Isoflavonoids and breast cancer risk
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Isoflavonoids and Breast Cancer Risk. Michelle D. Holmes , MD, DrPH. [email protected] 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

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Isoflavonoids and breast cancer risk

Isoflavonoids and Breast Cancer Risk

Michelle D. Holmes, MD, DrPH

[email protected]


Isoflavonoids and breast cancer risk

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


Isoflavonoids and breast cancer risk

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


Isoflavonoids and breast cancer risk

Interests

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.


Overview

Overview

  • 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

    Structure and Food Sources

    • Flavonoids are plant-derived polyphenols

    • Isoflavonoid subgroup weakly estrogenic

      • examples: genistein, daidzein, equol


    Isoflavonoids and breast cancer risk

    Structure of Isoflavonoids and Estradiol

    Messina, Nutr Cancer 1994;21:113


    Intake

    Intake

    • 1 gram soybeans  2 mg isoflavonoids

    • Typical daily intake:

      • Asian countries  50-100 mg

      • Western countries  <1 mg


    International data

    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


    Estrogenic effects

    EstrogenicEffects

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

    • Produce estrogenic responses in mice

    • May be antagonistic by competing for estrogen receptors


    Isoflavonoids and breast cancer risk

    What is the evidence that isoflavonoids prevent breast cancer?


    In vitro studies of genistein

    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 genistein1

    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


    Isoflavonoids and breast cancer risk

    Genistein as an Angiogenesis Inhibitor

    5

    4

    3

    Length,

    mm

    2

    1

    0

    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 genistein2

    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


    Isoflavonoids and breast cancer risk

    Animal Studies: Isoflavonoids and Mammary Tumors

    StudyResultsStudyResults

    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


    Isoflavonoids and breast cancer risk

    Mammary Tumor Incidence in Rats

    Casein

    SPI+Met

    SPI

    Percent of rats with mammary tumors

    Weeks after NMU administration

    100

    Casein

    NMU

    INJECTION

    DIET

    CHANGE

    10

    8

    0

    5

    26


    Adolescent soy intake and breast cancer risk shu cebp 2001

    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

    Adolescent Diet

    Quintile of IntakeRR95% CI

    11.00-

    Total20.75(0.60-0.93)

    soy30.69(0.55-0.87)

    foods40.69(0.55-0.86)

    50.51(0.41-0.65)

    p-trend <0.01


    Isoflavonoids and breast cancer risk

    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


    Isoflavonoids and breast cancer risk

    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

    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


    Cont d

    Cont’d

    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

    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

    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 proliferation1

    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

    -Results:

    - High soy  density

    - High soy  breast size


    Isoflavonoids and breast cancer risk

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

    Evidence:

    • 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

    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

    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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