Diet, Lifestyle and
Breast Cancer Risk
Barbour S Warren, PhD
Program on Breast Cancer &
Environmental Risk Factors
Sprecher Institute for Comparative Cancer
Research
Scope of Breast Cancer
- Most common cancer (31%) in women
- 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)
- 0.6% of all cases are in men
Overview
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
Breast Cancer Arises
From The Interaction of
Two Processes
1) The Cancer Formation Process
2) The Process of Development
of the Breast
Latency Period, 20 years or more
Unspecialized
Cell
Initiated
Cell
Initiation
•Mutation
•Cancer Gene
Benign
Tumor
Promotion
•Proliferation
•Independence
Malignant
Tumor
Progression
•Mutation
•Invade & Spread
Stages of Cancer Formation
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 Tree
Differentiation Occurs With Pregnancy
Birth
2 years
Proliferation
After
Puberty
Proliferation
After
Pregnancy
Proliferation
Differentiation
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
• The key event during tumor promotion
• Allows less time for mutation repair
Proliferation Decreases Mutation Repair
Carcinogen
DNA
Cancer Gene
Time For
Within a Cell
Repair Before
Low
DNA
Proliferation
Duplication
Normal
Cancer Gene
In Each Daughter Cell
High
Proliferation
Little Time
For Repair
Before DNA
Duplication
Permanently Mutated
Cancer Gene
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
• Key event during the tumor promotion
Proliferating cells at risk to undergo initiation,
promotion and progression stages of cancer
formation
Estrogen and other reproductive hormones
cause proliferation of breast cells
Proliferation and Differentiation
A Ying-Yang Relationship in Breast Cancer Formation
Proliferation
Differentiation
Development of the Breast Ductal Tree
Differentiation Occurs With Pregnancy
Birth
2 years
After
Puberty
Lobules
After
Pregnancy
Differentiation of A Breast Lobule
Growth to a Functioning Entity
Puberty
Terminal
End Bud
Sexual
Maturity
Lobule
Type 1
Pregnancy
Lobule
Type 2
Level of Proliferation
60
22
4
Lactation
Lobule
Type 3
1
Lobule
Type 4
Breast Lobule Types
Lobule
Type 1
Puberty
Contains cells at highest risk
to become breast cancer
- cells that are proliferating
- cells that are not differentiated
Lobule
Type 2
Premenopausal Women Have
Different Lobule Types
Pregnancy
Lobule
Type 3
Lactation
Lobule
Type 4
Childless
50%-60% type 1 lobules
30%-35% type 2 lobules
5%-10% type 3 lobules
Childbearing
80%-100% type 3 lobules
Key Biological Factors for
Breast Cancer Risk
1) Number of Cells at Risk to become
breast tumors
- Cells which are not differentiated Cells Susceptible to
Become Tumors
- Cells which are proliferating
- Measure of vulnerability to cancer
2) Estrogen and other hormones
- Levels of these hormones in blood
- Level of receptors for these hormones
Cells at Risk Are Analogous
to a Target’s Bull’s-eye
Cells
at
Risk
Cells
at
Risk
Cells
at
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
Cells
at
Risk
• 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
Number of Cells at Risk
To Become Breast Tumors
Lifetim e C h ang es in N um be r o f
C ells at R isk to B ecom e B reast Tum ors
in a T h eo retical C h ildb earing W o m an
B irth
P ub erty Preg nancy
Men arche Child b irth
M e nop au se
Age
E ven ts D uring A W om an’s Lif etim e
Number of Cells at Risk
To Become Breast Tumors
Lifetim e C h ang es in N um be r o f
C ells at R isk to B ecom e B reast Tum ors
in a T h eo retical C h ildb earing W o m an
B irth
P ub erty Preg nancy
Men arche Child b irth
M e nop au se
Age
E ven ts D uring A W om an’s Lif etim e
Number of Cells at Risk
To Become Breast Tumors
Lifetim e C h ang es in N um be r o f
C ells at R isk to B ecom e B reast Tum ors
in a T h eo retical C h ildb earing W o m an
B irth
P ub erty Preg nancy
Men arche Child b irth
M e nop au se
Age
E ven ts D uring A W om an’s Lif etim e
Number of Cells at Risk
To Become Breast Tumors
Lifetim e C h ang es in N um be r o f
C ells at R isk to B ecom e B reast Tum ors
in a T h eo retical C h ildb earing W o m an
B irth
P ub erty Preg nancy
Men arche Child b irth
M e nop au se
Age
E ven ts D uring A W om an’s Lif etim e
Number of Cells at Risk
To Become Breast Tumors
Lifetim e C h ang es in N um be r o f
C ells at R isk to B ecom e B reast Tum ors
in a T h eo retical C h ildb earing W o m an
B irth
P ub erty Preg nancy
Men arche Child b irth
M e nop au se
Age
E ven ts D uring A W om an’s Lif etim e
Number of Cells at Risk
To Become Breast Tumors
Lifetim e C h ang es in N um be r o f
C ells at R isk to B ecom e B reast Tum ors
in a T h eo retical C h ildb earing W o m an
B irth
P ub erty Preg nancy
Men arche Child b irth
M e nop au se
Age
E ven ts D uring A W om an’s Lif etim e
Number of Cells at Risk
To Become Breast Tumors
Lifetim e C h ang es in N um be r o f
C ells at R isk to B ecom e B reast Tum ors
in a T h eo retical C h ildb earing W o m an
B irth
P ub erty Preg nancy
Men arche Child b irth
M e nop au se
Age
E ven ts D uring A W om an’s Lif etim e
Number of Cells at Risk
To Become Breast Tumors
Lifetim e C h ang es in N um be r o f
C ells at R isk to B ecom e B reast Tum ors
in a T h eo retical C h ildb earing W o m an
B irth
P ub erty Preg nancy
Men arche Child b irth
M e nop au se
Age
E ven ts D uring A W om an’s Lif etim e
Number of Cells at Risk
To Become Breast Tumors
L ife tim e C ha n ge s in N u m b e r o f
C e lls a t R is k to B e c o m e B r e a s t T u m or s
in a T h e o r e t ic a l C h i ldle s s W o m a n
B i rth
P u b e rty
M e n a rc h e
M eno p a us e
A ge
E v e n t s D u rin g A W o m a n ’s L if e ti m e
Number of Cells at Risk
To Become Breast Tumors
L ife tim e C ha n ge s in N u m b e r o f
C e lls a t R is k to B e c o m e B r e a s t T u m or s
in a T h e o r e t ic a l C h i ldle s s W o m a n
B i rth
P u b e rty
M e n a rc h e
M eno p a us e
A ge
E v e n t s D u rin g A W o m a n ’s L if e ti m e
Key Biological Factors for
Breast Cancer Risk
1) Number of Cells at Risk to become
breast tumors
- Cells which are not differentiated Cells Susceptible to
Become Tumors
- Cells which are proliferating
- Measure of vulnerability to cancer
2) Estrogen and other hormones
- Levels of these hormones in blood
- Level of receptors for these hormones
Estrogen
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’
Estrogen may be metabolized to form a
carcinogen which could cause mutations and
form initiated cells
How Is The Risk Of
Breast Cancer Increased?
1) Larger number of mutations
Increased initiation & progression
Estrogen
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
Established Risk Factors
for Breast Cancer
Risk Factor
Relative Risk
Age Related
- Age (>50 vs <50 yr)
Reproduction Related
- Age of menarche (<12 vs >14 yr)
- Age of menopause (>55 vs <55 yr)
- Age at first birth (>30 vs < 20 yr)
6.5
1.2-1.5
1.5-2.0
1.3-2.2
Established Risk Factors
for Breast Cancer
Risk Factor
Environment Related
- Exposure to ionizing radiation
Breast Disease
- Breast Biopsy (any finding)
- Atypical hyperplasia
Relative Risk
1.0 - 8.7
1.5 - 1.8
4.0 - 4.4
Vegetables and Fruits
• Eating large amounts of vegetables, in general,
may be linked to a small decrease in breast
cancer risk
• Evidence is stronger for a decrease in risk
with dark green and yellow vegetables
• Vegetables may have a greater effect for
women with a family history of breast cancer
• Eating fruit, in general, is unrelated to breast
cancer risk
• Supplements do not appear to offer the
same protection as food
Anti-cancer Agents in Vegetables & Fruits
Inhibition of Initiation Stage of Cancer Formation
Latency Period, 20 years or more
Unspecialized
Cell
Initiated
Cell
Initiation
•Mutation
•Cancer Gene
Benign
Tumor
Promotion
•Proliferation
•Independence
Malignant
Tumor
Progression
•Mutation
•Invade & Spread
Stages of Cancer Formation
Anti-cancer Agents in Vegetables & Fruits
Inhibition of Initiation Stage of Cancer Formation
A) 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
Latency Period, 20 years or more
Unspecialized
Cell
Initiated
Cell
Initiation
•Mutation
•Cancer Gene
Benign
Tumor
Promotion
•Proliferation
•Independence
Malignant
Tumor
Progression
•Mutation
•Invade & Spread
Stages of Cancer Formation
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
- 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
- Exposure before puberty may be necessary for
a protective effect
- 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
- Eating meat may be associated with increased
risk of breast cancer
- Women who eat red meat may have a higher
incidence of breast cancer
- Association of eating poultry and breast
cancer risk is unclear
- 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
- 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
- Dairy products contain conjugated linoleic
acid (CLA) which decreases mammary tumor
formation in rats
Dietary Fat
Contradictory findings
- Positive association (increased risk)
Ecological studies, Animal studies
- Inconclusive association
Case-control studies of women
- No association
Cohort 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 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
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
Modifying the Stages of Cancer Formation
Decrease cells at risk
1) Childbirth
2) Diet?
Eliminate Initiated Cells
1) Childbirth?
2) Diet?
Initiated
Cell
Unspecialized
Cell
Initiation
•Mutation
•Cancer Gene
Decrease Initiation Process
1) Minimize Exposures
2) Childbirth
3) Diet
4) Avoid radiation exposure
Benign
Tumor
Promotion
•Proliferation
•Independence
Decrease Promotion Process
1) Decrease estrogenic exposures
2) Childbirth
3) Diet
4) Physical Activity