Abstract
Folic acid supplementation may prevent the development of cancer in normal tissues but may promote the progression of established (pre)neoplastic lesions. However, whether or not folic acid supplementation can promote the progression of established (pre)neoplastic mammary lesions is unknown. This is a critically important issue because breast cancer patients and survivors in North America are likely exposed to high levels of folic acid owing to folic acid fortification and widespread supplemental use after cancer diagnosis. We investigated whether folic acid supplementation can promote the progression of established mammary tumors. Female Sprague-Dawley rats were placed on a control diet and mammary tumors were initiated with 7,12-dimethylbenza[a]anthracene at puberty. When the sentinel tumor reached a predefined size, rats were randomized to receive a diet containing the control, 2.5x, 4x, or 5x supplemental levels of folic acid for up to 12 weeks. The sentinel mammary tumor growth was monitored weekly. At necropsy, the sentinel and all other mammary tumors were analyzed histologically. The effect of folic acid supplementation on the expression of proteins involved in proliferation, apoptosis, and mammary tumorigenesis was determined in representative sentinel adenocarcinomas. Although no clear dose-response relationship was observed, folic acid supplementation significantly promoted the progression of the sentinel mammary tumors and was associated with significantly higher sentinel mammary tumor weight and volume compared with the control diet. Furthermore, folic acid supplementation was associated with significantly higher weight and volume of all mammary tumors. The most significant and consistent mammary tumor-promoting effect was observed with the 2.5x supplemental level of folic acid. Folic acid supplementation was also associated with an increased expression of BAX, PARP, and HER2. Our data suggest that folic acid supplementation may promote the progression of established mammary tumors. The potential tumor-promoting effect of folic acid supplementation in breast cancer patients and survivors needs further clarification.
Highlights
The role of folate, a water-soluble B vitamin, and its synthetic form, folic acid, in cancer development and progression is highly controversial [1,2,3]
Based on the biological function of folate and the previously observed tumor-promoting effect of folic acid supplementation made in preclinical colorectal cancer models, our a priori hypothesis was that folic acid supplementation would promote the progression of established mammary tumors
Cancer patients and survivors in North America have a high prevalence of multivitamin and supplement use with breast cancer patients and survivors having the highest prevalence
Summary
The role of folate, a water-soluble B vitamin, and its synthetic form, folic acid, in cancer development and progression is highly controversial [1,2,3]. Recent epidemiologic studies have even suggested that high folate intake, largely from folic acid, [9,10,11,12] and high plasma folate concentrations [13,14] may increase breast cancer risk. A combined analysis of 3 large randomized clinical trials of folic acid supplementation for the prevention of recurrent colorectal adenomas in those with an adenoma history including the Asprin/Folate Polyp Prevention study reported a null effect, with shorter follow-up times [17]. Combined or meta-analyses of several randomized clinical trials that investigated the effect of folic acid supplementation with or without other B vitamins on cardiovascular disease outcomes as the primary endpoint reported either a tumor promoting [18] or null [19] effect on cancer risk as the secondary endpoint. With respect to breast cancer trials of folic acid, vitamin B6 and vitamin B12 conducted among individuals at high risk of cardiovascular disease found no effect on breast cancer outcomes [21,22,23,24]
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