# Presentation: 517385

## Food, Facts and Fantasies:  Can Your Diet Really Reduce Cancer Risk? 

**Food, Facts and Fantasies:  Can Your Diet Really Reduce Cancer Risk? **

**Nutrition Science Research Group**
**Division of Cancer Prevention**
**National Cancer Institute**
**Bethesda, MD 20892**

**J. A. Milner**
**milnerj@mail.nih.gov**

## Unprecedented Opportunities Exist for Expanded Use of Foods and Components to Achieve Genetic Potential, to Increase Productivity and Decrease Risk of Disease

## While we have come a long way since this 1940’s United Kingdom Advertisement, we still can not identify who will and will not benefit from dietary intervention strategies

**While we have come a long way since this 1940’s United Kingdom Advertisement, we still can not identify who will and will not benefit from dietary intervention strategies**

## Fruits, Vegetables & Cancer Prevention

**Fruits, Vegetables & Cancer Prevention**

- WCRF/AICR Expert Committee Conclusions

## Nutritional Genomics and Proteomics

- DNA

**Nutritional Genomics and Proteomics**

- Proteins

- Enzymes, structural,
- Transport,signaling caused by phosphorylation, glycosylation, etc.

- mRNA

- CH3-DNA

- Genomic 					Post-translational

**Bioactive**
**Food **
**Components**

- Epigenomic

## < 300 mg 

- < 300 mg

- Caffeine

- > 300 mg

- 6

- -12

- 0

- -6

- Vitamin D Receptor Genotype

- TT        Tt       tt

- TT       Tt        tt

- Spine Bone Mass Density (%)

**Influence of Caffeine on Bone Mass May Depend on Genes**

**Rapuri  et al. Am J Clin Nutr 2001 Nov;74(5):694-700**

**Notes:**
BACKGROUND: The role of caffeine as a risk factor for bone loss is controversial. OBJECTIVE: Our goals were 1) to compare in both a cross-sectional study and a 3-y longitudinal study the bone mineral density (BMD) of postmenopausal women consuming high or low amounts of caffeine and 2) to study the interaction between caffeine intake, vitamin D receptor (VDR)polymorphism, and BMD in the longitudinal study. DESIGN: The results are derived from cross-sectional measurements of BMD in 489 elderly women (aged 65-77 y) and from longitudinal measurements made in 96 of these women who were treatedwith a placebo for 3 y. Changes in BMD were adjusted for confounding factors and were compared between groups with eitherlow (< or =300 mg/d) or high (>300 mg/d) caffeine intakes and between the VDR genotype subgroups of the low- andhigh-caffeine groups. RESULTS: Women with high caffeine intakes had significantly higher rates of bone loss at the spine than did those with low intakes (-1.90 +/- 0.97% compared with 1.19 +/- 1.08%; P = 0.038). When the data were analyzed according to VDR genotype and caffeine intake, women with the tt genotype had significantly (P = 0.054) higher rates of boneloss at the spine (-8.14 +/- 2.62%) than did women with the TT genotype (-0.34 +/- 1.42%) when their caffeine intake was>300 mg/d. CONCLUSIONS: Intakes of caffeine in amounts >300 mg/d ( approximately 514 g, or 18 oz, brewed coffee) accelerate bone loss at the spine in elderly postmenopausal women. Furthermore, women with the tt genetic variant of VDRappear to be at a greater risk for this deleterious effect of caffeine on bone.

## Diet-Gene Interactions in Colon Cancer

***Yang et al, Cancer Res. 61, 565, 2001***

- 0

- 4

- 8

- 12

- 16

- 20

- 24

- 28

- 32

- 36

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- 70

- 80

- 90

- 100

**     ****Weeks**

**Percent survival**

***p21+/+***** AIN-76A Diet**

***p21+/-***** AIN-76A Diet**

**p21-/- AIN-76A Diet**

***p21+/+***** Western Diet**

***p21+/-***** Western Diet**

***p21-/-***** Western Diet**

## Slide 8

## Selenium & Skin Cancer Prevention Trial 

**Skin Cancer**
**	****Squamous cell****	****	****218****	****	****190****	****1.14****	****0.93-1.39**
**	****Basal cell****	****	****377****	****	****350****	****1.10****	****0.95-1.28**
**Cancer (- Skin)**
**	****Lung****	****	****17****	****	****31****	****0.54****	****0.30-0.98**
**	****Prostate****	****	****13****	****	****35****	****0.37****	****0.18-0.71**
**	****Colorectal****	****	****8****	****	****19****	****0.42****	****0.18-0.95**
**	****Breast****	****	****9****	****	****3****	****2.88****	****0.72-16.5**
**All Sites (- Skin)****	****	****77****	****	****119****	****0.63****	****0.47-0.85**

- Selenium & Skin Cancer Prevention Trial

**Clark et al. JAMA 276: 1957, 1996. **

- Phase III trial with 1,312 skin cancer subjects

- Se (200 g) as Brewers Yeast vs. Placebo, follow-up 6.4 yrs

## Prostate Cancer Prevention Selenium and Vitamin E

- Cancer Prevention Trail (SELECT) ($175M)

- 32,000 men, age _>_55 (_>_ 50 for Black Men)

- Selenium 200 ug/d
- Vitamin E 400 mg/d

- Vitamin E

- Placebo

- Selenium

- 7 + Years Treatment
- Endpoint Prostate Cancer Incidence

## Early Biomarkers Needed

- _Ideal Qualities_:
- Readily accessible
- Easily & reliably assayed
- Differentially expressed
- Directly associated with disease progression
- Modulable
*Predictive*

## Slide 12

## Diet May Influence Genetic & Epigenetic Events Associated with Several Cancer Processes

**Diet May Influence Genetic & Epigenetic Events Associated with Several Cancer Processes**

**DNA Repair**

**Hormonal Regulation**

**Carcinogen**** **
**Metabolism**

**Apoptosis**

**Bioactive**
**Food**
**Components**

**Differentiation**

**Cell**** ****Cycle**

- U54 RFA Review Nov

## Numerous Dietary Components Can Alter Genetic and Epigenetic Events

- Essential Nutrients- Ca, Zn, Se, Folate, C, E
- Non-Essential
- 	Phytochemicals- Carotenoids, Flavonoids, Indoles, Isothiocyanates, Allyl  Sulfur
- 	Zoochemicals - Conjugated linoleic acid, n-3 fatty acids
- 	Fungochemicals - Several compounds in mushrooms
- 	Bacteriochemical - Those formed from food fermentations and those resulting from intestinal flora

## Gene Expression in Human Cultured Colon Cells

**Mariadason et al, Cancer Res . 60, 4561, 2000**

***.***

**Gene Expression in Human Cultured Colon Cells**

**Red - increased**
**Green - decreased**
**Black - unchanged**

- Butyrate

- Curcumin

## How Should We Consume Bioactive Food Components?

**150 mg**

**3 grams**

**150 grams**

**MARKET STAGE BROCCOLI**

**3-DAY SPROUTS**

**FREEZE-DRIED**
**SPROUT EXTRACT**

**All preparations contain the same quantity of detoxification enzyme inducer activity, (Glutathione S-transferase and Quinone Reductase)**

**How Should We Consume Bioactive Food Components?**

## S     S

- ARE

**keap-1**

**nrf2**

**keap-1**

**nrf2**

**nrf2**

- small

- maf

**Isothiocyanates**
**(OLTIPRAZ)**

- Cytoplasm

- Nucleus

**OLTIPRAZ**

- Gene expression

- HS

- SH

- “antioxidant responsive element”

## Effect of Nrf2 genotype on induction of GST and NQO1 activities by oltipraz in mouse liver (Ramos-Gomez et al. Proc Natl Acad Sci U S A 2001;98:3410)

**Effect of Nrf2 genotype on induction of GST and NQO1 activities by oltipraz in mouse liver (****Ramos-Gomez *****et al.****** *****Proc Natl Acad Sci U S A 2001;98:3410)**

**Oltipraz (drug)**
** ****and**
**isothiocyanates (nutrient) have ****similar**** mechanism of action**

## Tea (Camellia sinensis)

**Green Tea**

**Black Tea**

- 30-40%   Catechins
-     3-6%	  Caffeine
- ~310 mg polyphenols
- per 6 ounces

- 3-10%	 Catechins
-   2-6%	 Theaflavins
- > 20%	 Thearubigens
-   3-6%    Caffeine
- ~340 mg polyphenols
- per 6 ounces

- Dried
- Tea Leaves

- Crushed tea leaves
- Polyphenol oxidase
- Oxidation,
- Polymerization

**Yang CS. Personal Communication**

## Tea and Cancer Prevention

***Camellia Sinensis***

**Yang CS. Personal Communication**

- Skin

- Liver

- Colon

- Oral

- Esophagus

- Lung

- Stomach

- Prostate

- Mammary

## Tomato Varieties  

**Tomato Varieties**** **

**Types of Bioactive ****Compounds**** May Vary with New Varieties**

## Recent Epidemiologic Studies of Lycopene and Cancer Risk

_**Cancer **_** ****	**_**Type of Study**_** ****	**_**Reference**_
**Breast    ****	****Cohort****	****	****Dorgan et al.                                ****	****	****	****	****	****	****Can Cau Cont 9: 89-97, 1998**
**Colon****	****    ****	****Case-control****	****	****Franceschi et al.                       ****	****	****	****	****	****	****Int J Cancer ****	****72:56-61, 1997  **
**Lung****	****    ****	****Case-control****	****	****Agudo et al.                           ****	****	****	****	****	****	****Eur J Cancer 33:1256-61, 1997 **
**Prostate   ****	****Cohort****	****	****Giovannucci et al.                            ****	****	****	****	****	****J Natl. Cancer Inst. 87:1767-76, ****	****	****	****	****	****1995**
**	****	****	****	****	****	****	**

## Recent meta-analysis of Data from 11 trials concluded The random-effects relative risk (RR) estimate for raw and cooked garlic and colorectal cancer was 0.69 and for stomach was 0.53.  

***Fleischauer, et al.  Amer  JClin Nutr 72, 1047, 2000.***

**Prospective cohort study with 41,837 women age 55 to 69,  examined 127 food items. ****“The strongest association in the present study was that for garlic consumption, with an approximate 50% lesser risk associated with high consumption.” *****Steinmetz et al. Amer. J. Epidemiology 139:1, 1994***

## Effects of Microwave Heating of Garlic on Total DMBA-Induced DNA Adducts

**a**

**b**

**b**

**0**

**250**

**500**

**750**

**1000**

**          ****DNA Adducts**
**(nmol Adducts/mol DNA)**

**Control**

**Peel/**
**Crushed**

**30 seconds**

**60 seconds**

**Microwave/ Peel/**
**Crushed**

**a**

- Song and Milner** **J Nutr 1999;129:657-61

## Indole 3-carbinol changes site of hydroxylation of  estradiol (>2 and <16 OH).  Causes depression in tumor growth and apoptosis.

**(Telang, et al. PSEBM 216: 246: 1997).**

**How Much of A Given Food is Needed**

## Top 20 down-regulated genes from 3 microarray analysis from MCF-7 cells    (T: with, C: without 100μM indole-3-carbinol)

**ALOX5AP--arachidonate 5-lipoxygenase-a****	****	****0.451****	****0.016**
**BMP7--bone morphogenetic protein 7 ****	****	****0.309****	****0.017**
**ERCC6--excision repair cross-complemen****	****	****0.455****	**** .046**
**ESR1--estrogen receptor 1****	****	****	****	****0.415****	****0.001**
**EXTL3--exostoses (multiple)-like 3****	****	****	****0.509****	****0.011**
**GATA3--GATA-binding protein 3****	****	****	****0.521****	****0.013**
**HMG2--high-mobility group (nonhistone****	****	****0.479****	****0.011**
**Homo sapiens cDNA FLJ14201 fis, clone****	****	****0.444****	****0.015**
**Homo sapiens clone 23836 mRNA sequence****	****	****0.526****	****0.026**
**KIAA0165--extra spindle poles, S. cere****	****	****0.532****	****0.003**
**KRT7--keratin 7****	****	****	****	****	****0.505****	****0.001**
**LAP18--leukemia-associated phosphoprot****	****	****0.528****	****0.013**
**NRCAM--neuronal cell adhesion molecule****	****	****0.482****	****0.016**
**SFRP5--secreted frizzled-related prote****	****	****0.498****	****0.048**
**TCF3--transcription factor 3 ****	****	****	****0.528****	****0.034**
**UGDH--UDP-glucose dehydrogenase****	****	****	****0.536****	****0.029**
**Unknown****	****	****	****	****	****0.488****	****0.008**
**Unknown****	****	****	****	****	****0.481****	****0.015**
**Unknown****	****	****	****	****	****0.479****	****0.019**
**ZXDA--zinc finger, X-linked, duplicate****	****	****0.358****	****0.021**

**Top 20 ****down-regulated**** genes from 3 microarray analysis from MCF-7 cells    (****T:** **with,** **C: without 100μM indole-3-carbinol)**

**Wang, Kim and MilnerAACR 2002**

## Indole 3-Carbinol and Tamoxifen Interactions in Attached MCF-7 Cells

**Indole 3-Carbinol and Tamoxifen Interactions in Attached MCF-7 Cells**

- M Tamoxifen

- Integrated Density/Area

- (pixel value/mm2)

- 0

- 0.5

- 1

- 0-

- 20-

- 40-

- 60-

- 80-

- 100-

- 0

- 50

- 100

- I3C (M)

## Soy Intake and Cancer

**Concerns**
**Growth enhancement of human mammary tumors transplanted into mice that were fed soy or isoflavonids ****(Hsieh, et al. Cancer Res. 58:3833, 1998).**** **

**17 of 26 animal studies reveal soy or soybean isoflavones reduce tumor tumor development**

**19 or 21 human epidemiological studies provide evidence of protection against cancer, especially rectal and stomach cancers (1 study reported increase)**

## Soymilk Intake & Prostate Cancer Risk

- Cancer Causes Control 9: 553, 1998

- 0

- <1

- 1

- >1

- Daily Intake (servings)

- Relative Risk

- 1.0

- 0.9

- 0.8

- 0.3*

## More is Not Always Better: Energy Intakes and Expenditures Are Linked to Health!

**More is Not Always Better: Energy Intakes and Expenditures Are Linked to Health!**

## Caloric Restriction in Yeast causes silencing of genes and extended life span (Guarente and Kenyon Nature 2000; 408:255

## Colon Cancer and Exercise

**Colon Cancer and Exercise**

## Is it Possiblethat Bioactive Compoundsmight be beneficial in some circumstancesanddetrimental in other?

## Some Women Appear Susceptible to Flavonoids

- Several flavonoids found to cause change in MLL gene  on chromosome band 11q23
- Associated with increased risk of infant leukemia linked to MLL gene
- Some cancer patients treated with drugs that modify topoisomerase develop leukemia involving MLL gene.
- Ross (2000) Proc. Natl Acad. Sci. 97: 4411-4413.
- Strick et al. (2000) Proc. Natl Acad. Sci. 97:4790-4795

## Vitamin E Inhibits Cisplatin-InducedApoptosis in MCF-7 Breast Cancer Cells.

***Salganik, et al. Carcinogenesis 21: 909, 2000.***

**Control**

**     ****E**

**CP**

**CP+E**

**6 -**

**4 -**

**2 -**

**0 -**

**% Apoptosis +**

- *

- **

**Antioxidant reduces efficacy of cisplatin**

## One Size Does Not Fit All!

**One Size Does Not Fit All!**

## Just when I knew all of life’s answers,

**Just when I knew all of life’s answers,**
**They changed all the questions!!**