Diet, Lifestyle and Breast Cancer Risk Barbour S Warren, PhD Program on Breast Cancer & Environmental Risk Factors Sprecher Institute for Comparative Cancer Research

1) Biology of the development of breast cancer 2) Risk factors for breast cancer (in light of the biology) 3) Potential for modification of breast cancer risk Overview

Initiation Promotion Progression Proliferation Independence Stages of Cancer Formation Unspecialized Cell Initiated Cell Benign Tumor Malignant Tumor Latency Period, 20 years or more Mutation Cancer Gene Mutation Invade & Spread

Proliferation

Independence

Mutation

Cancer Gene

Mutation

Invade & Spread

Development of the Breast Ductal Tree Differentiation Occurs With Pregnancy 2 years After Puberty After Pregnancy Proliferation Proliferation Differentiation Proliferation Birth

Proliferation and Differentiation A Ying-Yang Relationship in Breast Cancer Formation Proliferation Differentiation

Proliferation – Cell Multiplication Essential for normal growth & development of the breast Important factor in breast cancer Allows less time for mutation repair The key event during tumor promotion

Allows less time for mutation repair

The key event during tumor promotion

Proliferation Decreases Mutation Repair Time For Repair Before DNA Duplication Little Time For Repair Before DNA Duplication Within a Cell In Each Daughter Cell In Each Daughter Cell

Proliferation – Cell Multiplication Essential for normal growth & development of the breast Important factor in breast cancer Decreases time for mutation repair Estrogen and other reproductive hormones cause proliferation of breast cells Key event during the tumor promotion Proliferating cells at risk to undergo initiation, promotion and progression stages of cancer formation

Decreases time for mutation repair

Key event during the tumor promotion

Proliferation and Differentiation A Ying-Yang Relationship in Breast Cancer Formation Proliferation Differentiation

Development of the Breast Ductal Tree Differentiation Occurs With Pregnancy 2 years After Puberty After Pregnancy Birth Lobules

Puberty Sexual Maturity Pregnancy Lactation Terminal End Bud Lobule Type 1 Lobule Type 2 Lobule Type 3 Lobule Type 4 60 22 4 1 Level of Proliferation Differentiation of A Breast Lobule Growth to a Functioning Entity

Cells at Risk Are Analogous to a Target’s Bull’s-eye A larger number of cells at risk produces a larger (and easier to hit) bull’s-eye. Carcinogens

A larger number of cells at risk produces a larger (and easier to hit) bull’s-eye.

Interaction of a Cell at Risk with a Carcinogen Can Produce an Initiated Cell An initiated cell is the first step in formation of a tumor For an initiated cell to become a tumor both the Promotion and Progression stages have to occur The larger the number of initiated cells the higher the breast cancer risk

An initiated cell is the first step in formation of a tumor

For an initiated cell to become a tumor both the Promotion and Progression stages have to occur

The larger the number of initiated cells the higher the breast cancer risk

Estrogen Estrogen acts with other reproductive to increase proliferation in the breast Proliferation is linked to: Tumor promotion Decreased mutation repair Increases in the number of ‘cells at risk’ Estrogen may be metabolized to form a carcinogen which could cause mutations and form initiated cells Relation to Breast Cancer Risk

Estrogen acts with other reproductive to increase proliferation in the breast

Proliferation is linked to:

Tumor promotion

Decreased mutation repair

Increases in the number of ‘cells at risk’

How Is The Risk Of Breast Cancer Increased? Larger number of mutations Increased initiation & progression 2) Greater level of proliferation Increased promotion & progression 3) Increase number of cells at risk to become breast cancer 4) Increase the time of high risk for tumor initiation

Larger number of mutations

Increased initiation & progression

Vegetables and Fruits Eating large amounts of vegetables, in general, may be linked to a small decrease in breast cancer risk Supplements do not appear to offer the same protection as food Evidence is stronger for a decrease in risk with dark green and yellow vegetables Eating fruit, in general, is unrelated to breast cancer risk Vegetables may have a greater effect for women with a family history of breast cancer

Eating large amounts of vegetables, in general, may be linked to a small decrease in breast cancer risk

Supplements do not appear to offer the same protection as food

Evidence is stronger for a decrease in risk with dark green and yellow vegetables

Eating fruit, in general, is unrelated to breast cancer risk

Vegetables may have a greater effect for women with a family history of breast cancer

Anti-cancer Agents in Vegetables & Fruits Inhibition of Initiation Stage of Cancer Formation

Initiation Promotion Progression Proliferation Independence Stages of Cancer Formation Unspecialized Cell Initiated Cell Benign Tumor Malignant Tumor Latency Period, 20 years or more Mutation Cancer Gene Mutation Invade & Spread

Proliferation

Independence

Mutation

Cancer Gene

Mutation

Invade & Spread

Anti-cancer Agents in Vegetables & Fruits Inhibition of Initiation Stage of Cancer Formation Block carcinogen activation Flavonoids and isoflavonoids Coumarins Isothiocyanates in cruciferous vegetables Organosulfur compounds in garlic & onions Enhance carcinogen detoxification Antioxidants in plants Isothiocyanates in cruciferous vegetables Organosulfur compounds in garlic & onions C) Increase DNA repair Polyphenols in green tea Selenium

Block carcinogen activation

Flavonoids and isoflavonoids

Coumarins

Isothiocyanates in cruciferous vegetables

Organosulfur compounds in garlic & onions

Enhance carcinogen detoxification

Antioxidants in plants

Isothiocyanates in cruciferous vegetables

Organosulfur compounds in garlic & onions

C) Increase DNA repair

Polyphenols in green tea

Selenium

Initiation Promotion Progression Proliferation Independence Stages of Cancer Formation Unspecialized Cell Initiated Cell Benign Tumor Malignant Tumor Latency Period, 20 years or more Mutation Cancer Gene Mutation Invade & Spread

Proliferation

Independence

Mutation

Cancer Gene

Mutation

Invade & Spread

Anti-cancer Agents in Fruits & Vegetables Inhibition of Promotion Stage of Cancer Formation Scavenge reactive oxygen species Antioxidants in plants Alter proliferation & differentiation Phytoestrogens (+/-) Retinoids

Scavenge reactive oxygen species

Antioxidants in plants

Alter proliferation & differentiation

Phytoestrogens (+/-)

Retinoids

Physical Activity May be associated with decreased breast cancer risk for women of all ages Thought to possibly act by changing: Menstrual activity Exercise may increase age at menarche 2) Body characteristics Exercise can decrease body fat 3) Hormone levels Exercise may decrease estrogen levels

May be associated with decreased breast cancer risk for women of all ages

Thought to possibly act by changing:

Menstrual activity

Exercise may increase age at menarche

2) Body characteristics

Exercise can decrease body fat

3) Hormone levels

Exercise may decrease estrogen levels

Smoking Tobacco Effect of adult smoking (active & passive) is unclear Age beginning smoking may be important Heavy smokers below age 20 have a 30% to 80% increase in breast cancer risk Cigarette smoke contains numerous chemical which can initiate and promote cancer Breast fluids of smokers contain chemicals from cigarette smoke

Effect of adult smoking (active & passive) is unclear

Age beginning smoking may be important

Heavy smokers below age 20 have a 30% to 80% increase in breast cancer risk

Cigarette smoke contains numerous chemical which can initiate and promote cancer

Breast fluids of smokers contain chemicals from cigarette smoke

Alcohol Use Adult use associated with risk (about 10% increase for each drink per day) All studies have reported impact of early age alcohol use on breast cancer risk About twice the risk of breast cancer for women below 35 years Alcohol use increases estrogen levels Adequate folic acid (B vitamin) may decrease risk in women who have more than 1 drink per day

Adult use associated with risk (about 10% increase for each drink per day)

All studies have reported impact of early age alcohol use on breast cancer risk

About twice the risk of breast cancer for women below 35 years

Alcohol use increases estrogen levels

Adequate folic acid (B vitamin) may decrease risk in women who have more than 1 drink per day

Obesity Associated with decreased premenopausal breast cancer risk (25% decrease) Interferes with regular menstrual cycling Less proliferation in breast Associated with increased postmenopausal breast cancer risk (about 200% increase) Increases estrogen exposure Fat cells form estrogen from other hormones

Associated with decreased premenopausal breast cancer risk (25% decrease)

Interferes with regular menstrual cycling

Less proliferation in breast

Associated with increased postmenopausal breast cancer risk (about 200% increase)

Increases estrogen exposure

Fat cells form estrogen from other hormones

Initiation Promotion Proliferation Independence Unspecialized Cell Initiated Cell Benign Tumor Decrease Initiation Process 1) Minimize Exposures 2) Childbirth 3) Diet 4) Avoid radiation exposure Decrease cells at risk Childbirth Diet? Eliminate Initiated Cells Childbirth? Diet? Decrease Promotion Process Decrease estrogenic exposures Childbirth Diet Physical Activity Mutation Cancer Gene Modifying the Stages of Cancer Formation

Proliferation

Independence

Decrease cells at risk

Childbirth

Diet?

Eliminate Initiated Cells

Childbirth?

Diet?

Decrease Promotion Process

Decrease estrogenic exposures

Childbirth

Diet

Physical Activity

Mutation

Cancer Gene