Skip to main content

Folate and breast cancer: what about high-risk women?

Cancer Causes & Control volume 23, pages 1405–1420 (2012)Cite this article

Abstract

Folate is a water-soluble B-vitamin and is an important cofactor in one-carbon metabolism. This vitamin plays an important role in the pathogenesis of several chronic diseases. In recent years, there has been much interest in the relationship between folate status and breast cancer risk, particularly given the dramatic increase in dietary intake and blood serum folate levels in North America as a result of mandatory folic acid fortification and the widespread use of folic acid supplementation. The well-described dual effects of folate on carcinogenesis underscore the need to clarify the role of folate in the development and progression of breast cancer. This is of particular importance among those at high risk of developing breast cancer because of benign breast disease, a strong family history of breast cancer or an inherited mutation in BRCA1 or BRCA2. BRCA mutation carriers face a high lifetime risk of developing breast cancer, estimated at 80 % compared with 11 % in the general population. Predictive genetic testing permits the identification of these high-risk women prior to diagnosis; however, prevention is limited to surgery and chemoprevention, and the importance of modifiable risk factors such as diet and lifestyle has not been elucidated. Our goal is to develop practical and safe interventions for high-risk women leading to a decrease in the number of breast cases and deaths attributed to breast cancer.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Lucock M (2000) Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab 71(1–2):121–138

    PubMed  CAS  Article  Google Scholar 

  2. Shane B (1995) Folate chemistry and metabolism. In: Bailey LB (ed) Folate in health and disease. Marcel Dekker, New York, pp 1–22

    Google Scholar 

  3. Camilo E, Zimmerman J, Mason JB, Golner B, Russell R, Selhub J, Rosenberg IH (1996) Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology 110(4):991–998

    PubMed  CAS  Article  Google Scholar 

  4. Institute of Medicine: Folate. In: Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. National Academy Press, Washington, DC, pp 196–305, 1998

  5. Gregory JF III (2001) Case study: folate bioavailability. J Nutr 131(4 Suppl):1376S–1382S

    PubMed  CAS  Google Scholar 

  6. Canada H (1997) Regulations amending the Food and Drug Regulations (1066). Canada Gazette, Part 1. 131:3702–3737

  7. Tamura T, Picciano MF (2006) Folate and human reproduction. Am J Clin Nutr 83(5):993–1016

    PubMed  CAS  Google Scholar 

  8. Shane B (2003) Folate fortification: enough already? Am J Clin Nutr 77(1):8–9

    PubMed  CAS  Google Scholar 

  9. Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF (2002) Folic acid intake from fortification in United States exceeds predictions. J Nutr 132(9):2792–2798

    PubMed  CAS  Google Scholar 

  10. Quinlivan EP, Gregory JF III (2003) Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr 77(1):221–225

    PubMed  CAS  Google Scholar 

  11. Caudill MA, Le T, Moonie SA, Esfahani ST, Cogger EA (2001) Folate status in women of childbearing age residing in Southern California after folic acid fortification. J Am Coll Nutr 20(2 Suppl):129–134

    PubMed  CAS  Google Scholar 

  12. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 340(19):1449–1454

    PubMed  CAS  Article  Google Scholar 

  13. Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ (2005) Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999–2000. Am J Clin Nutr 82(2):442–450

    PubMed  CAS  Google Scholar 

  14. Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF (2004) Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999–2000. Am J Epidemiol 160(4):339–349

    PubMed  Article  Google Scholar 

  15. Colapinto CK, O’Connor DL, Tremblay MS (2011) Folate status of the population in the Canadian Health Measures Survey. CMAJ 183(2):E100–E106

    PubMed  Article  Google Scholar 

  16. Giovannucci E, Chan AT (2010) Role of vitamin and mineral supplementation and aspirin use in cancer survivors. J Clin Oncol 28(26):4081–4085

    PubMed  CAS  Article  Google Scholar 

  17. Bright-Gbebry M, Makambi KH, Rohan JP, Llanos AA, Rosenberg L, Palmer JR, Adams-Campbell LL (2011) Use of multivitamins, folic acid and herbal supplements among breast cancer survivors: the black women’s health study. BMC Complement Altern Med 11:30

    PubMed  Article  Google Scholar 

  18. Kim YI (2007) Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res 51(3):267–292

    PubMed  CAS  Article  Google Scholar 

  19. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428

    PubMed  CAS  Google Scholar 

  20. Duthie SJ (1999) Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull 55(3):578–592

    PubMed  CAS  Article  Google Scholar 

  21. Ames BN (2001) DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat Res 475(1–2):7–20

    PubMed  CAS  Google Scholar 

  22. Kim YI (2004) Folate, colorectal carcinogenesis, and DNA methylation: lessons from animal studies. Environ Mol Mutagen 44(1):10–25

    PubMed  CAS  Article  Google Scholar 

  23. Kim YI (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10(2):66–88

    PubMed  CAS  Article  Google Scholar 

  24. Choi SW, Mason JB (2002) Folate status: effects on pathways of colorectal carcinogenesis. J Nutr 132(8 Suppl):2413S–2418S

    PubMed  CAS  Google Scholar 

  25. Fenech M (2001) The role of folic acid and vitamin B12 in genomic stability of human cells. Mutat Res 475(1–2):57–67

    PubMed  CAS  Google Scholar 

  26. Lamprecht SA, Lipkin M (2003) Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 3(8):601–614

    PubMed  CAS  Article  Google Scholar 

  27. Kim YI (2003) Role of folate in colon cancer development and progression. J Nutr 133(11 Suppl 1):3731S–3739S

    PubMed  CAS  Google Scholar 

  28. Campbell NR (1996) How safe are folic acid supplements? Arch Intern Med 156(15):1638–1644

    PubMed  CAS  Article  Google Scholar 

  29. Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY (2001) Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 285(23):2981–2986

    PubMed  CAS  Article  Google Scholar 

  30. Persad VL, Van den Hof MC, Dube JM, Zimmer P (2002) Incidence of open neural tube defects in Nova Scotia after folic acid fortification. CMAJ 167(3):241–245

    PubMed  Google Scholar 

  31. Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K (2006) Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 354(15):1578–1588

    PubMed  CAS  Article  Google Scholar 

  32. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C et al (2006) Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354(15):1567–1577

    PubMed  CAS  Article  Google Scholar 

  33. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang CH, Stampfer M (2004) Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the vitamin intervention for stroke prevention (VISP) randomized controlled trial. JAMA 291(5):565–575

    PubMed  CAS  Article  Google Scholar 

  34. Kim YI (2007) Folic acid fortification and supplementation—good for some but not so good for others. Nutr Rev 65(11):504–511

    PubMed  Article  Google Scholar 

  35. Kim YI (2006) Does a high folate intake increase the risk of breast cancer? Nutr Rev 64(10 Pt 1):468–475

    PubMed  Article  Google Scholar 

  36. Kim YI (2008) Folic acid supplementation and cancer risk: point. Cancer Epidemiol Biomarkers Prev 17(9):2220–2225

    PubMed  Article  Google Scholar 

  37. Ulrich CM (2008) Folate and cancer prevention—where to next? Counterpoint. Cancer Epidemiol Biomarkers Prev 17(9):2226–2230

    PubMed  Article  Google Scholar 

  38. Farber S, Cutler EC, Hawkins JW, Harrison JH, Peirce EC II, Lenz CG (1947) The action of pteroylglutamic conjugates on man. Science 106(2764):619–621

    PubMed  CAS  Article  Google Scholar 

  39. Farber S, Diamond LK (1948) Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med 238(23):787–793

    PubMed  CAS  Article  Google Scholar 

  40. Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, McKeown-Eyssen G, Summers RW, Rothstein RI, Burke CA et al (2007) Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297(21):2351–2359

    PubMed  CAS  Article  Google Scholar 

  41. Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, Burke CA, McKeown-Eyssen GE, Baron JA (2009) Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst 101(6):432–435

    PubMed  CAS  Article  Google Scholar 

  42. Paspatis GA, Karamanolis DG (1994) Folate supplementation and adenomatous colonic polyps. Dis Colon Rectum 37(12):1340–1341

    PubMed  CAS  Article  Google Scholar 

  43. Jaszewski R, Misra S, Tobi M, Ullah N, Naumoff JA, Kucuk O, Levi E, Axelrod BN, Patel BB, Majumdar AP (2008) Folic acid supplementation inhibits recurrence of colorectal adenomas: a randomized chemoprevention trial. World J Gastroenterol 14(28):4492–4498

    PubMed  CAS  Article  Google Scholar 

  44. Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR (2008) Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 134(1):29–38

    PubMed  CAS  Article  Google Scholar 

  45. Wu K, Platz EA, Willett WC, Fuchs CS, Selhub J, Rosner BA, Hunter DJ, Giovannucci E (2009) A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma. Am J Clin Nutr 90(6):1623–1631

    PubMed  CAS  Article  Google Scholar 

  46. Figueiredo JC, Mott LA, Giovannucci E, Wu K, Cole B, Grainge MJ, Logan RF, Baron JA (2011) Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials. Int J Cancer 129(1):192–203

    PubMed  CAS  Article  Google Scholar 

  47. Ebbing M, Bonaa KH, Nygard O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njolstad I, Refsum H, Nilsen DW et al (2009) Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 302(19):2119–2126

    PubMed  CAS  Article  Google Scholar 

  48. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, Bonaa KH, Spence JD, Nygard O, Jamison R et al (2010) Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 170(18):1622–1631

    PubMed  CAS  Article  Google Scholar 

  49. Wien TN, Pike E, Wisloff T, Staff A, Smeland S, Klemp M (2012) Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open 2(1):e000653

    PubMed  Article  Google Scholar 

  50. Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE (2008) Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA 300(17):2012–2021

    PubMed  Article  Google Scholar 

  51. Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, Johnson KA, Johnson C, Buys SS, Hoover RN, Ziegler RG (2006) Folate intake, alcohol use, and postmenopausal breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Am J Clin Nutr 83(4):895–904

    PubMed  CAS  Google Scholar 

  52. Stevens VL, McCullough ML, Sun J, Gapstur SM (2010) Folate and other one-carbon metabolism-related nutrients and risk of postmenopausal breast cancer in the cancer prevention study II nutrition cohort. Am J Clin Nutr 91(6):1708–1715

    PubMed  CAS  Article  Google Scholar 

  53. Lin J, Lee IM, Cook NR, Selhub J, Manson JE, Buring JE, Zhang SM (2008) Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women. Am J Clin Nutr 87(3):734–743

    PubMed  CAS  Google Scholar 

  54. Charles D, Ness AR, Campbell D, Davey Smith G, Hall MH (2004) Taking folate in pregnancy and risk of maternal breast cancer. BMJ 329(7479):1375–1376

    PubMed  Article  Google Scholar 

  55. Kotsopoulos J, Sohn KJ, Martin R, Choi M, Renlund R, McKerlie C, Hwang SW, Medline A, Kim YI (2003) Dietary folate deficiency suppresses N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats. Carcinogenesis 24(5):937–944

    PubMed  CAS  Article  Google Scholar 

  56. Lewisohn R, Leuchtenberger C et al. (1946) The influence of liver L. casei factor on spontaneous breast cancer in mice. Science 104(2706):436

    Google Scholar 

  57. Leuchtenberger R, Leuchtenberger C, Laszlo D, Lewisohn R (1945) The influence of “folic acid” on spontaneous breast cancers in mice. Science 101(2611):46

    PubMed  CAS  Article  Google Scholar 

  58. Kotsopoulos J, Medline A, Renlund R, Sohn KJ, Martin R, Hwang SW, Lu S, Archer MC, Kim YI (2005) Effects of dietary folate on the development and progression of mammary tumors in rats. Carcinogenesis 26(9):1603–1612

    PubMed  CAS  Article  Google Scholar 

  59. Baggott JE, Vaughn WH, Juliana MM, Eto I, Krumdieck CL, Grubbs CJ (1992) Effects of folate deficiency and supplementation on methylnitrosourea-induced rat mammary tumors. J Natl Cancer Inst 84(22):1740–1744

    PubMed  CAS  Article  Google Scholar 

  60. Sie KK, Chen J, Sohn KJ, Croxford R, Thompson LU, Kim YI (2009) Folic acid supplementation provided in utero and during lactation reduces the number of terminal end buds of the developing mammary glands in the offspring. Cancer Lett 280(1):72–77

    PubMed  CAS  Article  Google Scholar 

  61. Russo IH, Russo J (1996) Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect 104(9):938–967

    PubMed  CAS  Article  Google Scholar 

  62. Ly A, Lee H, Chen J, Sie KK, Renlund R, Medline A, Sohn KJ, Croxford R, Thompson LU, Kim YI (2011) Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Cancer Res 71(3):988–997

    PubMed  CAS  Article  Google Scholar 

  63. Wilson RD, Johnson JA, Wyatt P, Allen V, Gagnon A, Langlois S, Blight C, Audibert F, Desilets V, Brock JA et al (2007) Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can 29(12):1003–1026

    PubMed  Google Scholar 

  64. Lewis SJ, Harbord RM, Harris R, Smith GD (2006) Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk. J Natl Cancer Inst 98(22):1607–1622

    PubMed  CAS  Article  Google Scholar 

  65. Larsson SC, Giovannucci E, Wolk A (2007) Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst 99(1):64–76

    PubMed  CAS  Article  Google Scholar 

  66. Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SM, Motola J Jr, Laginha FM, Tsugane S (2009) Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women. BMC Cancer 9:122

    PubMed  Article  CAS  Google Scholar 

  67. Zhang CX, Ho SC, Chen YM, Lin FY, Fu JH, Cheng SZ (2011) Dietary folate, vitamin B6, vitamin B12 and methionine intake and the risk of breast cancer by oestrogen and progesterone receptor status. Br J Nutr 106(6):936–943

    PubMed  CAS  Article  Google Scholar 

  68. Rohan TE, Jain MG, Howe GR, Miller AB (2000) Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 92(3):266–269

    PubMed  CAS  Article  Google Scholar 

  69. Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR, Gao YT, Zheng W (2001) Dietary folate intake and breast cancer risk: results from the Shanghai breast cancer study. Cancer Res 61(19):7136–7141

    PubMed  CAS  Google Scholar 

  70. Zhang SM, Hankinson SE, Hunter DJ, Giovannucci EL, Colditz GA, Willett WC (2005) Folate intake and risk of breast cancer characterized by hormone receptor status. Cancer Epidemiol Biomarkers Prev 14(8):2004–2008

    PubMed  CAS  Article  Google Scholar 

  71. Larsson SC, Bergkvist L, Wolk A (2008) Folate intake and risk of breast cancer by estrogen and progesterone receptor status in a Swedish cohort. Cancer Epidemiol Biomarkers Prev 17(12):3444–3449

    PubMed  CAS  Article  Google Scholar 

  72. Hillman RS, Steinberg SE (1982) The effects of alcohol on folate metabolism. Annu Rev Med 33:345–354

    PubMed  CAS  Article  Google Scholar 

  73. Rossi E, Hung J, Beilby JP, Knuiman MW, Divitini ML, Bartholomew H (2006) Folate levels and cancer morbidity and mortality: prospective cohort study from Busselton, Western Australia. Ann Epidemiol 16(3):206–212

    PubMed  Article  Google Scholar 

  74. Harris HR, Bergkvist L, Wolk A (2012) Folate intake and breast cancer mortality in a cohort of Swedish women. Breast Cancer Res Treat 132(1):243–250

    PubMed  CAS  Article  Google Scholar 

  75. Freudenheim JL, Marshall JR, Vena JE, Laughlin R, Brasure JR, Swanson MK, Nemoto T, Graham S (1996) Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients. J Natl Cancer Inst 88(6):340–348

    PubMed  CAS  Article  Google Scholar 

  76. Negri E, La Vecchia C, Franceschi S (2000) Re: dietary folate consumption and breast cancer risk. J Natl Cancer Inst 92(15):1270–1271

    PubMed  CAS  Article  Google Scholar 

  77. Lajous M, Romieu I, Sabia S, Boutron-Ruault MC, Clavel-Chapelon F (2006) Folate, vitamin B12 and postmenopausal breast cancer in a prospective study of French women. Cancer Causes Control 17(9):1209–1213

    PubMed  Article  Google Scholar 

  78. Wu K, Helzlsouer KJ, Comstock GW, Hoffman SC, Nadeau MR, Selhub J (1999) A prospective study on folate, B12, and pyridoxal 5’-phosphate (B6) and breast cancer. Cancer Epidemiol Biomarkers Prev 8(3):209–217

    PubMed  CAS  Google Scholar 

  79. Graham S, Hellmann R, Marshall J, Freudenheim J, Vena J, Swanson M, Zielezny M, Nemoto T, Stubbe N, Raimondo T (1991) Nutritional epidemiology of postmenopausal breast cancer in western New York. Am J Epidemiol 134(6):552–566

    PubMed  CAS  Google Scholar 

  80. Lajous M, Lazcano-Ponce E, Hernandez-Avila M, Willett W, Romieu I (2006) Folate, vitamin B(6), and vitamin B(12) intake and the risk of breast cancer among Mexican women. Cancer Epidemiol Biomarkers Prev 15(3):443–448

    PubMed  CAS  Article  Google Scholar 

  81. Thorand B, Kohlmeier L, Simonsen N, Croghan C, Thamm M (1998) Intake of fruits, vegetables, folic acid and related nutrients and risk of breast cancer in postmenopausal women. Public Health Nutr 1(3):147–156

    PubMed  CAS  Article  Google Scholar 

  82. Tjonneland A, Christensen J, Olsen A, Stripp C, Nissen SB, Overvad K, Thomsen BL (2006) Folate intake, alcohol and risk of breast cancer among postmenopausal women in Denmark. Eur J Clin Nutr 60(2):280–286

    PubMed  CAS  Article  Google Scholar 

  83. Zhang S, Hunter DJ, Hankinson SE, Giovannucci EL, Rosner BA, Colditz GA, Speizer FE, Willett WC (1999) A prospective study of folate intake and the risk of breast cancer. JAMA 281(17):1632–1637

    PubMed  CAS  Article  Google Scholar 

  84. Cho E, Spiegelman D, Hunter DJ, Chen WY, Zhang SM, Colditz GA, Willett WC (2003) Premenopausal intakes of vitamins A, C, and E, folate, and carotenoids, and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 12(8):713–720

    PubMed  CAS  Google Scholar 

  85. Ericson U, Borgquist S, Ivarsson MI, Sonestedt E, Gullberg B, Carlson J, Olsson H, Jirstrom K, Wirfalt E (2010) Plasma folate concentrations are positively associated with risk of estrogen receptor beta negative breast cancer in a Swedish nested case control study. J Nutr 140(9):1661–1668

    PubMed  CAS  Article  Google Scholar 

  86. Maruti SS, Ulrich CM, White E (2009) Folate and one-carbon metabolism nutrients from supplements and diet in relation to breast cancer risk. Am J Clin Nutr 89(2):624–633

    PubMed  CAS  Article  Google Scholar 

  87. Ericson U, Sonestedt E, Gullberg B, Olsson H, Wirfalt E (2007) High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmo diet and cancer cohort. Am J Clin Nutr 86(2):434–443

    PubMed  CAS  Google Scholar 

  88. Hu FB, Stampfer MJ, Rimm E, Ascherio A, Rosner BA, Spiegelman D, Willett WC (1999) Dietary fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements. Am J Epidemiol 149(6):531–540

    PubMed  CAS  Article  Google Scholar 

  89. Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, Colditz GA, Hankinson SE (2003) Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 95(5):373–380

    PubMed  CAS  Article  Google Scholar 

  90. Hirsch S, Sanchez H, Albala C, de la Maza MP, Barrera G, Leiva L, Bunout D (2009) Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol 21(4):436–439

    PubMed  Article  Google Scholar 

  91. Claus EB, Risch NJ, Thompson WD (1990) Age at onset as an indicator of familial risk of breast cancer. Am J Epidemiol 131(6):961–972

    PubMed  CAS  Google Scholar 

  92. Hankinson SE, Colditz GA, Willett WC (2004) Towards an integrated model for breast cancer etiology: the lifelong interplay of genes, lifestyle, and hormones. Breast Cancer Res 6(5):213–218

    PubMed  CAS  Article  Google Scholar 

  93. Collaborative Group on Hormonal Factors in Breast Cancer (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 358(9291):1389–1399

    Google Scholar 

  94. Metcalfe KA, Finch A, Poll A, Horsman D, Kim-Sing C, Scott J, Royer R, Sun P, Narod SA (2009) Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation. Br J Cancer 100(2):421–425

    PubMed  CAS  Article  Google Scholar 

  95. Sellers TA, Grabrick DM, Vierkant RA, Harnack L, Olson JE, Vachon CM, Cerhan JR (2004) Does folate intake decrease risk of postmenopausal breast cancer among women with a family history? Cancer Causes Control 15(2):113–120

    PubMed  Article  Google Scholar 

  96. Byrne C, Schairer C, Wolfe J, Parekh N, Salane M, Brinton LA, Hoover R, Haile R (1995) Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 87(21):1622–1629

    PubMed  CAS  Article  Google Scholar 

  97. Boyd NF, Lockwood GA, Martin LJ, Knight JA, Jong RA, Fishell E, Byng JW, Yaffe MJ, Tritchler DL (1999) Mammographic densities and risk of breast cancer among subjects with a family history of this disease. J Natl Cancer Inst 91(16):1404–1408

    PubMed  CAS  Article  Google Scholar 

  98. Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ, Paterson AD (2005) Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol 6(10):798–808

    PubMed  Article  Google Scholar 

  99. Boyd NF, Martin LJ, Stone J, Greenberg C, Minkin S, Yaffe MJ (2001) Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention. Curr Oncol Rep 3(4):314–321

    PubMed  CAS  Article  Google Scholar 

  100. Yaffe M, Hendrix S, Pike M, Santen R, Eden J, Genazzani A (2005) Is mammographic density, as currently measured, a robust surrogate marker for breast cancer? Gynecol Endocrinol 21(Suppl 1):17–21

    PubMed  Article  Google Scholar 

  101. Page DL, Dupont WD, Rogers LW, Rados MS (1985) Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer 55(11):2698–2708

    PubMed  CAS  Article  Google Scholar 

  102. Dupont WD, Page DL (1985) Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312(3):146–151

    PubMed  CAS  Article  Google Scholar 

  103. Li CI, Anderson BO, Daling JR, Moe RE (2002) Changing incidence of lobular carcinoma in situ of the breast. Breast Cancer Res Treat 75(3):259–268

    PubMed  Article  Google Scholar 

  104. Habel LA, Moe RE, Daling JR, Holte S, Rossing MA, Weiss NS (1997) Risk of contralateral breast cancer among women with carcinoma in situ of the breast. Ann Surg 225(1):69–75

    PubMed  CAS  Article  Google Scholar 

  105. Warnberg F, Yuen J, Holmberg L (2000) Risk of subsequent invasive breast cancer after breast carcinoma in situ. Lancet 355(9205):724–725

    PubMed  CAS  Article  Google Scholar 

  106. Franceschi S, Levi F, La Vecchia C, Randimbison L, Te VC (1998) Second cancers following in situ carcinoma of the breast. Int J Cancer 77(3):392–395

    PubMed  CAS  Article  Google Scholar 

  107. Li CI, Daling JR, Malone KE (2005) Age-specific incidence rates of in situ breast carcinomas by histologic type, 1980 to 2001. Cancer Epidemiol Biomarkers Prev 14(4):1008–1011

    PubMed  Article  Google Scholar 

  108. Liu Y, Tamimi RM, Berkey CS, Willett WC, Collins LC, Schnitt SJ, Connolly JL, Colditz GA (2012) Intakes of alcohol and folate during adolescence and risk of proliferative benign breast disease. Pediatrics 129(5):1192–1198

    Google Scholar 

  109. Cui Y, Page DL, Chlebowski RT, Beresford SA, Hendrix SL, Lane DS, Rohan TE (2007) Alcohol and folate consumption and risk of benign proliferative epithelial disorders of the breast. Int J Cancer 121(6):1346–1351

    PubMed  CAS  Article  Google Scholar 

  110. Scott R (2004) DNA double strand break repair and its association with inherited predispositions to breast cancer. Hered Cancer Clin Pract 2(1):37–43

    PubMed  CAS  Article  Google Scholar 

  111. Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481(7381):287–294

    PubMed  CAS  Article  Google Scholar 

  112. Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR, van Zwieten MJ (1990) Comparative study of human and rat mammary tumorigenesis. Lab Invest 62(3):244–278

    PubMed  CAS  Google Scholar 

  113. Sukumar S, McKenzie K, Chen Y (1995) Animal models for breast cancer. Mutat Res 333(1–2):37–44

    PubMed  CAS  Google Scholar 

  114. Mehta RG (2000) Experimental basis for the prevention of breast cancer. Eur J Cancer 36(10):1275–1282

    PubMed  CAS  Article  Google Scholar 

  115. Chen S, Parmigiani G (2007) Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25(11):1329–1333

    PubMed  Article  Google Scholar 

  116. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE (1994) Risks of cancer in BRCA1-mutation carriers. Breast cancer linkage consortium. Lancet 343(8899):692–695

    PubMed  CAS  Article  Google Scholar 

  117. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130

    PubMed  CAS  Article  Google Scholar 

  118. Robson ME (2002) Clinical considerations in the management of individuals at risk for hereditary breast and ovarian cancer. Cancer Control 9(6):457–465

    PubMed  Google Scholar 

  119. Thompson D, Easton DF (2002) Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94(18):1358–1365

    PubMed  CAS  Article  Google Scholar 

  120. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91(15):1310–1316, 1999

  121. Narod SA (2010) BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin Oncol 7(12):702–707

    PubMed  CAS  Article  Google Scholar 

  122. Metcalfe K, Gershman S, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, Olopade OI, Domchek S, McLennan J, Eisen A et al (2011) Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 104(9):1384–1392

    PubMed  CAS  Article  Google Scholar 

  123. Metcalfe K, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, Olopade OI, Domchek S, Eisen A, Foulkes WD, Rosen B et al (2011) Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 127(1):287–296

    PubMed  CAS  Article  Google Scholar 

  124. Da Silva L, Lakhani SR (2010) Pathology of hereditary breast cancer. Mod Pathol 23(Suppl 2):S46–S51

    PubMed  Article  CAS  Google Scholar 

  125. Metcalfe KA, Snyder C, Seidel J, Hanna D, Lynch HT, Narod S (2005) The use of preventive measures among healthy women who carry a BRCA1 or BRCA2 mutation. Fam Cancer 4(2):97–103

    PubMed  Article  Google Scholar 

  126. Narod S, Lynch H, Conway T, Watson P, Feunteun J, Lenoir G (1993) Increasing incidence of breast cancer in family with BRCA1 mutation. Lancet 341(8852):1101–1102

    PubMed  CAS  Article  Google Scholar 

  127. King MC, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302(5645):643–646

    PubMed  CAS  Article  Google Scholar 

  128. Foulkes WD, Brunet JS, Wong N, Goffin J, Chappuis PO (2002) Change in the penetrance of founder BRCA1/2 mutations? A retrospective cohort study. J Med Genet 39(6):407–409

    PubMed  CAS  Article  Google Scholar 

  129. Jernstrom H, Lubinski J, Lynch HT, Ghadirian P, Neuhausen S, Isaacs C, Weber BL, Horsman D, Rosen B, Foulkes WD et al (2004) Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 96(14):1094–1098

    PubMed  CAS  Article  Google Scholar 

  130. Kotsopoulos J, Lubinski J, Lynch HT, Neuhausen SL, Ghadirian P, Isaacs C, Weber B, Kim-Sing C, Foulkes WD, Gershoni-Baruch R et al (2005) Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer Causes Control 16(6):667–674

    PubMed  Article  Google Scholar 

  131. Kotsopoulos J, Narod SA (2005) Towards a dietary prevention of hereditary breast cancer. Cancer Causes Control 16(2):125–138

    PubMed  Article  Google Scholar 

  132. Nkondjock A, Ghadirian P, Kotsopoulos J, Lubinski J, Lynch H, Kim-Sing C, Horsman D, Rosen B, Isaacs C, Weber B et al (2006) Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Int J Cancer 118(1):103–107

    PubMed  CAS  Article  Google Scholar 

  133. Kowalska E, Narod SA, Huzarski T, Zajaczek S, Huzarska J, Gorski B, Lubinski J (2005) Increased rates of chromosome breakage in BRCA1 carriers are normalized by oral selenium supplementation. Cancer Epidemiol Biomarkers Prev 14(5):1302–1306

    PubMed  CAS  Article  Google Scholar 

  134. Kotsopoulos J, Chen Z, Vallis KA, Poll A, Ghadirian P, Kennedy G, Ainsworth P, Narod SA (2010) Toenail selenium status and DNA repair capacity among female BRCA1 mutation carriers. Cancer Causes Control 21(5):679–687

    PubMed  Article  Google Scholar 

  135. Kotsopoulos J, Olopado OI, Ghadirian P, Lubinski J, Lynch HT, Isaacs C, Weber B, Kim-Sing C, Ainsworth P, Foulkes WD et al (2005) Changes in body weight and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 7(5):R833–R843

    PubMed  CAS  Article  Google Scholar 

  136. Kotsopoulos J, Sukiennicki G, Muszyńska M, Gackowski D, Kąklewski K, Durda K, Jaworska K, Huzarski T, Gronwald J, Byrski T, Ashuryk O, Dębniak T, Tołoczko-Grabarek A, Stawicka M, Godlewski D, Oliński R, Jakubowska A, Narod SA, Lubinski J (2012) Plasma micronutrients, trace elements, and breast cancer in BRCA1 mutation carriers: an exploratory study Cancer Causes Control 23(7):1065–1974

    Google Scholar 

  137. Toffoli G, Cernigoi C, Russo A, Gallo A, Bagnoli M, Boiocchi M (1997) Overexpression of folate binding protein in ovarian cancers. Int J Cancer 74(2):193–198

    PubMed  CAS  Article  Google Scholar 

  138. Kelemen LE (2006) The role of folate receptor alpha in cancer development, progression and treatment: cause, consequence or innocent bystander? Int J Cancer 119(2):243–250

    PubMed  CAS  Article  Google Scholar 

  139. Sellers TA, Vierkant RA, Cerhan JR, Gapstur SM, Vachon CM, Olson JE, Pankratz VS, Kushi LH, Folsom AR (2002) Interaction of dietary folate intake, alcohol, and risk of hormone receptor-defined breast cancer in a prospective study of postmenopausal women. Cancer Epidemiol Biomarkers Prev 11(10 Pt 1):1104–1107

    PubMed  CAS  Google Scholar 

  140. Feigelson HS, Jonas CR, Robertson AS, McCullough ML, Thun MJ, Calle EE (2003) Alcohol, folate, methionine, and risk of incident breast cancer in the American cancer society cancer prevention study II nutrition cohort. Cancer Epidemiol Biomarkers Prev 12(2):161–164

    PubMed  CAS  Google Scholar 

  141. Baglietto L, English DR, Gertig DM, Hopper JL, Giles GG (2005) Does dietary folate intake modify effect of alcohol consumption on breast cancer risk? Prospective cohort study. BMJ 331(7520):807

    PubMed  CAS  Article  Google Scholar 

  142. Duffy CM, Assaf A, Cyr M, Burkholder G, Coccio E, Rohan T, McTiernan A, Paskett E, Lane D, Chetty VK (2009) Alcohol and folate intake and breast cancer risk in the WHI observational study. Breast Cancer Res Treat 116(3):551–562

    PubMed  CAS  Article  Google Scholar 

  143. Kabat GC, Miller AB, Jain M, Rohan TE (2008) Dietary intake of selected B vitamins in relation to risk of major cancers in women. Br J Cancer 99(5):816–821

    PubMed  CAS  Article  Google Scholar 

  144. Xu X, Gammon MD, Wetmur JG, Bradshaw PT, Teitelbaum SL, Neugut AI, Santella RM, Chen J (2008) B-vitamin intake, one-carbon metabolism, and survival in a population-based study of women with breast cancer. Cancer Epidemiol Biomarkers Prev 17(8):2109–2116

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge Shaidah Deghan Manshadi for contributing the summary table of the prospective literature on folate and breast cancer.

Author information

Affiliations

  1. Women’s College Research Institute, Women’s College Hospital, 790 Bay Street, 7th Floor, Room 710, Toronto, ON, M5G IN8, Canada

    Joanne Kotsopoulos & Steven A. Narod

  2. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

    Joanne Kotsopoulos & Steven A. Narod

  3. Departments of Medicine and Nutritional Sciences, University of Toronto, Toronto, ON, Canada

    Young-In Kim

  4. The Keenan Research Center at the Li Ka Shing Knowledge Institute, St. Michael’s Hopsital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada

    Young-In Kim

  5. Division of Gastroenterology, St. Michael’s Hospital, Toronto, ON, Canada

    Young-In Kim

Authors
  1. Joanne Kotsopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Young-In Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steven A. Narod
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joanne Kotsopoulos.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kotsopoulos, J., Kim, YI. & Narod, S.A. Folate and breast cancer: what about high-risk women? . Cancer Causes Control 23, 1405–1420 (2012). https://doi.org/10.1007/s10552-012-0022-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-012-0022-y

Keywords

  • Folate
  • Breast cancer
  • High risk