Cancer Causes & Control

, 22:1383 | Cite as

Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression

  • Hu Fulan
  • Jiang Changxing
  • Wang Yi Baina
  • Zhang Wencui
  • Lin Chunqing
  • Wang Fan
  • Li Dandan
  • Sun Dianjun
  • Wang Tong
  • Pang DaEmail author
  • Zhao YashuangEmail author
Original paper



To comprehensively summarize the associations between retinol, vitamins A, C, and E and breast cancer, and quantitatively estimate their dose–response relationships.


We searched PubMed, Embase, and Cochrane databases (from January 1982 to 15 March 2011) and the references of the relevant articles in English with sufficient information to estimate relative risk or odds ratio and the 95% confidence intervals, and comparable categories of vitamins. Two reviewers independently extracted data using a standardized form, with any discrepancy adjudicated by the third reviewer.


Overall, 51 studies met the inclusion criteria. Comparing the highest with the lowest intake, total vitamin A intake reduced the breast cancer risk by 17% (pooled OR = 0.83, 95% CI: 0.78–0.88). Further subgroup analysis based on study design did not change the significant reduction. Although the dietary vitamin A, dietary vitamin E, and total vitamin E intake all reduced breast cancer risk significantly when data from all studies were pooled, the results became nonsignificant when data from cohort studies were pooled. The significant association between total retinol intake and breast cancer in all studies became nonsignificant in case–control studies but remain significant in cohort studies. No significant dose–response relationship was observed in the higher intake of these vitamins with reduced breast cancer risk.


Our results indicate that both the total intake of vitamin A and retinol could reduce breast cancer risk. However, associations between other vitamins and breast cancer seem to be limited.


Retinol Vitamin A Vitamin C Vitamin E Breast cancer Meta-analysis 



Thanks J. Love for reviewing the paper.

Conflict of interest

All authors read and approved the final manuscript. None of the authors had any conflicts of interest.

Supplementary material

10552_2011_9811_MOESM1_ESM.doc (1.2 mb)
Supplementary material 1 (DOC 1.17 MB)


  1. 1.
    Buell P (1973) Changing incidence of breast cancer in Japanese-American women. J Natl Cancer Inst 51(5):1479–1483PubMedGoogle Scholar
  2. 2.
    Thomas DB, Karagas MR (1987) Cancer in first and second generation Americans. Cancer Res 47(21):5771–5776PubMedGoogle Scholar
  3. 3.
    Armstrong B, Doll R (1975) Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer 15(4):617–631PubMedCrossRefGoogle Scholar
  4. 4.
    Kelsey JL, Horn-Ross PL (1993) Breast cancer: magnitude of the problem and descriptive epidemiology. Epidemiol Rev 15(1):7–16PubMedGoogle Scholar
  5. 5.
    Altucci L, Gronemeyer H (2001) The promise of retinoids to fight against cancer. Nat Rev Cancer 1(3):181–193PubMedCrossRefGoogle Scholar
  6. 6.
    Aggarwal BB, Sundaram C, Prasad S, Kannappan R (2010) Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol 80(11):1613–1631PubMedCrossRefGoogle Scholar
  7. 7.
    Ullah MF, Khan HY, Zubair H, Shamim U, Hadi SM (2011) The antioxidant ascorbic acid mobilizes nuclear copper leading to a prooxidant breakage of cellular DNA: implications for chemotherapeutic action against cancer. Cancer Chemother Pharmacol 67(1):103–110PubMedCrossRefGoogle Scholar
  8. 8.
    Zhang S, Hunter DJ, Forman MR, Rosner BA, Speizer FE, Colditz GA, Manson JE, Hankinson SE, Willett WC (1999) Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst 91(6):547–556PubMedCrossRefGoogle Scholar
  9. 9.
    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):713–720PubMedGoogle Scholar
  10. 10.
    Bohlke K, Spiegelman D, Trichopoulou A, Katsouyanni K, Trichopoulos D (1999) Vitamins A, C and E and the risk of breast cancer: results from a case-control study in Greece. Br J Cancer 79(1):23–29PubMedCrossRefGoogle Scholar
  11. 11.
    Ronco A, De Stefani E, Boffetta P, Deneo-Pellegrini H, Mendilaharsu M, Leborgne F (1999) Vegetables, fruits, and related nutrients and risk of breast cancer: a case-control study in Uruguay. Nutr Cancer 35(2):111–119PubMedCrossRefGoogle Scholar
  12. 12.
    Adzersen KH, Jess P, Freivogel KW, Gerhard I, Bastert G (2003) Raw and cooked vegetables, fruits, selected micronutrients, and breast cancer risk: a case-control study in Germany. Nutr Cancer 46(2):131–137PubMedCrossRefGoogle Scholar
  13. 13.
    Nissen SB, Tjonneland A, Stripp C, Olsen A, Christensen J, Overvad K, Dragsted LO, Thomsen B (2003) Intake of vitamins A, C, and E from diet and supplements and breast cancer in postmenopausal women. Cancer Causes Control 14(8):695–704PubMedCrossRefGoogle Scholar
  14. 14.
    Levi F, Pasche C, Lucchini F, La Vecchia C (2001) Dietary intake of selected micronutrients and breast-cancer risk. Int J Cancer 91(2):260–263PubMedCrossRefGoogle Scholar
  15. 15.
    Michels KB, Holmberg L, Bergkvist L, Ljung H, Bruce A, Wolk A (2001) Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women. Int J Cancer 91(4):563–567PubMedCrossRefGoogle Scholar
  16. 16.
    Do MH, Lee SS, Jung PJ, Lee MH (2003) Intake of dietary fat and vitamin in relation to breast cancer risk in Korean women: a case-control study. J Korean Med Sci 18(4):534–540PubMedGoogle Scholar
  17. 17.
    Moorman PG, Ricciuti MF, Millikan RC, Newman B (2001) Vitamin supplement use and breast cancer in a North Carolina population. Public Health Nutr 4(3):821–827PubMedCrossRefGoogle Scholar
  18. 18.
    Dorjgochoo T, Shrubsole MJ, Shu XO, Lu W, Ruan Z, Zheng Y, Cai H, Dai Q, Gu K, Gao YT et al (2008) Vitamin supplement use and risk for breast cancer: the Shanghai Breast Cancer Study. Breast Cancer Res Treat 111(2):269–278PubMedCrossRefGoogle Scholar
  19. 19.
    Wang C, Baumgartner RN, Yang D, Slattery ML, Murtaugh MA, Byers T, Hines LM, Giuliano AR, Baumgartner KB (2009) No evidence of association between breast cancer risk and dietary carotenoids, retinols, vitamin C and tocopherols in Southwestern Hispanic and non-Hispanic White women. Breast Cancer Res Treat 114(1):137–145PubMedCrossRefGoogle Scholar
  20. 20.
    Challier B, Perarnau JM, Viel JF (1998) Garlic, onion and cereal fibre as protective factors for breast cancer: a French case-control study. Eur J Epidemiol 14(8):737–747PubMedCrossRefGoogle Scholar
  21. 21.
    Cui Y, Shikany JM, Liu S, Shagufta Y, Rohan TE (2008) Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women’s Health Initiative Observational Study. Am J Clin Nutr 87(4):1009–1018PubMedGoogle Scholar
  22. 22.
    Malin AS, Qi D, Shu XO, Gao YT, Friedmann JM, Jin F, Zheng W (2003) Intake of fruits, vegetables and selected micronutrients in relation to the risk of breast cancer. Int J Cancer 105(3):413–418PubMedCrossRefGoogle Scholar
  23. 23.
    Gaudet MM, Britton JA, Kabat GC, Steck-Scott S, Eng SM, Teitelbaum SL, Terry MB, Neugut AI, Gammon MD (2004) Fruits, vegetables, and micronutrients in relation to breast cancer modified by menopause and hormone receptor status. Cancer Epidemiol Biomarkers Prev 13(9):1485–1494PubMedGoogle Scholar
  24. 24.
    Mannisto S, Pietinen P, Virtanen M, Kataja V, Uusitupa M (1999) Diet and the risk of breast cancer in a case-control study: does the threat of disease have an influence on recall bias? J Clin Epidemiol 52(5):429–439PubMedCrossRefGoogle Scholar
  25. 25.
    Mignone LI, Giovannucci E, Newcomb PA, Titus-Ernstoff L, Trentham-Dietz A, Hampton JM, Willett WC, Egan KM (2009) Dietary carotenoids and the risk of invasive breast cancer. Int J Cancer 124(12):2929–2937PubMedCrossRefGoogle Scholar
  26. 26.
    Sharhar S, Normah H, Fatimah A, Fadilah RN, Rohi GA, Amin I, Cham BG, Rizal RM, Fairulnizal MN (2008) Antioxidant intake and status, and oxidative stress in relation to breast cancer risk: a case-control study. Asian Pac J Cancer Prev 9(2):343–349PubMedGoogle Scholar
  27. 27.
    Nagel G, Linseisen J, van Gils CH, Peeters PH, Boutron-Ruault MC, Clavel-Chapelon F, Romieu I, Tjonneland A, Olsen A, Roswall N et al (2010) Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Breast Cancer Res Treat 119(3):753–765PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang CX, Ho SC, Chen YM, Fu JH, Cheng SZ, Lin FY (2009) Greater vegetable and fruit intake is associated with a lower risk of breast cancer among Chinese women. Int J Cancer 125(1):181–188PubMedCrossRefGoogle Scholar
  29. 29.
    Bonilla-Fernandez P, Lopez-Cervantes M, Torres-Sanchez LE, Tortolero-Luna G, Lopez-Carrillo L (2003) Nutritional factors and breast cancer in Mexico. Nutr Cancer 45(2):148–155PubMedCrossRefGoogle Scholar
  30. 30.
    Potischman N, Swanson CA, Coates RJ, Gammon MD, Brogan DR, Curtin J, Brinton LA (1999) Intake of food groups and associated micronutrients in relation to risk of early-stage breast cancer. Int J Cancer 82(3):315–321PubMedCrossRefGoogle Scholar
  31. 31.
    Lee MM, Chang IY, Horng CF, Chang JS, Cheng SH, Huang A (2005) Breast cancer and dietary factors in Taiwanese women. Cancer Causes Control 16(8):929–937PubMedCrossRefGoogle Scholar
  32. 32.
    Longnecker MP, Newcomb PA, Mittendorf R, Greenberg ER, Willett WC (1997) Intake of carrots, spinach, and supplements containing vitamin A in relation to risk of breast cancer. Cancer Epidemiol Biomarkers Prev 6(11):887–892PubMedGoogle Scholar
  33. 33.
    Howe GR, Hirohata T, Hislop TG, Iscovich JM, Yuan JM, Katsouyanni K, Lubin F, Marubini E, Modan B, Rohan T et al (1990) Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies. J Natl Cancer Inst 82(7):561–569PubMedCrossRefGoogle Scholar
  34. 34.
    Gandini S, Merzenich H, Robertson C, Boyle P (2000) Meta-analysis of studies on breast cancer risk and diet: the role of fruit and vegetable consumption and the intake of associated micronutrients. Eur J Cancer 36(5):636–646PubMedCrossRefGoogle Scholar
  35. 35.
    Alkhenizan A, Hafez K (2007) The role of vitamin E in the prevention of cancer: a meta-analysis of randomized controlled trials. Ann Saudi Med 27(6):409–414PubMedCrossRefGoogle Scholar
  36. 36.
    Berlin JA, Longnecker MP, Greenland S (1993) Meta-analysis of epidemiologic dose-response data. Epidemiology 4(3):218–228PubMedCrossRefGoogle Scholar
  37. 37.
    Chene G, Thompson SG (1996) Methods for summarizing the risk associations of quantitative variables in epidemiologic studies in a consistent form. Am J Epidemiol 144(6):610–621PubMedGoogle Scholar
  38. 38.
    Trock BJ, Hilakivi-Clarke L, Clarke R (2006) Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst 98(7):459–471PubMedCrossRefGoogle Scholar
  39. 39.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560PubMedCrossRefGoogle Scholar
  40. 40.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634PubMedGoogle Scholar
  41. 41.
    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101PubMedCrossRefGoogle Scholar
  42. 42.
    Negri E, La Vecchia C, Franceschi S, D’Avanzo B, Talamini R, Parpinel M, Ferraroni M, Filiberti R, Montella M, Falcini F et al (1996) Intake of selected micronutrients and the risk of breast cancer. Int J Cancer 65(2):140–144PubMedCrossRefGoogle Scholar
  43. 43.
    Graham S, Marshall J, Mettlin C, Rzepka T, Nemoto T, Byers T (1982) Diet in the epidemiology of breast cancer. Am J Epidemiol 116(1):68–75PubMedGoogle Scholar
  44. 44.
    Zaridze D, Lifanova Y, Maximovitch D, Day NE, Duffy SW (1991) Diet, alcohol consumption and reproductive factors in a case-control study of breast cancer in Moscow. Int J Cancer 48(4):493–501PubMedCrossRefGoogle Scholar
  45. 45.
    Katsouyanni K, Willett W, Trichopoulos D, Boyle P, Trichopoulou A, Vasilaros S, Papadiamantis J, MacMahon B (1988) Risk of breast cancer among Greek women in relation to nutrient intake. Cancer 61(1):181–185PubMedCrossRefGoogle Scholar
  46. 46.
    Lee HP, Gourley L, Duffy SW, Esteve J, Lee J, Day NE (1991) Dietary effects on breast-cancer risk in Singapore. Lancet 337(8751):1197–1200PubMedCrossRefGoogle Scholar
  47. 47.
    London SJ, Stein EA, Henderson IC, Stampfer MJ, Wood WC, Remine S, Dmochowski JR, Robert NJ, Willett WC (1992) Carotenoids, retinol, and vitamin E and risk of proliferative benign breast disease and breast cancer. Cancer Causes Control 3(6):503–512PubMedCrossRefGoogle Scholar
  48. 48.
    Qi XY, Zhang AY, Wu GL, Pang WZ (1994) The association between breast cancer and diet and other factors. Asia Pac J Public Health 7(2):98–104PubMedCrossRefGoogle Scholar
  49. 49.
    Levi F, La Vecchia C, Gulie C, Negri E (1993) Dietary factors and breast cancer risk in Vaud, Switzerland. Nutr Cancer 19(3):327–335PubMedCrossRefGoogle Scholar
  50. 50.
    Potischman N, McCulloch CE, Byers T, Nemoto T, Stubbe N, Milch R, Parker R, Rasmussen KM, Root M, Graham S (1990) Breast cancer and dietary and plasma concentrations of carotenoids and vitamin A. Am J Clin Nutr 52(5):909–915PubMedGoogle Scholar
  51. 51.
    Landa MC, Frago N, Tres A (1994) Diet and the risk of breast cancer in Spain. Eur J Cancer Prev 3(4):313–320PubMedCrossRefGoogle Scholar
  52. 52.
    Richardson S, Gerber M, Cenee S (1991) The role of fat, animal protein and some vitamin consumption in breast cancer: a case control study in southern France. Int J Cancer 48(1):1–9PubMedGoogle Scholar
  53. 53.
    Marubini E, Decarli A, Costa A, Mazzoleni C, Andreoli C, Barbieri A, Capitelli E, Carlucci M, Cavallo F, Monferroni N et al (1988) The relationship of dietary intake and serum levels of retinol and beta-carotene with breast cancer. Results of a case-control study. Cancer 61(1):173–180PubMedCrossRefGoogle Scholar
  54. 54.
    La Vecchia C, Decarli A, Franceschi S, Gentile A, Negri E, Parazzini F (1987) Dietary factors and the risk of breast cancer. Nutr Cancer 10(4):205–214PubMedCrossRefGoogle Scholar
  55. 55.
    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):340–348PubMedCrossRefGoogle Scholar
  56. 56.
    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):552–566PubMedGoogle Scholar
  57. 57.
    Iscovich JM, Iscovich RB, Howe G, Shiboski S, Kaldor JM (1989) A case-control study of diet and breast cancer in Argentina. Int J Cancer 44(5):770–776PubMedCrossRefGoogle Scholar
  58. 58.
    Rohan TE, McMichael AJ, Baghurst PA (1988) A population-based case-control study of diet and breast cancer in Australia. Am J Epidemiol 128(3):478–489PubMedGoogle Scholar
  59. 59.
    Rohan TE, Howe GR, Friedenreich CM, Jain M, Miller AB (1993) Dietary fiber, vitamins A, C, and E, and risk of breast cancer: a cohort study. Cancer Causes Control 4(1):29–37PubMedCrossRefGoogle Scholar
  60. 60.
    Verhoeven DT, Assen N, Goldbohm RA, Dorant E, van’t Veer P, Sturmans F, Hermus RJ, van den Brandt PA (1997) Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: a prospective cohort study. Br J Cancer 75(1):149–155PubMedCrossRefGoogle Scholar
  61. 61.
    Kushi LH, Fee RM, Sellers TA, Zheng W, Folsom AR (1996) Intake of vitamins A, C, and E and postmenopausal breast cancer. The Iowa Women’s Health Study. Am J Epidemiol 144(2):165–174PubMedGoogle Scholar
  62. 62.
    Hunter DJ, Manson JE, Colditz GA, Stampfer MJ, Rosner B, Hennekens CH, Speizer FE, Willett WC (1993) A prospective study of the intake of vitamins C, E, and A and the risk of breast cancer. N Engl J Med 329(4):234–240PubMedCrossRefGoogle Scholar
  63. 63.
    Graham S, Zielezny M, Marshall J, Priore R, Freudenheim J, Brasure J, Haughey B, Nasca P, Zdeb M (1992) Diet in the epidemiology of postmenopausal breast cancer in the New York State Cohort. Am J Epidemiol 136(11):1327–1337PubMedGoogle Scholar
  64. 64.
    Shibata A, Paganini-Hill A, Ross RK, Henderson BE (1992) Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements and cancer incidence among the elderly: a prospective study. Br J Cancer 66(4):673–679PubMedCrossRefGoogle Scholar
  65. 65.
    Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE (2005) Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. Jama 294(1):56–65PubMedCrossRefGoogle Scholar
  66. 66.
    Lonn E, Bosch J, Yusuf S, Sheridan P, Pogue J, Arnold JM, Ross C, Arnold A, Sleight P, Probstfield J et al (2005) Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293(11):1338–1347PubMedCrossRefGoogle Scholar
  67. 67.
    Lin J, Cook NR, Albert C, Zaharris E, Gaziano JM, Van Denburgh M, Buring JE, Manson JE (2009) Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. J Natl Cancer Inst 101(1):14–23PubMedGoogle Scholar
  68. 68.
    Gower JD (1988) A role for dietary lipids and antioxidants in the activation of carcinogens. Free Radic Biol Med 5(2):95–111PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Hu Fulan
    • 1
  • Jiang Changxing
    • 2
  • Wang Yi Baina
    • 1
  • Zhang Wencui
    • 1
  • Lin Chunqing
    • 1
  • Wang Fan
    • 1
  • Li Dandan
    • 1
  • Sun Dianjun
    • 2
  • Wang Tong
    • 2
  • Pang Da
    • 3
    Email author
  • Zhao Yashuang
    • 1
    Email author
  1. 1.Department of Epidemiology, Public Health CollegeHarbin Medical UniversityNangang District, HarbinPeople’s Republic of China
  2. 2.Center for Endemic Disease ControlHarbin Medical UniversityHarbinPeople’s Republic of China
  3. 3.Department of Breast SurgeryThird Affiliated Clinical Hospital of Harbin Medical UniversityNangang District, HarbinPeople’s Republic of China

Personalised recommendations