breast cancer in MNU-induced mammary carcinogenesis model of rats through RT-PCR and Western Blotting et al methods. Observe different n-6/n-3 PUFA ratios, namely, 1∶1 n-6/n-3 PUFA, 5∶1 n-6/n-3 PUFA, 10∶1 n-6/n-3 PUFA, n-6 PUFA, on breast tumors development and explored the underlying mechanism of the changes of the level of estrogen and its synthesis, the signal transduction mediated by estrogen, the mutation or abnormal expression of oncogenes or anti-oncogenes.The main results and conclusions were summarized as follows:1. Fifty-day-old female Sprangue-Dawley rats were given a single intraperitoneal injection of methyl-nitrosourea (MNU) at 50 mg/kg body weight to establish the rat model of mammary carcinogenesis. The breast tumors induced by MNU were confirmed to be mammary ductal carcinomas by histopathological evaluation of hematoxylin and eosin (HE) staining. Meanwhile, the study showed that the different n-6/n-3 PUFA ratios could diversely influence incidence of MNU-induced breast tumors in rats, that was, a high tumor incidence, tumor multiplicity was found in rats fed on n-6 PUFA, 5∶1 n-6/n-3 PUFA, 10∶1 n-6/n-3 PUFA diets (10~12/13, 83.33%~92.31%); while a low tumor incidence, tumor multiplicity was found in rats fed on 1∶1 n-6/n-3 PUFA diet (6/14, 42.86%).2. The level of serum estrogen was measured by radio-immunity method, the result suggested that the serum estrogen was lowest in 1∶1 n-6/n-3 PUFA group, and gradually increased with the ratio of n-6/n-3 PUFA increasing. It was significantly lower in 1∶1 n-6/n-3 PUFA group than in n-6 PUFA group.3. Different n-6/n-3 PUFA ratios could diversely influence the expression of CYP17 and CYP19. Compared with n-6 PUFA, 5∶1 n-6/n-3 PUFA, 10∶1 n-6/n-3 PUFA, 1∶1 n-6/n-3 PUFA can sigificantly inhibit the increase of expression of CYP17, CYP19 in breast cancer rats.4. The expression of ER in breast cancer rats were higher than normal control, they were highest in n-6 PUFA group and gradually decreased with the ratio of n-6/n-3 decreasing. Different n-6/n-3 PUFA ratios could diversely influence the expression of ER, 1∶1 n-6/n-3 PUFA can sigificantly inhibit the increase of expression of ER in breast cancer rats.5. The expression of BRCA1 in breast cancer rats were lower than normal control. Different n-6/n-3 PUFA ratios could diversely influence the expression of BRCA1, 1∶1 n-6/n-3 PUFA can sigificantly inhibit the decrease of expression of BRCA1 in breast cancer rats. The half-life time of wild type p53 in the cells is extremely short, the expression of p53 that we detected is mutant p53, so the increase of expression of p53 means the mutant p53 increase. The results of western-blotting show that the expression of p53 in breast cancer rats were higher than normal control. 1∶1 n-6/n-3 PUFA can sigificantly inhibit the increase of expression of p53 in breast cancer rats.In all, this study from in vivo suggest that different dietary n-6/n-3 PUFA ratios can diversely influence occurrence and progression of breast tumors in rats, 1∶1 n-6/n-3 PUFA can sigificantly reduce tumor incidence and tumor multiplicity, inhibit the increase of the level of serum estrogen and expression of ER, CYP17, CYP19, p53 and the decrease of expression of BRCA1 in breast cancer rats. It was showed that 1∶1 n-6/n-3 PUFA can sigificantly reduce the risk of breast cancer, these effects may be closely associated with inhibition of estrogen synthesis and regulation of expression of anti-oncogenes.
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