Folic acid supplementation promotes mammary tumor progression in a rat model.
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.
Department of Nutritional Sciences, University of Toronto and Keenan Research Center for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.
Shaidah
S
Deghan Manshadi
Department of Nutritional Sciences, University of Toronto and Keenan Research Center for Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.
Lisa
L
Ishiguro
Department of Medicine, University of Toronto and Keenan Research Center of Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.
Kyoung-Jin
KJ
Sohn
Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada ; Department of Pathology, Humber River Regional Hospital, Toronto, Ontario, Canada.
Alan
A
Medline
Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Richard
R
Renlund
Statistical Consultant, Toronto, Ontario, Canada.
Ruth
R
Croxford
Departments of Medicine & Nutritional Sciences, University of Toronto, Division of Gastroenterology, St. Michael's Hospital and Keenan Research Center of Biomedical Science at St. Michael's Hospital, Toronto, Ontario, Canada.
Young-In
YI
Kim
D015127:9,10-Dimethyl-1,2-benzanthracene; D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D019587:Dietary Supplements / Q000009:adverse effects*; D018450:Disease Progression; D005260:Female; D005492:Folic Acid / Q000009:adverse effects*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases; D047368:Tumor Burden / Q000187:drug effects; D051028:bcl-2-Associated X Protein
D015127:9,10-Dimethyl-1,2-benzanthracene; D005492:Folic Acid; D009363:Neoplasm Proteins; D011065:Poly(ADP-ribose) Polymerases; D018719:Erb-b2 Receptor Tyrosine Kinases; D051028:bcl-2-Associated X Protein; C494828:Bax protein, rat; C483804:Erbb2 protein, rat