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Epidemiologic studies have suggested that dietary intake and blood levels of folate may be inversely related to the risk of breast cancer. However, epidemiologic evidence has not been consistent nor has it provided unequivocal support for this purported inverse relationship. Recent evidence has also raised a concern that folate supplementation may promote carcinogenesis if provided after neoplastic foci are established in the target organ. This study investigated the effect of dietary folate deficiency and supplementation on the development and progression of mammary tumors in the N-methyl-N-nitrosourea (MNU) rat model. Weanling, female Sprague–Dawley rats were fed diets containing 0, 2 (control) or 8 mg folic acid/kg diet during the initiation or the promotion phase of MNU-induced mammary tumorigenesis. At necropsy, all macroscopic mammary tumors were identified and histologically confirmed. Dietary folate deficiency and supplementation provided during the initiation phase did not significantly modulate the development of mammary tumors. In contrast, dietary folate deficiency provided during the promotion phase significantly inhibited the rate of appearance, incidence, mean volume and weight of adenocarcinomas compared with the control and supplemental diets. Folate supplementation provided during the promotion phase did not significantly modulate mammary tumorigenesis compared with the control group. These data indicate that moderate folate deficiency inhibits, whereas dietary folate supplementation at four times the basal dietary requirement does not promote, the progression of MNU-induced mammary neoplastic foci in this rat model. However, the limitations associated with the route and dose of MNU administration preclude a definitive conclusion concerning the effect of folate status on the initiation of MNU-induced mammary tumorigenesis. [ABSTRACT FROM AUTHOR]

The purpose of this investigation was to determine whether fatty acid synthase (FAS) is a potential molecular target for the chemoprevention of breast cancer by evaluating the effect of the FAS inhibitor triclosan on rat mammary carcinogenesis. At 50 days of age, 60 female SpragueDawley rats received 50 mg/kg methylnitrosourea (MNU) i.p. to initiate mammary carcinogenesis. One week later, half of the rats were fed triclosan at a level of 1000 p.p.m. in an AIN-93G diet for the remainder of the experiment. The other 30 control rats were fed an AIN-93G diet without triclosan. Twelve weeks after MNU treatment, 70% of control rats had mammary adenocarcinomas compared with only 43.3% of the triclosan group (P < 0.05). The control rats had an average of 2.7 0.3 tumors/rat compared with 1.8 0.3 in the triclosan group (P < 0.05). Western analysis showed that the tumors in the control rats expressed high levels of FAS. Immunohistochemistry showed that sections of tumors that stained strongly for FAS also showed strong staining for proliferating cell nuclear antigen. Furthermore, at biologically relevant dose levels, triclosan inhibited the activity of FAS in mammary tumor homogenates. These results indicate that triclosan suppresses rat mammary carcinogenesis by inhibiting FAS and suggest that FAS is a promising molecular target for breast cancer chemoprevention. [ABSTRACT FROM AUTHOR]