BCrisk.warren (1)

8/13/2019 BCrisk.warren (1)

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Diet, L ifesty le and

Breast Cancer Risk

Barbour S Warren, PhDProgram on Breast Cancer &Environmental Risk Factors

Sprecher Institute for Comparative CancerResearch


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- 0.6% of all cases are in men

- 216,600 NEW cases o f breas t cancer

and 40,200 deaths from breast can cer

- Inc idence - 110/10k peop le = 3 m il l ion in US

- L ifetim e risk is 13.48 % (1 in 7)

- 86% o f women w ith breast cancer are al ive

5 years after d iagno sis (76% alive at 10 years )

- Most common cancer (31%) in wom en

Scope o f Breast Cancer


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1) B iology o f the development o f

b reast cancer2) Risk facto rs for breast cancer (in

l igh t of the biology)

3) Poten t ial for mod if icat ion of b reast

cancer r isk

Overview


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Breas t Cancer ArisesFrom The In terac t ion o f

Two Processes

1) The Cancer Formation Process

2) The Process o f Developmento f the Breast


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Initiation Promotion ProgressionMutationCancer Gene

ProliferationIndependence

MutationInvade Spread

Stages of Cancer Formation

UnspecializedCell

InitiatedCell BenignTumor

MalignantTumor

Latency Period, 20 years or more


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Breas t Cancer ArisesFrom The In terac t ion o fTwo Processes

1) The Cancer Formatio n Process

2) The Process o f Developmento f th e Breast


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Development o f the Breast Ductal TreeDifferent iat ion Occurs With Pregnancy

2 yearsAfter

Puberty

After

Pregnancy

Proli feration Prol i ferationDifferentiation

Prol i feration

Bir th


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Prol i ferat ion

Differentiat ion

Prol i ferat ion and Different iat ion

A Ying -Yang Relat ionship in B reast Cancer Form ation


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Proliferation Cell MultiplicationEssential for normal growth developmentof the breastImportant factor in breast cancer

Allows less time for mutation repairThe key event during tumor promotion


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Cancer Gene

DNA

Carc inogen

Low

Prol i ferat ion

Normal

Canc er Gene

High

Prol i ferat ion

Permanent ly Mutated

Cancer Gene

Proliferation Decreases Mutation Repair

Time ForRepair Before

DNADuplication

Little TimeFor RepairBefore DNADuplication

Within a Cell

In Each Daugh ter Cell In Each Daug hter Cell


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Proliferation Cell MultiplicationEssential for normal growth developmentof the breastImportant factor in breast cancer Decreases time for mutation repair

Estrogen and other reproductive hormonescause proliferation of breast cells

Key event during the tumor promotionProliferating cells at risk to undergo initiation,promotion and progression stages of cancerformation


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Prol i ferat ion

Differentiat ion

Prol i ferat ion and Different iat ion

A Ying -Yang Relat ionship in B reast Cancer Form ation


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Development o f the Breast Ductal TreeDifferent iat ion Occurs With Pregnancy

2 yearsAfter

Puberty

After

PregnancyBir th

Lobules


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PubertySexual

Matur i tyPregnancy Lactat ion

TerminalEnd Bud

Lobu leType 1

Lobu leType 2

LobuleTyp e 3

LobuleTyp e 4

60 22 4 1

Level of Prol i ferat ion

Different iat ion of A Breast Lobule

Growth to a Func t ioning Ent ity


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B reas t Lo bu le Types

Puberty

Pregnancy

Lactat ion

Lobule

Ty pe 2

Lobule

Type 3

Lobule

Type 4

Lobu le

Typ e 1

Cont ains cel ls at

to become breast cancer

h ighes t r is k

- c ells t ha t are

- c ells t ha t are

prol i ferat ing

not d i f ferent iated

Premenopausal Women Have

Dif ferent Lob ule Types

80%-100% type 3 lo bul esChildbearing

30%-35% ty pe 2 lob ules

5%-10% type 3 lob ules

Childless

50%-60% type 1 lobul es


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Key B iologic al Facto rs for

B reas t Cancer Risk

1) Number of to become

br east tumo rs

- Cells which are not d iffer entiated - Cells which are p ro li ferat ing

Cel l s at Risk

2) and o ther hormo nes

- Levels of th ese horm ones in blood

- Level of recept ors for these hormones

Estrogen

Cel ls Suscept ib l e toBecome Tumors

- Measure of to cancervulnerabi l i ty


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Cel ls at Risk A re Analogous

to a Targets Bulls-eye

Cellsat

Risk

Cells

at

Risk

Cells

at

Risk

Carcinogens

A larger num ber of cells at r isk p rodu ces a larger

(and easier to hit) bulls-eye.


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In terac t ion o f a Cel l at Riskw i th a Carcinogen Can Produce

an In it iated Cell

An ini t iated cel l is the first s tep

in format ion o f a tumor

For an ini t iated cel l to become a

tumo r both the Promot ion and

Progression s tages have to

occur

The larger the num ber of

ini t iated cel ls th e higher the

breast cancer r isk

Cells

at

Risk


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P u b er t y

M e n arc h e M e n o p a u s e P re g n a n c y

Ch i l d b i r t h B i r t h

A g e

Events During A Wom ans Lifetime

Num

bero

fCe

llsa

tRisk

To

Become

Bre

as

tTumors

L i f et im e C h a n g e s i n N um b e r o f

C e l l s a t R i s k to B e c om e B r e as t Tum o r s

i n a T h eo re t i c a l C h i l d b ea r in g Wo m a n


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P u b er t y



A g e


Num

bero

fCe

llsa

tRisk

To

Become

Bre

as

tTumors





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P u b er t y



A g e


Num

bero

fCe

llsa

tRisk

To

Become

Bre

as

tTumors





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P u b er t y



A g e


Num

bero

fCe

llsa

tRisk

To

Become

Bre

as

tTumors





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P u b er t y



A g e


Num

bero

fCe

llsa

tRisk

To

Become

Bre

as

tTumors





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P u b er t y



A g e


Num

bero

fCe

llsa

tRisk

To

Become

Bre

as

tTumors





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P u b er t y



A g e


Num

bero

fCe

llsa

tRisk

To

Become

Bre

as

tTumors





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P u b er t y



A g e


Num

bero

fCe

llsa

tRisk

To

Become

Bre

as

tTumors





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P u b e r t y

M e n a r c h e M e n o p a u s e B i r t h

A g e

E v e n t s D u rin g A W o m a n s L ife ti m e

N

um

bero

fCellsa

tRisk

To

Become

Breas

tTumors

L i f e t i m e C h a n g e s i n N u m b e r o f

C e l l s a t R i s k t o B e c o m e B r e a s t T u m o r s

in a T h e o r e t i c a l C h i l d l e s s W o m a n


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Key Bio log ical Facto rs for

B reas t Cancer Risk

1) Number of to become

br east tumo rs

- Cells which are not d ifferentiat ed - Cells which are p ro li ferat ing

Cel l s at Risk

2) and o ther hormones

- Levels of th ese horm ones in blood

- Level of recept ors for these ho rmones

Estrogen

Cells Susceptib le toBecome Tumor s

- Measure of to cancervulnerabi l i ty


30/49

Estrogen

Estrogen acts w i th other reproduct ive to

inc rease pro l i ferat ion in the breast

Prol i ferat ion is l inked to: Tumor promo t ion

Decreased mu tat ion repair

Increases in the number of cells at risk

Estrogen may be metabo l ized to form a

carc inogen which could cause mutat ions and

form ini t iated cel ls

Relat ion to B reast Cancer Risk


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Estrogen

How Is The Risk Of

Breas t Cancer Increased?

1) Larger number of mu tat ions

Increased ini t iat ion & progressio n

2) Greater level of p ro l i ferat ionIncreased promot ion & progression

3) Inc rease number of cells at r isk to

become breast cancer

4) Inc rease the t ime of h igh risk

for tumor in i t iat ion


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Age Related>- Age ( 50 vs 30 vs < 20 yr )

Reprod uct ion Related

>

- Age of menarche (


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Establ is hed Risk Factors

for B reas t Cancer

Enviro nment Related- Exp osure to ion izing radiation

Breast D isease

- Breast B iopsy (any f inding)

- Atypi cal hyperp lasia

Relative RiskRisk Facto r

1.0 - 8.7

1.5 - 1.8

4.0 - 4.4


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Vegetables and Fruits

Eating large amounts of vegetables, in general,may be l inked to a small decrease in b reast

cancer r isk

Supp lements do no t appear to o f fer the

same protect ion as food

Evidence is stronger for a decrease in r isk

w ith dark g reen and yel low vegetables

Eating fru i t , in general, is unrelated to b reast

cancer r isk

Vegetables may have a greater effect fo r

women wi th a fam i ly h is tory of b reast cancer


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Ant i -cancer Agents in Vegetables & Frui ts

Inh ibi t ion of Ini t iat ion Stage of Cancer Formation


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UnspecializedCell


MalignantTumor



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Ant i -cancer Agents in Vegetables & Frui ts

Inh ibi t ion of Ini t iat ion Stage of Cancer Formation

A) Block carcinogen act ivat ion

Flavono ids and iso f lavono ids

Coumar ins

Iso thioc yanates in cruc i ferou s vegetables

Organosul fur compounds in gar lic & onions

B) Enhance carcinogen detoxi f icat ion

An t ioxidants in plants

Iso thioc yanates in cruc i ferou s vegetables

Organosul fur compounds in garl ic & onions

C) Increase DNA repair

Polypheno ls in green tea

Selenium


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UnspecializedCell


MalignantTumor



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Ant i -cancer Agents in Frui ts & VegetablesInhibition of Promotion Stage of CancerFormation

A) Scavenge reactive oxygen species Antioxidants in plants

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


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Phytoestrogens

- Exposure befo re puberty m ay b e necessary for

a pro tect ive effect

- Estrog en-l ike ch emicals in p lan ts

- Soy produc ts

High levels of ph ytoestrogens

Most studi ed ph ytoestrogens

- Stud ies of soy and breast cancer r isk in

A sian popu lat ion are conf l ic t ing

- Concern vo iced because o f estro gen -l ike effects

- A rea o f high interest


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Whole Grains and Fiber

- A small decr ease in breast c ancer r isk has

been assoc iated with eat ing who le grains

- A small decr ease in b reast c ancer r isk

may be associated w ith dietary f iber

- 4 of 5 co hort no assoc iat ion

- 11 o f 14 case-c ont ro l small d ecrease

- Small decreases in tumo rs in anim als- Effects on c irculat ing est rogens unclear


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Meat and Fish

- As so ciat ion of eat ing poul t ry and breastcanc er r is k is unclear

- Eat ing m eat may be associated w ith in cr easedrisk o f breast c ancer

- Women wh o eat red meat may have a h igher

inc idence of breast cancer

- Most s tudies saw no asso ciat io n between

eating f ish and b reas t cancer r isk

- Studies examin ing m ethod s of cookin g anddoneness show a relat ion ship to b reast

canc er r is k


43/49

Dairy Produc ts

- Dairy p rodu cts co ntain conj ugated lin ole ic

acid (CLA) which dec reases mammary tumorformation in rats

- Studies examining dairy product consumpt ion

and b reast cancer r is k are con f l ict ing

- Stud ies of ch ildh ood and ado lesc entconsumpt ion of dai ry products and

b reas t cancer r is k are also conf l ict ing


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Dietary Fat

Con trad ictory f ind ings

- Pos i t ive as sociat ion (inc reased r isk )

Ecologi cal stud ies, Animal stud ies

- Inc onc lusive assoc iat ion

Case-con trol stud ies of women

- No asso ciat ionCoho rt s tudies of women


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Physical Act iv i ty

May be associated w ith decreased breast cancer

r isk for women of all ages

Though t to poss ib ly act by changing:1)Mens trual act iv i ty

Exercise may increase age at menarche

2) Body character is t ics

Exerc ise can decrease body fat3) Hormone levels

Exercise may decrease estro gen levels


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Smok ing Tobacco

Effect o f adu l t smok ing (act ive & passive) is

unclear

Age beginn ing sm oking m ay be impo r tant

Heavy smokers below age 20 have a30% to 80% increase in b reast cancer

r isk

Cigaret te smoke contains numerous

chemical wh ich can in i tiate and promotecancer

Breast f lu ids o f smokers con tain

chemicals f rom cigaret te smoke


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A lcoho l Use

Adul t use asso ciated with r isk (about 10%

inc rease for each d rink per day) A ll stu dies have repo rted impact of early age

alcoho l use on b reast cancer r isk

About tw ice the r isk o f breast cancer for wom en

below 35 years

Alco hol u se increases estrogen levels

Adequate fol ic acid (B v itamin) may decrease risk

in women who have mo re than 1 dr ink per day


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Obesi ty

Associated w ith decreased premenopausal

breast cancer risk (25% decrease)

Inter feres w ith regular menstrual cycl ing

Less p rol i ferat ion in breast Assoc iated wi th inc reased postmenopausal

breast cancer risk (about 200% increase)

Inc reases estro gen exposure

Fat cells form estrogen from other hormones


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Initiation PromotionMutationCancer Gene


Modifying the Stages of Cancer Formation

UnspecializedCell

InitiatedCell

BenignTumor

Decrease Init iat ion Pro cess

1) Minimize Exposures

2) Chi ldbir th

3) Diet

Decrease cells at risk

1) Chi ldb ir th2) Diet?

Elimin ate Init iated Cells

1) Chi ldb ir th?2) Diet?

Decrease Promotion Process

1) Decrease est rogen ic exposures

2) Chi ldb ir th

3) Diet

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