Isoflavonoids and breast cancer risk
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Isoflavonoids and Breast Cancer Risk. Michelle D. Holmes , MD, DrPH. Learning Objectives To understand the structure and food sources of isoflavonoids To understand the different types of research studies supporting an isoflavonoid-breast cancer link

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Isoflavonoids and Breast Cancer Risk

Michelle D. Holmes, MD, DrPH

Learning Objectives

  • To understand the structure and food sources of isoflavonoids

  • To understand the different types of research studies supporting an isoflavonoid-breast cancer link

  • To understand recommendations for soy intake for average risk women and also for women with a personal or family history of breast cancer

Performance Objectives

  • Students should be able to evaluate new research findings on isoflavonoids and breast cancer in light of the previous evidence

  • Be able to make recommendations on soy intake for average risk and high risk women based on the weight of present research evidence


I was trained as a primary care physician and have always had a strong interest in public health. I have always been interested in the impact of diet, exercise, and other lifestyle factors on chronic disease.

I became an epidemiologist in mid career. My research focus is diet and cancer.


  • Structure, food sources of isoflavonoids

  • Different types of studies supporting a isoflavonoid-breast cancer link

    • international

    • in vitro and animal

    • case-control and cohort

    • trials

  • Recommendations

  • Structure and Food Sources

    • Flavonoids are plant-derived polyphenols

    • Isoflavonoid subgroup weakly estrogenic

      • examples: genistein, daidzein, equol

    Structure of Isoflavonoids and Estradiol

    Messina, Nutr Cancer 1994;21:113


    • 1 gram soybeans  2 mg isoflavonoids

    • Typical daily intake:

      • Asian countries  50-100 mg

      • Western countries  <1 mg

    International Data

    • Asian countries: high soy intake and lower breast cancer rates

    • Japanese migrants assume host country rates of breast cancer

    • Western diet: minimal soy

    • Vegetarians in the US have lower cancer rates


    • Weakly estrogenic 1/1000th -1/100,000th the strength of estradiol

    • Produce estrogenic responses in mice

    • May be antagonistic by competing for estrogen receptors

    What is the evidence that isoflavonoids prevent breast cancer?

    In vitro studies of Genistein

    • Inhibits Tyrosine Kinase (important for cell proliferation, transformation)

      Markovits J, 1989, Cancer Res

      Linnasier C, 1993, Biochemical Pharmacology

    • Inhibits DNA topoisomerase II (causes DNA breaks)

      Markovits J, 1989, Cancer Res

    In vitro Studies of Genistein

    • Induces Differentiation

      Constantinou A, 1990, Cancer Res

      Kando K, 1991, Cancer Res

      Watanabe T, 1993, Cancer Res

    • Inhibits Angiogenesis

      Fotis T, 1993, Proc Natl Acad Sci

    Genistein as an Angiogenesis Inhibitor









    bFGF, µg/L 0 30 30 30 30

    genistein, µmol/L 0 0 50 100 200

    Fotsis,J. Nutr 1995,125;790S

    In vitro Studies of Genistein

    • Affects Growth of ER+ human breast cancer cells:

      • Stimulates at low dose

      • Inhibits at high dose

      Miodini P, 1999, Br J Cancer

      Nakagawa H, 2000, J Cancer Res Clin Oncol

    • Inhibits growth of ER- human breast cancer cells

      Shen F, 1999, Anticancer Res

    Animal Studies: Isoflavonoids and Mammary Tumors


    Carroll, 1975 Null Barnes, 1990 

    Troll, 1980  Barnes, 1990 

    Gridley, 1983 Null Constantinou 1998 

    Hawrylewics, 1989  Fritz, 1998 

    Hsueh, 1989 Null Hilakivi-Clarke 1999 

    Baggott, 1990  Hakkak, 2000 

    Santell, 2000 Null

    Mammary Tumor Incidence in Rats




    Percent of rats with mammary tumors

    Weeks after NMU administration












    Adolescent Soy Intake and Breast Cancer RiskShu, CEBP 2001

    • 1459 cases and 1556 controls in China

    • Diet age 13-15 by interview

    • Separately asked mothers of 296 cases and 359 controls

    Adolescent Diet

    Quintile of IntakeRR95% CI






    p-trend <0.01

    Cohort Studies of Soy and Breast Cancer

    Reference Populations Cases ExposureRR

    Nomura, 1978 Japanese in HI86 Husbands dietNull

    Hirayama, 1985 Japan- miso0.46

    Key, 1999 Japan 427 tofu, misoNull

    Problem:Assessment of dietary isoflavonoids is difficult in epidemiological studies

    Amoung U.S women, large amounts of isoflavonoids come from “hidden” soy:

    - soy protein isolate

    - soy concentrate

    - soy flour (white bread and donuts)

    Frequent in processed foods and is brand-dependent

    Horn-Ross, CCC, 2000

    Trials: Does Soy Lower Estrogens?

    Reference NDuration: MonthsResult

    Cassidy, 1994 61  FSH, LH

    follicular E2

    Duncan, 1999 143 FSH, LH

    Martini, 1999 362 No change

    Lu, 2000 81 shifted metabolism to more favorable estrogens metabolites

    Lu, 2000 101  progesterone levels

    Wu, 2000 207  luteal E2 only in 10 Asian women


    Reference NDuration: Months Result

    Duncan, 2000 14- estrogens only in 5 equol excreters regardless of soy intake

    Xu, 2000 18 9shifted metabolism to more favorable estrogen metabolites

    RCTs of Soy and Estrogen

    Nagata, 1998 Hi/Low SoyDuration/monthsResults

    31/29 2 E2 and estrone

    but N.S

    Does Soy Increase Breast cell Proliferation?

    McMichael-Phillips, AJCN, 1998

    - RCT of 48 premenopausal women scheduled for breast biopsy

    - 2 weeks soy supplemented diet

    - Normal breast tissue labelled for markers of proliferation

    - High soy group had  proliferation

    Hargreoues, J Clin Endoc Metab, 1999

    - Sequential trial of 84 premenopausal women

    - Underwent nipple aspiration (NA)

    -  markers of proliferation in NA fluid after soy intake

    Does Soy Increase Breast cell Proliferation?

    Maskarinec, Br Cancer Res, 2001

    - Cross-sectional study in HI

    - Soy intake assessed by questionnaire vs. density on mammogram


    - High soy  density

    - High soy  breast size

    Hypothesis: Could early-life soy exposure induce early breast maturation making it resistant to carcinogenesis?


    • Isoflavonoids promote differentiation in vitro

    • Some animal studies have shown large effects with pre-pubertal exposure

    • International differences persist until 2nd generation

    • Shu, 2001 case-control study of adolescent soy intake

    Isoflavonoids and Breast Cancer Risk: Conclusions

    • Biologically plausible:

      • estrogenic effects

      • effects on angiogenesis, cell growth

    • Animal data suggestive

    • Epidemiologic data suggestive but cohort studies are poor

    • Adverse effects possible, balance between proestrogen/anti estrogen effects is unclear

    What should clinicians recommend?

    • Modest intake of soy products similar to Asian cultures (1-2 servings/day) unlikely to be harmful in the average women and may be helpful

    • Many clinicians, NCI website suggest that high risk women avoid soy:

      • Women with breast cancer, particularly ER+ or on tamoxifen

      • Women with a strong family history

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