Diet, Lifestyle and Breast Cancer Risk

Barbour S Warren, PhDProgram on Breast Cancer & Environmental Risk FactorsSprecher Institute for Comparative Cancer Research

- 0.6% of all cases are in men

- 216,600 NEW cases of breast cancer and 40,200 deaths from breast cancer

- Incidence - 110/10k people = 3 million in US

- Lifetime risk is 13.48 % (1 in 7)

- 86% of women with breast cancer are alive 5 years after diagnosis (76% alive at 10 years)

- Most common cancer (31%) in women

Scope of Breast Cancer

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

Breast Cancer Arises From The Interaction of

Two Processes

1) The Cancer Formation Process

2) The Process of Development of the Breast

Initiation Promotion Progression•Mutation•Cancer Gene

•Proliferation•Independence

•Mutation•Invade & Spread

Stages of Cancer Formation

UnspecializedCell

InitiatedCell

BenignTumor

MalignantTumor

Latency Period, 20 years or more

Breast Cancer Arises From The Interaction of

Two Processes

1) The Cancer Formation Process

2) The Process of Development of the Breast

Development of the Breast Ductal TreeDifferentiation Occurs With Pregnancy

2 years After Puberty

AfterPregnancy

Proliferation ProliferationDifferentiation

Proliferation

Birth

Proliferation

Differentiation

Proliferation and DifferentiationA Ying-Yang Relationship in Breast Cancer Formation

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

Cancer Gene

DNA

Carcinogen

LowProliferation

Normal Cancer Gene

HighProliferation

Permanently MutatedCancer Gene

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 MultiplicationEssential 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

Proliferation

Differentiation

Proliferation and DifferentiationA Ying-Yang Relationship in Breast Cancer Formation

Development of the Breast Ductal TreeDifferentiation Occurs With Pregnancy

2 years After Puberty

AfterPregnancy

Birth

Lobules

PubertySexual

MaturityPregnancy Lactation

Terminal End Bud

LobuleType 1

LobuleType 2

LobuleType 3

LobuleType 4

60 22 4 1

Level of Proliferation

Differentiation of A Breast LobuleGrowth to a Functioning Entity

Breast Lobule Types

Puberty

Pregnancy

Lactation

LobuleType 2

LobuleType 3

LobuleType 4

LobuleType 1

Contains cells at to become breast cancer

highestrisk

- cells that are - cells that are

proliferatingnotdifferentiated

Premenopausal Women Have Different Lobule Types

80%-100% type 3 lobulesChildbearing

30%-35% type 2 lobules5%-10% type 3 lobules

Childless50%-60% type 1 lobules

Key Biological Factors for Breast Cancer Risk

1) Number of to become breast tumors - Cells which are not differentiated - Cells which are proliferating

CellsatRisk

2) and other hormones - Levels of these hormones in blood - Level of receptors for these hormones

Estrogen

Cells Susceptible to Become Tumors

- Measure of to cancervulnerability

Cells at Risk Are Analogous to a Target’s Bull’s-eye

Cellsat

Risk

Cellsat

Risk

Cellsat

Risk

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

Cellsat

Risk

Puberty Menarche

MenopausePregnancyChildbirth

Birth

AgeEvents During A Woman’s Lifetime

Lifetime Changes in Number of Cells at Risk to Become Breast Tumors

in a Theoretical Childbearing Woman

Puberty Menarche

MenopausePregnancyChildbirth

Birth

AgeEvents During A Woman’s Lifetime

Lifetime Changes in Number of Cells at Risk to Become Breast Tumors

in a Theoretical Childbearing Woman

Puberty Menarche

MenopausePregnancyChildbirth

Birth

AgeEvents During A Woman’s Lifetime

Lifetime Changes in Number of Cells at Risk to Become Breast Tumors

in a Theoretical Childbearing Woman

Puberty Menarche

MenopausePregnancyChildbirth

Birth

AgeEvents During A Woman’s Lifetime

Lifetime Changes in Number of Cells at Risk to Become Breast Tumors

in a Theoretical Childbearing Woman

Puberty Menarche

MenopausePregnancyChildbirth

Birth

AgeEvents During A Woman’s Lifetime

Lifetime Changes in Number of Cells at Risk to Become Breast Tumors

in a Theoretical Childbearing Woman

Puberty Menarche

MenopausePregnancyChildbirth

Birth

AgeEvents During A Woman’s Lifetime

Lifetime Changes in Number of Cells at Risk to Become Breast Tumors

in a Theoretical Childbearing Woman

Puberty Menarche

MenopausePregnancyChildbirth

Birth

AgeEvents During A Woman’s Lifetime

Lifetime Changes in Number of Cells at Risk to Become Breast Tumors

in a Theoretical Childbearing Woman

Puberty Menarche

MenopausePregnancyChildbirth

Birth

AgeEvents During A Woman’s Lifetime

Lifetime Changes in Number of Cells at Risk to Become Breast Tumors

in a Theoretical Childbearing Woman

Puberty Menarche

MenopauseBirth

AgeEvents During A Woman’s Lifetime

Lifetime Changes in Number of Cells at Risk to Become Breast Tumors

in a Theoretical Childless Woman

Puberty Menarche

MenopauseBirth

AgeEvents During A Woman’s Lifetime

Lifetime Changes in Number of Cells at Risk to Become Breast Tumors

in a Theoretical Childless Woman

Key Biological Factors for Breast Cancer Risk

1) Number of to become breast tumors - Cells which are not differentiated - Cells which are proliferating

CellsatRisk

2) and other hormones - Levels of these hormones in blood - Level of receptors for these hormones

Estrogen

Cells Susceptible to Become Tumors

- Measure of to cancervulnerability

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

How Is The Risk Of Breast Cancer Increased?

1) Larger number of mutationsIncreased initiation & progression

2) Greater level of proliferationIncreased promotion & progression

3) Increase number of cells at risk to become breast cancer

4) Increase the time of high risk for tumor initiation

Age Related> - Age (50 vs <50 yr)

Established Risk Factors for Breast Cancer

Risk Factor Relative Risk

- Age of menopause (55 vs <55 yr)>- Age at first birth (>30 vs < 20 yr)

Reproduction Related>

- Age of menarche (<12 vs 14 yr)

6.5

1.2-1.51.5-2.01.3-2.2

Established Risk Factors for Breast Cancer

Environment Related - Exposure to ionizing radiation

Breast Disease- Breast Biopsy (any finding)- Atypical hyperplasia

Relative RiskRisk Factor

1.0 - 8.7

1.5 - 1.84.0 - 4.4

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

Anti-cancer Agents in Vegetables & Fruits

Inhibition of Initiation Stage of Cancer Formation

Initiation Promotion Progression•Mutation•Cancer Gene

•Proliferation•Independence

•Mutation•Invade & Spread

Stages of Cancer Formation

UnspecializedCell

InitiatedCell

BenignTumor

MalignantTumor

Latency Period, 20 years or more

Anti-cancer Agents in Vegetables & Fruits

Inhibition of Initiation Stage of Cancer FormationA) Block carcinogen activation

• Flavonoids and isoflavonoids• Coumarins• Isothiocyanates in cruciferous vegetables• Organosulfur compounds in garlic & onions

B) 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•Mutation•Cancer Gene

•Proliferation•Independence

•Mutation•Invade & Spread

Stages of Cancer Formation

UnspecializedCell

InitiatedCell

BenignTumor

MalignantTumor

Latency Period, 20 years or more

Anti-cancer Agents in Fruits & Vegetables

Inhibition of Promotion Stage of Cancer Formation

A) Scavenge reactive oxygen species• Antioxidants in plants

B) Alter proliferation & differentiation• Phytoestrogens (+/-)• Retinoids

Phytoestrogens

- Exposure before puberty may be necessary for a protective effect

- Estrogen-like chemicals in plants

- Soy products High levels of phytoestrogens Most studied phytoestrogens

- Studies of soy and breast cancer risk in Asian population are conflicting

- Concern voiced because of estrogen-like effects

- Area of high interest

Whole Grains and Fiber

- A small decrease in breast cancer risk has been associated with eating whole grains

- A small decrease in breast cancer risk may be associated with dietary fiber - 4 of 5 cohort no association - 11 of 14 case-control small decrease

- Small decreases in tumors in animals

- Effects on circulating estrogens unclear

Meat and Fish

- Association of eating poultry and breast cancer risk is unclear

- Eating meat may be associated with increased risk of breast cancer- Women who eat red meat may have a higher incidence of breast cancer

- Most studies saw no association between eating fish and breast cancer risk- Studies examining methods of cooking and doneness show a relationship to breast cancer risk

Dairy Products

- Dairy products contain conjugated linoleic acid (CLA) which decreases mammary tumor formation in rats

- Studies examining dairy product consumption and breast cancer risk are conflicting

- Studies of childhood and adolescent consumption of dairy products and breast cancer risk are also conflicting

Dietary Fat

Contradictory findings

- Positive association (increased risk)Ecological studies, Animal studies

- Inconclusive associationCase-control studies of women

- No associationCohort studies of women

Physical Activity

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

Thought to possibly act by changing:1)Menstrual activity

Exercise may increase age at menarche2) Body characteristics

Exercise can decrease body fat3) 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

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

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

Initiation Promotion•Mutation•Cancer Gene

•Proliferation•Independence

Modifying the Stages of Cancer Formation

UnspecializedCell

InitiatedCell

BenignTumor

Decrease Initiation Process1) Minimize Exposures2) Childbirth3) Diet4) Avoid radiation exposure

Decrease cells at risk 1) Childbirth2) Diet?

Eliminate Initiated Cells1) Childbirth?2) Diet?

Decrease Promotion Process1) Decrease estrogenic exposures2) Childbirth3) Diet4) Physical Activity