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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Presentation Transcript
slide2
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
slide3
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
slide4

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
slide7

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
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

slide15

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

slide17
Animal Studies: Isoflavonoids and Mammary Tumors

Study ResultsStudy Results

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

slide18

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

1 1.00 -

Total 2 0.75 (0.60-0.93)

soy 3 0.69 (0.55-0.87)

foods 4 0.69 (0.55-0.86)

5 0.51 (0.41-0.65)

p-trend <0.01

slide22
Cohort Studies of Soy and Breast Cancer

Reference Populations Cases ExposureRR

Nomura, 1978 Japanese in HI 86 Husbands diet Null

Hirayama, 1985 Japan - miso 0.46

Key, 1999 Japan 427 tofu, miso Null

slide23
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 N Duration: Months Result

Cassidy, 1994 6 1  FSH, LH

follicular E2

Duncan, 1999 14 3 FSH, LH

Martini, 1999 36 2 No change

Lu, 2000 8 1 shifted metabolism to more favorable estrogens metabolites

Lu, 2000 10 1  progesterone levels

Wu, 2000 20 7  luteal E2 only in 10 Asian women

cont d
Cont’d

Reference N Duration: Months Result

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

Xu, 2000 18 9 shifted 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

slide29
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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