Breast Cancer Research and Treatment

, Volume 118, Issue 3, pp 553–563 | Cite as

Dietary intake of isoflavones and breast cancer risk by estrogen and progesterone receptor status

  • Min ZhangEmail author
  • Hongjian Yang
  • C. D’Arcy J. Holman


Epidemiological and experimental studies suggest that isoflavones may protect against breast cancer by acting as estrogen agonists or antagonists. A case-control study was conducted in southeast China in 2004–2005 to examine the association between dietary isoflavone intake and breast cancer risk by estrogen receptor (ER) and progesterone receptor (PR) status. The incident cases were 756 female patients with histologically confirmed breast cancer. The 1,009 age-matched controls were healthy women randomly recruited from outpatient breast clinics. We assessed isoflavone intake by face-to-face interview using a validated and reliable food-frequency questionnaire and obtained tumor ER and PR status from pathologic reports. Compared with women in the lowest intake quartiles, those in the highest quartile of total isoflavone intake had a reduced risk of all receptor status subtypes of breast cancer with a dose-response relationship. The adjusted ORs (95% CIs) were 0.39 (0.27–0.58) for ER+, 0.32 (0.21–0.49) for ER−, 0.43 (0.29–0.64) for PR+, and 0.30 (0.19–0.45) for PR− (P for trend <0.001). These inverse associations existed in both pre- and post-menopausal women after stratification. Stronger evidence of a protective effect of high isoflavone intake was observed for breast cancer tumors with concordant rather than discordant receptor status; i.e., those with ER+/PR+ (OR 0.39, 0.26–0.59) and ER−/PR− (OR 0.28, 0.17–0.44). The finding that isoflavones protect against all tumor subtypes of breast cancer have biological plausibility, being supported by evidence from experimental studies. Future studies are required to fully understand the complex regulation of isoflavone on breast cancer by tumor hormone status.


Breast cancer Dietary isoflavones Estrogen receptor Progesterone receptor 



The authors acknowledge with gratitude the participation of the Chinese women as subjects. We are grateful for the collaboration received from the participating hospitals and their staff. The first author is supported through a postdoctoral fellowship from the National Health and Medical Research Council (Australia, ID 303292).


  1. 1.
    Shu XO, Jin F, Dai Q et al (2001) Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. Cancer Epidemiol Biomarkers Prev 10:483–488PubMedGoogle Scholar
  2. 2.
    Iwasaki M, Inoue M, Otani T et al (2008) Plasma isoflavone level and subsequent risk of breast cancer among Japanese women: a nested case-control study from the Japan Public Health Center-based prospective study group. J Clin Oncol 26:1677–1683. doi: 10.1200/JCO.2007.13.9964 CrossRefPubMedGoogle Scholar
  3. 3.
    Wu AH, Koh WP, Wang R et al (2008) Soy intake and breast cancer risk in Singapore Chinese Health Study. Br J Cancer 99:196–200. doi: 10.1038/sj.bjc.6604448 CrossRefPubMedGoogle Scholar
  4. 4.
    Peeters PH, Keinan-Boker L, van der Schouw YT et al (2003) Phytoestrogens and breast cancer risk. Review of the epidemiological evidence. Breast Cancer Res Treat 77:171–183. doi: 10.1023/A:1021381101632 CrossRefPubMedGoogle Scholar
  5. 5.
    Trock BJ, Hilakivi-Clarke L, Clarke R (2006) Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst 98:459–471PubMedCrossRefGoogle Scholar
  6. 6.
    Zava DT, Dollbaum CM, Blen M (1998) Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med 217:369–378PubMedGoogle Scholar
  7. 7.
    Tham DM, Gardner CD, Haskell WL (1998) Clinical review 97: potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 83:2223–2235. doi: 10.1210/jc.83.7.2223 CrossRefPubMedGoogle Scholar
  8. 8.
    Banerjee S, Li Y, Wang Z et al (2008) Multi-targeted therapy of cancer by genistein. Cancer Lett 269:226–242. doi: 10.1016/j.canlet.2008.03.052 CrossRefPubMedGoogle Scholar
  9. 9.
    Messina MJ (1999) Legumes and soybeans: overview of their nutritional profiles and health effects. Am J Clin Nutr 70:439S–450SPubMedGoogle Scholar
  10. 10.
    Pike AC, Brzozowski AM, Hubbard RE et al (1999) Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J 18:4608–4618. doi: 10.1093/emboj/18.17.4608 CrossRefPubMedGoogle Scholar
  11. 11.
    Hwang CS, Kwak HS, Lim HJ et al (2006) Isoflavone metabolites and their in vitro dual functions: they can act as an estrogenic agonist or antagonist depending on the estrogen concentration. J Steroid Biochem Mol Biol 101:246–253. doi: 10.1016/j.jsbmb.2006.06.020 CrossRefPubMedGoogle Scholar
  12. 12.
    Lu LJ, Anderson KE, Grady JJ et al (2000) Decreased ovarian hormones during a soya diet: implications for breast cancer prevention. Cancer Res 60:4112–4121PubMedGoogle Scholar
  13. 13.
    Vanden Berghe W, Dijsselbloem N et al (2006) Attenuation of mitogen- and stress-activated protein kinase-1-driven nuclear factor-kappaB gene expression by soy isoflavones does not require estrogenic activity. Cancer Res 66:4852–4862. doi: 10.1158/0008-5472.CAN-05-2957 CrossRefGoogle Scholar
  14. 14.
    Lavigne JA, Takahashi Y, Chandramouli GV et al (2008) Concentration-dependent effects of genistein on global gene expression in MCF-7 breast cancer cells: an oligo microarray study. Breast Cancer Res Treat 110:85–98. doi: 10.1007/s10549-007-9705-6 CrossRefPubMedGoogle Scholar
  15. 15.
    Dai Q, Shu XO, Jin F et al (2001) Population-based case-control study of soyfood intake and breast cancer risk in Shanghai. Br J Cancer 85:372–378. doi: 10.1054/bjoc.2001.1873 CrossRefPubMedGoogle Scholar
  16. 16.
    Suzuki T, Matsuo K, Tsunoda N et al (2008) Effect of soybean on breast cancer according to receptor status: a case-control study in Japan. Int J Cancer 123:1674–1680. doi: 10.1002/ijc.23644 CrossRefPubMedGoogle Scholar
  17. 17.
    Hedelin M, Löf M, Olsson M et al (2008) Dietary phytoestrogens are not associated with risk of overall breast cancer but diets rich in coumestrol are inversely associated with risk of estrogen receptor and progesterone receptor negative breast tumors in Swedish women. J Nutr 138:938–945PubMedGoogle Scholar
  18. 18.
    Zhang M, Yang ZY, Binns CW et al (2002) Diet and ovarian cancer risk: a case-control study in China. Br J Cancer 86:712–717. doi: 10.1038/sj.bjc.6600085 CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang M, Binns CW, Lee AH (2005) A quantitative food frequency questionnaire for women in southeast China: development and reproducibility. Asia Pac J Public Health 17:29–35. doi: 10.1177/101053950501700108 CrossRefPubMedGoogle Scholar
  20. 20.
    Whitemore AS, Wu-Willians AH, Lee M et al (1990) Diet, physical activity and colorectal cancer among Chinese in North American and China. J Natl Cancer Inst 82:915–926. doi: 10.1093/jnci/82.11.915 CrossRefGoogle Scholar
  21. 21.
    Institute of Nutrition, Food Hygiene, Chinese Academic of Preventive Medicine (1999) Food composition table (National Representative Values), 1st edn. People’s Health Press, BeijingGoogle Scholar
  22. 22.
    United States Department of Agriculture (2008) USDA database for the isoflavone content of selected foods. Release 2.0. Nutrient data laboratory home page. Accessed 15 Jan 2009
  23. 23.
    Zhang M, Lee AH, Binns CW (2003) Physical activity and epithelial ovarian cancer risk: a case-control study in China. Int J Cancer 105:838–843. doi: 10.1002/ijc.11165 CrossRefPubMedGoogle Scholar
  24. 24.
    Ainsworth BE, Haskell WL, Whitt MC et al (2000) Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 32:S498–S504. doi: 10.1097/00005768-200009001-00009 CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang M, Holman CDJ, Huang JP et al (2007) Green tea and the prevention of breast cancer: a case-control study in Southeast China. Carcinogenesis 28:1074–1078. doi: 10.1093/carcin/bgl252 CrossRefPubMedGoogle Scholar
  26. 26.
    Shao ZM, Alpaugh ML, Fontana JA et al (1998) Genistein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by P21WAF1/CIP1 induction, G2/M arrest, and apoptosis. J Cell Biochem 69:44–54. doi: 10.1002/(SICI)1097-4644(19980401)69:1<44::AID-JCB5>3.0.CO;2-V CrossRefPubMedGoogle Scholar
  27. 27.
    Wagner J, Jiang L, Lehmann L (2008) Phytoestrogens modulate the expression of 17alpha-estradiol metabolizing enzymes in cultured MCF-7 cells. Adv Exp Med Biol 617:625–632. doi: 10.1007/978-0-387-69080-3_65 CrossRefPubMedGoogle Scholar
  28. 28.
    Kramer F, Johnson IT, Doleman JF et al (2008) A comparison of the effects of soya isoflavonoids and fish oil on cell proliferation, apoptosis and the expression of oestrogen receptors alpha and beta in the mammary gland and colon of the rat. Br J Nutr 12:1–8. doi: 10.1017/S0007114508137862 Google Scholar
  29. 29.
    Low YL, Taylor JI, Grace PB et al (2005) Phytoestrogen exposure correlation with plasma estradiol in postmenopausal women in European prospective investigation of cancer and nutrition-norfolk may involve diet-gene interactions. Cancer Epidemiol Biomarkers Prev 14:213–320PubMedGoogle Scholar
  30. 30.
    Low YL, Dunning AM, Dowsett M et al (2007) Phytoestrogen exposure is associated with circulating sex hormone levels in postmenopausal women and interact with ESR1 and NR1I2 gene variants. Cancer Epidemiol Biomarkers Prev 16:1009–1016. doi: 10.1158/1055-9965.EPI-06-0899 CrossRefPubMedGoogle Scholar
  31. 31.
    Wood CE, Register TC, Cline JM (2007) Soy isoflavonoid effects on endogenous estrogen metabolism in postmenopausal female monkeys. Carcinogenesis 28:801–808. doi: 10.1093/carcin/bgl163 CrossRefPubMedGoogle Scholar
  32. 32.
    Ge KY, Zhai FY, Yan HC et al (1995) The dietary and nutritional status of Chinese populations in 1990s. Ying Yang Xue Bao 17:123–134Google Scholar
  33. 33.
    Wu AH, Yu MC, Tseng CC et al (2004) Plasma isoflavone levels versus self-reported soy isoflavone levels in Asian-American women in Los Angeles County. Carcinogenesis 25:77–81. doi: 10.1093/carcin/bgg189 CrossRefPubMedGoogle Scholar
  34. 34.
    Verkasalo PK, Appleby PN, Allen NE et al (2001) Soya intake and plasma concentrations of daidzein and genistein: validity of dietary assessment among eighty British women (Oxford arm of the European prospective investigation into cancer and nutrition). Br J Nutr 86:415–421. doi: 10.1079/BJN2001424 CrossRefPubMedGoogle Scholar
  35. 35.
    Maskarinec G, Singh S, Meng L et al (1998) Dietary soy intake and urinary isoflavone excretion among women from a multiethnic population. Cancer Epidemiol Biomarkers Prev 7:613–619PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Min Zhang
    • 1
    Email author
  • Hongjian Yang
    • 2
  • C. D’Arcy J. Holman
    • 1
  1. 1.School of Population HealthThe University of Western AustraliaPerthAustralia
  2. 2.Department of Breast SurgeryZhejiang Cancer HospitalHangzhouPeople’s Republic of China

Personalised recommendations