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(1)

Berry Polyphenols in the

Prevention of Primary and

Recurrent Breast Cancer

Harini S Aiyer, Ph.D.

Lombardi Comprehensive Cancer Center

Georgetown University

Berry Health Symposium

June 27, 2011

(2)

Overview

Breast cancer – incidence and risk factors

Selection of berries for breast cancer

prevention

Berries in mammary tumor prevention

Mechanisms by which berries prevent

breast cancer

(3)

Breast Cancer- Causes

Sporadic breast cancer 90% Familial breast cancer 10%

Causes

(4)

Breast cancer- risk factors

Non-Modifiable

Risk Factors

Modifiable Risk

Factors

Hormonal Risk

Factors

Age

Diet

Cumulative exposure to

estrogen

Gender

Alcohol

Age at menarche and

menopause

Genetics

Smoking

Parity

Family history

Body weight

Lactation

Previous breast disease

Exercise

Hormone replacement

therapy

(5)

Berry polyphenols

Berry Phenolics Anthocyanidins Pelargonidin Delphinidin Cyanidin n n Flavonols Kaempferol Quercetin K Tannins Stibenoids Proanthocyanidins Ellagitannins

Condensed Tannins Hydrolysable Tannins

Me ta b o lis m Me ta b o lis m

Anthocyanidins Ellagic acid

Pterostilbeneost

™

Excellent antioxidant properties

™

Interaction with Estrogen receptor

™

Cause cell-cycle arrest

™

Interfere with cell-signaling pathways

™

Interact with multiple pathways involved in

carcinogenesis

(6)

Effect of ellagic acid on 4-hydroxy

etsradiol-induced oxidative DNA damage

0

100

200

300

400

0

500

1000

1500

2000

P-1

8-oxodG

EA dose in µM

A

dduct

s

/1

0

6

N

(7)

Next step-

in vivo

study

(

Short-Term)

Control Diet

5% (w/w) berries based on EA content1 Blueberry (low <100 ppm)

Strawberry (moderate ppm)

Red raspberry (high ppm)

Ellagic acid (400 ppm) DNA damage (32P-postlabeling) Genomics (microarray) Euthanized Day 25 Day 5 Received Mice Day 1

Liver

Supplemented Diet

1- Daniel et al., 1993

(8)

These diets also significantly reduced baseline hepatic-DNA damage

in a similar fashion

-10 -5 0 5 10 Fold Change

Raspberry supplemented diet

-10 -5 0 5 10 Fold Change

Ellagic acid supplemented diet

Short-term

in vivo

study

(9)

Next step- tumorigenesis

study

- 3

Termination

24

- 2

Control diet

Weeks

Receive Animals Sham or 17ß-Estradiol Implants

0

Experimental diet

DIET DOSE Control (AIN 93M) NA Blueberry 2.5% (w/w) Black raspberry 2.5% (w/w) Ellagic acid 400 ppm

(10)

Rationale for berry types used

DIET DOSE Ellagic acid content Anthocyanin content

Blueberry 2.5% (w/w) Low (<100 ppm) Moderate ( 4000 ppm) Black raspberry 2.5% (w/w) High ( ppm) High ( 7000 ppm)

Ellagic acid 400 ppm Pure compound

Aiyer et al., Berries and Cancer Prevention, Eds Stoner GD and Seeram NP, Springer, 2011

0 5 10 15 20

Anthocyanins Total Phenolics

4.3 17.2 1.3 10.7 mg/ g dry wt Cyanidin Petunidin Delphinidin Pelargonidin Malvidin Peonidin 0% 20% 40% 60% 80% 100% 31.2 33.8 8.8 18.6 7.7 97.4 2.5 Blueberry Black Raspberry

(11)

Berry diets increase mammary tumor latency

E2+ Control diet E2+ Blueberry diet

E2+ Black raspberry diet E2+ Ellagic acid diet Sham treatment

90

135

180

0

20

40

60

80

100

%

Tum

or Inc

ide

nc

e

Days after E

2

implant

(12)

Estrogen treatment associated

morbidity in ACI rats

(13)

Berry diets reduce treatment-associated morbidity

in ACI rats

(14)

Morbidity score – 1 to 5

(1- best; 5-worst. )

Weight loss > 1 g per day

Hair loss

Crouch

Eye deposits

Loss of balance

---Tumor size

in mortality index)

Berry diets diminish treatment-associated

mortality

0 0 30 16 18 20 22 24 40 50 60 70 80 90 100

Weeks after estrogen implant

S

u

rv

ival %

Control diet Blueberry diet

Black raspberry diet

Ellagic acid diet

(15)

Berry diets decrease tumor volume and

multiplicity

(16)

15 18 21 24 27 0 20 40 60 80 100 % o f an im al s w it h t u m o rs 15 18 21 24 27 0 20 40 60 80 100 15 18 21 24 27 0 20 40 60 80 100

A

B

C

Weeks after E2 implantation

# #

#

#

BRB diet

BB diet

EA diet

(17)

BERry diets modulate phase I

enzymes

17

E

-HSD7

0 1 2 3 4 5 Relativ e fold change §

CYP1A1

0 10 20 30 40 50 §

*

CYP1B1

0.0 0.5 1.0 1.5 § Sham-Control diet E2-Control diet E2-Blueberry diet

E2-Black raspberry diet

E2-Ellagic acid diet

Weeks after estrogen treatment

(18)

BERRY diets also modulate phase II

enzyme

COMT

0 1 2 3 4 5 6 Relativ e fold change Sham-Control diet E2-Control diet E2-Blueberry diet

E2-Black raspberry diet

E2-Ellagic acid diet

Weeks after estrogen treatment

§

CYP1A1

0 10 20 30 40 50 §

*

(19)

Berry diets inhibit E2-induced cell proliferation

PCNA positiv

e

cells (%)

Estrogen

-

+

+

+

+

Diet

(2.5% w/w)

0

5

10

15

20

25

30

35

*

http://www.niper-ddnptm.com/ProceedingsOfDDNPTM2008.pdf#page=51

(20)

Berry phytochemicals act as

antiestrogens

0 20 40 60 80 100 Sham + Control diet E2 + Control diet E2 + 2.5% Blueberry diet E2 + 2.5% Black raspberry diet E2 + 400 ppm Ellagic acid diet

Pituit a ry w e t w e ight (mg)

**

*

0 200 400 600 800 1,000 Sham + Control diet

E2 + Control diet E2 + 5% Blueberry diet E2 + 5% Black raspberry diet Serum Pr olactin lev e ls (mg / ml)

(21)

Berry phytochemicals act as

antiestrogens

0 100 200 300 400 500 600 700 800 900 1,000 Sham + Control diet E2 + Control diet E2 + 2.5% Blueberry diet E2 + 2.5% Black raspberry diet E2 + 400 ppm Ellagic acid diet Ov ar y and Ut erus co mb in e d wet we ig ht (m g) P < 0.05

*

*

*

#

(22)

Overall mechanism of primary cancer

prevention by berries

Effectors

Mediators

Effects

Cancer Stage

Tumor Initiation

Tumor Promotion

?

(23)

So how much berries do you need to

eat?

Control Diet

Blueberry diet Black raspberry diet

Units 1% 2.5% 5% 1% 2.5% 5%

Berries consumed by rats based on

caloric intake (1g feed = 4 kcal)

mg/kcal

/day

-

2.5

6.25 12.5

2.5

6.25 12.5

Allometric scaling to human

consumption (2,000 kcal/day).

g dried

berry

powder

- 5 12.5 25 5 12.5 25

Common conversion for dried berries Tbsp/d - 0.5 1.25 2.5 0.5 1.25 2.5

Common conversion for fresh berries

Cups/d -

0.4

1

2

0.4

1

2

Source: Aiyer et al., Berries and Cancer Prevention, Eds Stoner GD and Seeram NP, Springer, 2011

(24)

Future- questions & directions

Mechanistic

What is the effect of berry diets on E2 metabolism and

clearance in the liver?

What is the effect of berry diets on pituitary-ovarian axis?

Do berry diets affect other cell-signaling pathways

(Erbb2, MAPK etc) involved in E2-induced tumorigenesis?

Translational

What is the effect of berry-intervention on women who

have been diagnosed with breast cancer?

What are the possible interactions between berry

constituents and current chemotherapy regimens in breast

cancer?

(25)

Proposed mechanisms of AntiEstrogen action

Free radicals NFkB mediated signaling Cell membrane Cytoplasm Nucleus ER Membrane Receptors Kinase signaling CoA CoR

AE

E2 Stromal Cells Paracrine effects Immune function Liver Metabolism of and to estrogens Effect on Bone/Ovary Pituitary-Ovarian axis Autocrine effects ER-independent signaling Transcriptional effects

(26)

Acknowledgements

Mentors

Ramesh Gupta, PhD

Robert Clarke, PhD, DSc

Leena Hilakivi-Clarke, PhD

Labs

Clarke Labs

Gupta Lab

Special

Gary Stoner, PhD

Jim Shull, PhD

Funding

AICR postdoctoral

Fellowship to HSA

NCI (CA-90892 and 92758 )

to RCG

References

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