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The Role of Phytoestrogens in Cancer Etiology. Susan E. McCann, PhD, RD Department of Epidemiology Division of Cancer Prevention and Population Sciences Roswell Park Cancer Institute susan.mccann@roswellpark.org. What are phytoestrogens?.

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the role of phytoestrogens in cancer etiology

The Role of Phytoestrogens in Cancer Etiology

Susan E. McCann, PhD, RD

Department of Epidemiology

Division of Cancer Prevention and Population Sciences

Roswell Park Cancer Institute

susan.mccann@roswellpark.org

what are phytoestrogens
What are phytoestrogens?

phy·to·es·tro·gen (plural phy·to·es·tro·gens) noun

Plant sterol: any one of a group of sterols found in plants that can have an effect on the body like that of a hormone. Soybeans and their products contain phytoestrogens.

sources of exogenous estrogen exposure
Sources of Exogenous Estrogen Exposure

Dietary Estrogens

Synthetic

Contaminants

Naturally Occurring

Growth

Promoters

Xeno

estrogens

Lignans

Others

Isoflavonoids

(diethy

lstilboestrol)

Coumestans

Isoflavones

(DDT, PCB)

classification of phytoestrogens
Classification of phytoestrogens
  • Isoflavones
    • Genistein (plant precursor biochanin A)
    • Daidzein (plant precursor formononetin)
  • Lignans
    • Enterolactone (plant precursor matairesinol)
    • Enterodiol (plant precursor secoisolariciresinol )
  • Coumestans
food sources isoflavones
Food Sources-Isoflavones
  • Soybeans
    • Soy meal
    • Soy grits
    • Soy flour
    • Tofu, fermented soy products (miso, etc)
    • Soy milk
  • Lentils
  • Dried beans (haricot, broad, kidney, lima)
  • Chickpeas
  • Processed foods (lunch meats, meal replacement beverages, donuts)
food sources lignans
Food Sources-Lignans
  • Flaxseed
  • Whole grain cereals (wheat, wheat germ, barley, hops, rye, rice, brans, oats)
  • Fruits, vegetables, seeds (cherries, apples, pears, stone fruits, sunflower seeds, carrots, fennel, onion, garlic)
  • Beer from hops, bourbon from corn
food sources coumestans
Food Sources-Coumestans
  • Alfalfa sprouts
  • Soybean sprouts
mean urinary excretion of phytoestrogens among different populations

18000

Mean urinary excretion of phytoestrogens among different populations

16000

14000

12000

10000

8000

6000

4000

2000

0

Daidzein

Japanese Women

Finnish Omnivores

Finnish Vegetarians

Enterolactone

Oriental Immigrants

American Omnivores

Finnish Breast Cancer

American Vegetarians

American Macrobiotics

Enterodiol

Adapted from Adlercreutz Bailliere’s Clinical Endocrinology and Metabolism 1998;12(4):605-623

chemical structure lignans
Chemical Structure-Lignans

Enterolactone

Matairesinol

Secoisolariciresinol

Enterodiol

potential mechanisms of action
Potential mechanisms of action
  • Competitive inhibition of endogenous estrogen
  • Stimulation of sex hormone binding globulin synthesis
  • Inhibition of angiogenesis and cell cycle progression
  • Additional anticarcinogenic effects:
    • Aromatase enzyme inhibition
    • Antioxidant properties
potential mechanisms of action1
Potential mechanisms of action
  • At high concentrations, genistein inhibits proliferation of ER-positive MCF-7 breast cancer cell lines
  • At low concentrations, however, genistein stimulates proliferation. Also competes with estradiol for ER binding and stimulates expression of pS2 mRNA
  • Similar stimulatory effects have been reported for daidzein, equol, and enterolactone
animal studies
Animal studies
  • Reproductive disturbances in livestock grazing on clover
  • Isoflavone-stimulated uterine hypertrophy in lab animals
  • Decreased breast tumor proliferation in soy-fed animals
epidemiologic evidence
Epidemiologic evidence
  • Ecologic
    • Populations with high soy food intake tend to have lower rates of breast, prostate, and colon cancer
    • Migrant populations (presumably adapting western diet) tend to develop cancer rates of adopted country
    • Specific population subgroups, e.g., vegetarians tend to have higher phytoestrogen intakes and lower cancer rates
slide19

Analytic studies: Phytoestrogens and hormone sensitive cancers

Phytoestrogen

Cancer

Study

Study design

OR

(95% CI)

Den Tonkelaar

Urinary genistein

Urinary enterlactone

Breast

0.83 (0.46-1.51)

1.43 (0.79-2.59)

Prospective

Urinary enterlactone

Pietinen

Breast

Prospective

0.38 (0.18-0.77)

Breast

Urinary equol

Urinary enterlactone

0.27 (0.10-0.69)

0.36 (0.15-0.86)

Ingram

Case-control

Horn-Ross

Case-control

FFQ isoflavones

FFQ lignans

Breast

0.92 (0.72-1.2)

1.1 (0.89-1.5)

FFQ daidzein

FFQ coumestrol

Case-control

Prostate

0.57 (0.31-1.05)

0.48 (0.25-0.94)

Strom

slide20
Odds ratios and 95% confidence intervals for risk of breast cancer associated with dietary lignan intake, Western New York Diet Study

Odds ratio

(95% confidence interval)

Lignans, mcg/d

Cases

(n)

Controls

(n)

Premenopausal

Low (60-460)

136

103

1.00

Medium (460-670)

98

109

0.70 (0.47-1.03)

High (670-2480)

67

104

0.49 (0.32-0.75)

Postmenopausal

173

164

1.00

Low (60-460)

Medium (460-670)

139

167

0.75 (0.55-1.04)

High (670-2480)

127

163

0.72 (0.51-1.02)

slide21
Odds ratios and 95% confidence intervals for risk of ovarian cancer associated with dietary lignan intake, WNYDS

Lignans, mcg/d

Odds ratio

(95% confidence interval)

Cases

(n)

Controls

(n)

< 304

31

139

1.00

304-408

21

139

0.59 (0.32-1.11)

408-536

30

140

0.81 (0.46-1.46)

536-708

26

139

0.74 (0.41-1.37)

> 708

16

139

0.43 (0.21-0.85)

slide22
Odds ratios and 95% confidence intervals for risk of breast cancer associated with dietary lignan intake by CYP17 genotype, WNYDS

Lignans, mcg/d

Odds ratio

(95% confidence interval)

Cases

(n)

Controls

(n)

Premenopausal

A1A2 and A2A2

23

14

1.00

Low (130-500)

10

9

0.50 (0.14-1.80)

Medium (500-690)

High (690-2110)

5

15

0.12 (0.03-0.50)

A1A1

Low (130-500)

23

19

0.67 (0.25-1.81)

Medium (500-690)

17

15

0.59 (0.20-1.73)

High (690-2110)

18

14

0.71 (0.24-2.08)

slide23
Odds ratios and 95% confidence intervals for risk of breast cancer associated with dietary lignan intake by CYP17 genotype, WNYDS

Lignans, mcg/d

Odds ratio

(95% confidence interval)

Cases

(n)

Controls

(n)

Postmenopausal

A1A2 and A2A2

1.00

Low (130-500)

22

15

0.58 (0.23-1.48)

20

23

Medium (500-690)

17

17

0.61 (0.22-1.69)

High (690-2110)

A1A1

Low (130-500)

19

14

1.05 (0.39-2.87)

Medium (500-690)

15

14

0.59 (0.21-1.67)

High (690-2110)

19

18

0.62 (0.23-1.71)

future directions
Future directions
  • Much of the epidemiologic literature is supportive of a beneficial effect of phytoestrogens in cancer prevention
  • Biologic mechanisms need to be better elucidated
  • Methods of phytoestrogen quantification need to be improved
  • Genetic susceptibility may play an important role