Epigenetics in the

Anti-Cancer KitchenJeanne M. Wallace, PhD, CNC • www.Nutritional-Solutions.net

Harnessing the Power of Food

Diet & Nutrition?For Cancer?

With our most aggressive weapons, we aren’t winning the War Against Cancer.How could some wimpy foods have any effect?

Cancer Type

Greater Survival Associated With... REF

Breast

≥5 servings veggies/fruit per day + exercise 30 min, 6x/wk (45% more likely to

survive 10 yrs)

J Clin Oncol.,2007 Jun

10;25(17):2345-51.

Ovarian↑ intake of cruciferous

veggies (45% more likely to survive 5 yrs)

Int J Cancer, Aug

2003;106(2):264-9.

Gastric less commercially-raised meat & animal fat

Cancer, Sept 2000;89:

1205-13.

Pancreatic lower fat, higher fiber, avoid excess calorie intake

J Am Coll Nutr, Jun 1993;

12(3):109-26.

Post-Diagnosis Diet & Cancer Survival

Base pairsLetters

Chromosome Library

GeneRecipe

DNAWord

GeneticsPrimer

Studies of cancer in identical twins:Somatic gene mutations account for < 5-10% of cancers PNAS, 2005;102:10604-9. • Biometrics 2005;61, 55-63.

Every cellhas the entire

LIBRARYat its disposal

“Give me the coding sequences of a chimpanzee and the regulatory mechanisms of a mouse,

and I’ll give you a mouse.”—Susumu Ohno

Evolutionary Geneticist

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

1801

1548

1365

1086971916

709599

478383

Number of PublicationsEpigenetics & Cancer

Microbiome

Ecosystem ➠ Gene Expression

PositiveEmotions

Stress

Toxins

Oxidation

Radiation

Infection

Diet

Disease Health

Carcinogens CircadianRhythm

HealthyLifestyle

Ways toModifyGene Expression

4

12

34

Initiate

Unwrap

Unzip

Assemble

1Start withthe Master Switch

How do theseenvironmentalinfluences“talk”to the genes?

Stress

Toxins

Oxidation

Radiation

Infection

Disease

Carcinogens

NFkßCancer’s MasterSwitch

Curr Allergy Asthma Rep, 2013;13: 44–9. • Curr Signal Transduc Ther, 2006:1:25-52. • Cancer Res, Feb 15, 2007;13(4):1076-82.

TRIGGERS carcinogensoxidationviral infectioninflammationradiationchemotherapy

NF

kß

NFkß Activates 400+ Genes

Exp Biol Med (Maywood), 2008;233(1):21-31.Curr Signal Transduc Ther, 2006:1:25-52.

AngiogenesisVEGF, TNF, IL-8

InflammationIL-6, COX-2,

TNF, chemokines

Survival/Anti-apoptosisbcl/bax, survivin

Proliferationmyc, IL-6,

Metastasis5-LOX, CAMs

NF

kß

Dee

per

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ails

Spices Inhibit NFkß

Ann NY Acad Sci, 2004 Dec;1030:434-41.

anise

basil

black pepper

caraway

cardamom

chili pepper

cinnamon

clove

coriander

cumin

fennel

fenugreek

flaxseed

garlic

ginger

Holy basil

lemongrass

licorice

mint

mustard seed

nutmeg

oregano

parsley

rosemary

saffron

tamarind

turmeric

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Having fresh herbs available willchange the way that you eat

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enBerbere

Spice Mix(Ethiopian)

dried red chiles, black peppercorns, ginger, cloves, coriander seeds, ajowan, allspice berries, cardamom, fenugreek,

cinnamon stick

Chat Masala

(Indian)

asafoetida, mint, ginger, ajowan, cayenne, black salt, mango powder, cumin, dried pomegranate seeds

CurryPowder

dried red chiles, coriander seeds, mustard seeds, black peppercorns, fenugreek seeds, ginger, turmeric

5 Spice Powder

star anise, fagara, cassia, fennel seeds, cloves

GaramMasala

(Indian)

cumin, coriander seeds, cardamom, black peppercorns, cloves, mace,

bay leaf, cinnamon

JamaicanJerk

chiles, thyme, cinnamon, ginger, allspice, cloves, garlic, onions

Suppressing NFkß

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en Suppressing NFkßQuatre-Epices(French)

black peppercorns, whole cloves, nutmeg, ginger

PanchPhoran

(Indian)

cumin seeds, fennel, mustard, fenugreek, nigella

Ras-el Hanout

(North African)

peppercorns, cardamom, mace, galangal, nutmeg, allspice, cinnamon, ash berries, cloves, ginger, turmeric, nigella, lavender, rosebuds, orrisroot,

cassia, fennel seeds

Sansho7 Spice(Japanese)

sansho, seaweed, chile, orange peel, poppy seeds,

white or black sesame seeds

Zahtar(Middle Eastern)

sumac, roasted sesame seeds, ground thyme

Beans (dried)

cumin, cayenne, chili, epazote, parsley, pepper, sage, savory, thyme

Beef(grass-fed)

basil, bay, chili, cilantro, curry, cumin, garlic, marjoram, mustard, oregano, parsley, pepper,

rosemary, sage, savory, tarragon, thyme

Cheese(pasture-

raised)

basil, caraway, celery seed, chervil, chili, chives, coriander, cumin, dill, garlic, horseradish,

lemon peel, marjoram, mint, mustard, nutmeg, paprika, parsley, pepper, sage, tarragon, thyme

Chickenallspice, basil, bay, cinnamon, curry, dill,

fennel, garlic, ginger lemongrass, mustard, paprika, rosemary, saffron, sage,

savory, tarragon, thyme

Eggs(omega-3)

basil, chervil, chili, chives, curry, dill, fennel, ginger, marjoram, oregano, paprika, parsley,

pepper, sage, tarragon, thyme

Fish(wild, cold-

water)

anise, basil, bay, cayenne, celery seed, chives, curry, dill fennel, garlic, ginger, lemon peel,

mustard, oregano, parsley, rosemary, thyme, saffron, sage, savory, tarragon, marjoramin

the

kit

chen

What does it go with?

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en Lamb(grass-fed)

basil, bay, cinnamon, coriander, cumin, curry, dill, garlic, marjoram, mint, mustard,

oregano, parsley, rosemary, savory, tarragon, thyme

Potatoesbasil, caraway, celery seed, chervil, chives, coriander, dill, marjoram, oregano, paprika,

parsley, rosemary, tarragon, thyme

Salad Dressings

basil, celery seed, chives, dill, fennel, garlic, horseradish, marjoram, mustard, oregano, paprika, parsley, pepper, rosemary, saffron,

tarragon, thyme

Saladsbasil, caraway, chives, dill, garlic, lemon peel, lovage, marjoram, mint, oregano,

parsley, rosemary, tarragon, thyme

Soupsbasil, bay, chervil, chili, chives, cumin, dill, fennel, garlic, marjoram, parsley, pepper,

rosemary, sage, savory, thyme

Tomatoesbasil, bay , celery seed, cinnamon, chili,

curry, dill, fennel, garlic, ginger, gumbo file, lemongrass, marjoram, oregano, parsley,

rosemary, savory, tarragon, thyme

What does it go with?

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enJeanne’s

Green Tea Chai 8 cups water

2 tsp cardamom pods (green)2 tsp whole black peppercorns

2 tsp whole cloves4 tsp cinnamon chips

4 tsp zest from an organic orange4 whole star anise

4 whole nutmeg bulbs4 tsp minced fresh ginger2 tsp pure vanilla extract

4 tea bags (4 TBSP loose) green tea

Bring water to boil, add spices (don’t add the tea yet). Cover, reduce heat and simmer for 20 minutes, or longer if you like it spicier. Remove from heat, add tea leaves and steep for 3 minutes. Strain into glass pitcher. Store refrigerated for up to 10 days.

To make one cup of chai, warm 1/2 cup unsweetened soy milk or organic grass-fed cow’s milk with one 1/2 cup of the liquid chai blend. Add stevia to sweeten if desired. Makes 8-10 servings.

Spiced

Chai

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enSpa in a Pitcher

1 orange, thinly sliced into rounds 1 Meyer lemon, thinly sliced into

rounds 1 unpeeled English cucumber,

thinly sliced into rounds 3 sprigs fresh thyme, tarragon, or mint

or fennel fronds, or a combination 1 TBSP freshly squeezed Meyer lemon

juice 8 cups water or sparkling water

Put the orange, lemon, cucumber, herbs, and lemon juice in a large pitcher. Press the fruit, cucumber, and herbs against the bottom of the pitcher with a wooden spoon, pushing down and twisting slightly to release their juices and volatile oils. Add the water and stir to combine. Refrigerate for 1 hour before serving.

Variation: In place of the water, use a weak tea made with 8 cups of boiling water and 4 chamomile, ginger, or green tea bags. Let the tea cool to room temperature before adding it to the pitcher.

Rebecca Katz, The Longevity Kitchen, p. 200.

HerbedWater

photo credit: Leo Gong

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When lettuce is not in season, this makes a lovely green salad and accompaniment to meals.

1 bunch parsley, stems removed

1 shallot, thinly sliced

1 tsp drained capers

4 cornichons, thinly sliced

juice of 1 lemon

3 TBSP olive oil

sea salt & fresh ground blk pepper

Roughly chop the parsley. Mix parsley, shallots, capers and cornichons. Mix the lemon juice and olive oil together and add to the salad. Sprinkle lightly with salt to taste. Top with freshly ground pepper.

Tamar Adler An Everlasting Meal, p. 94

SalsaVerde

DON’T MISS Chef Rebecca Katz’ Parsley Mint Drizzle

in The Longevity Kitchen, p. 189.

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enSpice Rub Dallas & Melissa’s

Mocha Steak Rub1 TBSP black peppercorns

1 TBSP coriander

2 tsp sea salt

1/2 tsp cloves

1 tsp cinnamon

1 tsp unsweetened cocoa

2 tsp coffee beans

Crush all ingredients with a mortar and pestle (or in a spice grinder). Massage the spice rub generously into the surface of the steaks, cover and allow to rest for at least 30 minutes before cooking. Makes enough for about 4 grass-fed/grass-finished steaks.

It Starts with Food, p. 279

Nuts Inhibit NFkß

Ann NY Acad Sci, 2004 Dec;1030:434-41.

almondscashewsflaxseedshazelnutspecanssesame seedswalnuts

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en CURRY SPICED ALMONDS1 TBSP olive oil

2 cups raw almonds

1 tsp sea salt

1 tsp turmeric

½ tsp ground black pepper

¼ tsp cumin

¼ tsp coriander

Place olive oil in a large cast iron skillet over medium heat (warm the pan first, then add oil).

Add almonds to skillet. Stir in salt, turmeric, pepper, cumin and coriander. Continue toasting the almonds in the skillet until they are fragrant, about 5 minutes. Remove from heat and allow the nuts to cool then serve!

www.elanaspantry.com

SpicedNuts

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en Pesto!Basil Pistachio Pesto

1 cup tightly packed basil1 TBSP lemon juice

1/4 tsp sea salt1/4 tsp freshly ground pepper

1/2 cup raw pistachios1/3 cup extra virgin olive oil

1 TBSP water (optional)

Combine all the ingredients in a food processor and process until well blended. Do a FASS check to see whether you need to add another squeeze of lemon juice or a pinch of salt. Add a tablespoon of water if you want a thinner consistency.

Rebecca Katz, The Longevity Kitchen, p. 179.

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Dukkah

Rebecca Katz’ Pistachio Dukkah2 TBSP white sesame seeds

1 TBSP whole coriander seeds

1 TBSP whole cumin seeds

2 tsp fennel seeds

¼ cup raw almonds

¼ cup pistachios

1/4 tsp freshly ground black pepperHeat a medium size pan over low heat and toast the sesame seeds until just golden, about 1 ½ minutes. Remove and let cool. Place the coriander, cumin and fennel seeds in a pan and toast until aromatic, another 1 ½ minutes. Remove and let cool.

Place the almonds and pistachios in a food processor with a fitted blade and pulse until like sand. Add the sesame seeds, coriander, cumin, fennel and process until well blended.

Store in an airtight container in the refrigerator for up to 1 month.

Histone modifiers UNWRAP the DNA strand

Unwrapthe Gene

2

Dee

per

Det

ails

‣ Nucleosome, 4 histones pairs wrapped by 147 base pairs DNA

‣ Histone tails epigenetically active

‣ Tails modified by acetylation

‣ Also via: methylation, phosphorylation, isomerization, ubiquitination

Dee

per

Det

ails Euchromatic

UNWRAPPEDpermissive of

gene transcription

HeterochromaticWRAPPED

gene silencing

H3H4

acetylation of histone tails

Histone acetylasetransferases

(HATs)add

acetyl groups

Histonedeacetylase

(HDAC)remove

acetyl groups

WrappedoncogenesD

eepe

r D

etai

ls

Unwrappedtumor suppressor genes

Cancer reflectsan imbalance

of HATs to HDACs

Epigenomics, 2011;3(4):503-18. • Ann Rev Nutr, 2008;28:347-66.

Histone Modifiers

Wrapped

Unwrapped

InhibitHDACs

InhibitHATs

Histone Acetyl-Transferase

HAT

HistoneDeacetylase

HDAC

Genisteinsoy

Curcuminturmeric, curry

EGCGgreen tea

Seleniumbrazil nuts

Sulforaphanecruciferous veggies

Resveratrolgrapes, wine

Allyl mercaptangarlic

➠

➡➡➡

➡➡➡

➡➡➡

P-COUMARIC ACIDPHYTIC ACIDQUERCETINQUERCITRINRUTINSALICYLIC ACIDSINAPIC ACIDSINIGRINSQUALENESTEARIC ACIDSTIGMASTEROLSUCCINIC ACIDSULFORAPHANETRANS-FERULIC ACIDVANILLIC ACID

ALLYL-ISOTHIOCYANATEALPHA-LINOLENIC ACIDCAFFEIC ACIDCHLOROGENIC ACIDCINNAMIC ACIDCITRIC ACIDDIINDOLYLMETHANE (DIM)FERULIC ACIDFUMARIC ACIDHISTIDINEINDOLE-3-ACETONITRILEINDOLE-3-CARBINOLKAEMPFEROL4-PE-ISOTHIOCYANATE6-MS-ISOTHIOCYANATE

Can’t I just take a pill?

Broccoli SproutsCHALLENGE: “These veggies are too bitter.” “These veggies upset my digestion.”

‣50x ↑ sulforaphane than mature broccoli (1 oz sprouts = 1+lbs broccoli)

‣Purchase certified pathogen-free seed specifically for sprouting

‣Sprout in light (not dark) for 33% ↑ glucosinolates; 62% ↑ phenolics

PNAS. 1997 Sep 16;94(19):10367-72. • J Sci Food Agric, 2008;88:904-10. • http://anrcatalog.ucdavis.edu/pdf/8151.pdf

SPRING/SUMMERarugula

bok choybroccoli sprouts

collardsdaikon radish

kalemustard greens

radishsalad turnipwatercress

FALL/WINTERbroccoli

broccoli sproutsBrussels sprouts

cabbagecauliflower

kalekohlrabirutabaga

turnipwasabiin

the

kit

chen

OptimizingPhytonutrientContent

Molecules, 2011 Aug;16(8):6816-32.J Sci Food Agric 2007;87(6):930-44.

‣SEASONAL: autumn grown broccoli, cabbage & turnips ↑ levels of glucosinolates

‣ORGANIC: field pests needed to signal plant to produce phytonutrients

‣LOCAL/FRESH: broccoli ↓ 60% flavonoids in 10 days

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PEITC4-PENTENYL-

ISOTHIOCYANATE

6-MSITC6-METHYL-SULFINYL-

HEXYL-ISOTHIOCYANATE

ALLYL-ISOTHIOCYANATE

Wasabi

Exp Ther Med 2010 Jan;1(1):33-40. J Cell Mol Med 2012 Apr;16(4):836-43.

‣406 genes↑≥3-fold

‣717 genes↓≥3-fold

NFKß IL-6 COX-2 IL-10

12

53

1711

6

71957 ControlWasabi

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Spread1 cup fresh or frozen shelled

edamame, mixed with a spritz of fresh lime juice and a pinch sea salt2 TBSP freshly squeezed lime juice

3 TBSP extra-virgin olive oil

1/2 tsp sea salt2 tsp wasabi powder, mixed with 1

tsp water

1 tsp chopped fresh cilantro or parsley

1/4 cup filtered water

Combine all of the ingredients in a food processor and process until smooth. Do a FASS check and add additional lime juice or salt if needed. Store in an airtight container in the refrigerator for 2 days. Cook Note: If you’re up for it, go the extra mile and add some additional heat! Another 1/4 tsp of wasabi powder will turn up the zip-zowie factor in this dip.

Rebecca Katz, The Longevity Kitchen, p. 172.

Wasabi

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1 head cauliflower

1 TSP paprika

1 tsp unsweetened raw cocoa

1/2 tsp sea salt

1/4 tsp ground black pepper

1 clove garlic, minced

2 TBSP olive oil or pastured ghee

Preheat the oven to 375°F. Cover a baking sheet with unbleached parchment paper. Cut the cauliflower into bite-sized florets and place in a large mixing bowl. In a small bowl, combine oil and spices. Drizzle spiced oil over florets and toss to thoroughly cover. Spread cauliflower on the baking sheet in a single layer. Bake for 25-35 minutes until fork tender.

Melissa Joulwan’s Well Fed, p. 127

RoastedCauliflower

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BRUSSELS SPROUTS with Caraway

2 TBSP extra-virgin olive oil

1 TBSP Grade B maple syrup

1 TBSP Dijon mustard

1 tsp caraway seeds

Pinch of red pepper flakes

1 pound Brussels sprouts, trimmed, cut in half, rinsed, and patted dry

1/4 tsp sea salt Preheat the oven to 400°F. Line a rimmed baking sheet with parchment paper. Put the olive oil, maple syrup, mustard, caraway seeds, and red pepper flakes in a large bowl and whisk to combine. Add the Brussels sprouts and toss until evenly coated. Transfer to the lined baking sheet and spread in an even layer. Sprinkle with the salt. Bake for 20 to 25 minutes, until the outer leaves are crispy and the Brussels sprouts are tender all the way through. Transfer to a bowl and serve immediately.

Rebecca Katz, The Longevity Kitchen, p. 99.

BrusselsSprouts

✦Rate of DNA damage reduced to normal levels

✦Cancer incidence in BrCa1 carriers reduced 50%

n=55 BrCa1+ women (compared to BrCa1- siblings)275mcg selenium x 2mo - 2 yrsCompare DNA damage and cancer rates

BrCa1

Hered Cancer Clin Pract 2006 Jan 15;4(1):58. Cancer Epidemiol Biomarkers Prev 2005;14:1302-6.

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en Brazil Nut Pizza CrustGround Brazil nuts serve as a high-protein, low-carbohydrate substitute for wheat flour in this creative and tasty pizza dough. Brazil nut flour bakes up into the most “bread” like consistency of all the nut flours.

1 cup ground Brazil nut flour

1/4 c of arrowroot powder

3 TBSP olive oil

2 large omega-3 eggs

½ tsp sea salt

Combine all ingredients in a mixing bowl (it will be the consistency of pancake batter). Pour onto parchment paper-lined baking sheet (11”x15”), and spread evenly with a spatula to form a thin crust.

Bake in a preheated 350°F oven for 10-12 minutes. Remove from oven, and spread a thin layer of tomato sauce on the bread, leaving ½” crust zone at the edges. Add your favorite toppings. Bake for another 10-12 minutes until heated and bubbly. Enjoy!

Brazil Nuts

Methyl groups prevent the DNA strand from being

UNZIPPED

Unzipthe Gene

3

‣ Added via DNA Methyltransferase enzymes (DNMTs)

‣ Sits on C-paired-to-G (CpG) dinucleotide

‣ CpGs—rare in genome—cluster in islands of promoter regions for housekeeping and tumor suppressor genesD

eepe

r D

etai

lsEARLY

CH₃MethylGroup

‣ Added via DNA Methyltransferase enzymes (DNMTs)

‣ 3 families DNMTs: DNMT1, DNMT3a, DNMT3b

‣ DNMT3b most implicated in cancer

Dee

per

Det

ails

EARLY

CH₃MethylGroup

Disrupted Patternof DNA Methylation

GlobalHYPO-

methylation

Promoter RegionHYPER-

methylation

‣Genomic instability

‣Increase cancer risk

‣Silencing of housekeeping & tumor suppressor genes

Top Curr Chem 2012;29:2175-81.

J Mol Cell Biol 2011;3:51-8.Dee

per

Det

ails

DNA Repair GeneDetoxification Gene

Tumor Suppressor Gene

HealthyCells

Promoter RegionHYPER-

methylation

Global DNAHYPO-

methylation

Cancer

Methylation ModifiersPromoter Region

HYPER-methylation

DNMT InhibitorsDNMT InhibitorsSeleniumCurcumin

EGCGResveratrolGenisteinVitamin ALycopene

Apple polyphenolsCrucifers:

isothiocyanates& sulforaphane

Berry polyphenolsCoffee

Butyrate

Global DNAHYPO-methylation

Methylation Support

FolateVitamin B12Vitamin B6

BetaineCholine

MagnesiumZinc

Top Curr Chem 2012;29:2175-81.

‣Deficiency leads to global hypomethylation

‣Folate deficiency increases risk of many types of cancer

‣Excess folic acid may accelerate growth of pre-cancerous lesions

‣Choose food sources and ensure ample intake DNMT regulators

Folate vs folic

Top Curr Chem 2012;29:2175-81.

✦Wnt signaling pathway regulates cell growth and apoptosis

✦Methylation of its promoter region leads to evasion of apoptosis

✦Significant reduction of its methylation w/blk raspberries

Ph 1 Pilot Study n=20 CRC pts

20gm TID freeze-dried blk raspberry pdr (~1.3#/d fresh) x 4 wks

Wnt/WIF-1

Clin Cancer Res, 2011 Feb 1;17(3):598-610.

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enGlobal Dark Leafy Greens8 cups, stemmed & chopped dino kale in bite size

pieces2 TBSP extra virgin olive oil

2 ½ cups or one medium red onion, cut into half moons

Sea salt3 cloves garlic, minced

1/4 tsp cumin seeds, (toasted) Pinch of cayenne1 tsp lemon zest

1 1/2 tsp freshly squeezed lemon juice1 1/2 tsp freshly squeezed lime juice1/2 tsp grade B organic maple syrup

2 TBSP toasted pepitas (garnish)

Cover the kale with cold water and set aside. Heat the olive oil in a large, deep sauté pan over medium-high heat, then add the onion, a pinch of salt and sauté for 3 minutes. Decrease the heat to low and cook slowly until the onions are caramelized. While the onions are caramelizing toast the cumin seeds in a small pan over medium heat, shaking a few times for even toasting until they become aromatic and start to brown slightly. Transfer to a small bowl and set aside. In the same pan, add the pepitas, shaking the pan for even toasting, until they become aromatic. Transfer to a small bowl and reserve. Increase the heat to medium; add the garlic, cumin, pinch of cayenne and pinch of salt and sauté for 3 to 4 minutes. Drain the kale and add it to the pan. Sauté until the greens turn bright green and wilt, about 4 minutes. While the greens are cooking whisk together the lemon, orange juice, zests and maple syrup together. Test the greens and continue cooking, covered until they become a little more tender. Drizzle with the citrus maple mixture. Top with the toasted pepitas.

photo credit: Leo Gong

Rebecca Katz, The Longevity Kitchen, p. 95-98.

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enCARROT APPLE SLAW

1 /4 cup unsweetened dried cranberries 1/4 cup very thinly sliced red onion

3 TBSP freshly squeezed orange juice 1 TBSP freshly squeezed lemon juice 8 ounces carrots, peeled and thinly

sliced into 1/4-inch strips 1 Granny Smith apple, thinly sliced into

1/4-inch strips 1 TBSP chopped fresh mint

1 /4 tsp sea salt 2 TBSP extra-virgin olive oil

1 TBSP slivered almonds, toastedPut the cranberries, onion, 1 TBSP of the orange juice, and the lemon juice in a small bowl and stir to combine. Let sit for a few minutes to allow the juices to penetrate the cranberries and onion. Put the carrots, apple, mint, salt, cranberry mixture, and remaining 2 tablespoons of orange juice, and salt in a large bowl and toss gently to combine. Drizzle with the olive oil and toss again. Scatter the almonds over the top.

Rebecca Katz, The Longevity Kitchen, p. 84.

Slaw

photo credit: Leo Gong

‣Not estrogen, rather SERM - in vivo competes with estrogen and xenoestrogens

‣Modulates estrogen via many pathways - ↑ SHBG, ↓ circulating estrogen, ↑ 2:16-OH estrogen ratio

‣Rodents metabolize soy differently - lower isoflavone conjugation leads to 20-150-fold ↑ circulating levels than in humans

FAQ: Is SOY safe forER+ breast cancer?

Population Findings Reference

Meta-Analysis:9,514 US & Asian

BrCa pts over ~7.5 yrs

↓Risk of recurrence in those eating soy foods

Am J Clin Nutr. 2012 Jul;96(1):123-32.

3,088 U.S. BrCa pts followed 5 yrs

↓ mortality with increasing intake soy isoflavones

Cancer Epidemiol Biomark & Prev.  2011;20(5):854-8.

5,042 Asian BrCa pts, followed 5 yrs

↓ risk mortality and ↓ recurrence in those with higher soy intake

JAMA. 2009 Dec 9;302(22):2437-43.

1,954 U.S. BrCa pts, followed 6 yrs

60% ↓ rate of recurrence with high isoflavone intake in post-menopausal pts on Tamoxifen

Breast Cancer Res Treat. 2009 Nov;118(2):395-405.

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enJALAPEÑO LIME

HUMMUS4 packages tempeh

6 cloves garlic, roasted2 small limes juiced

5 TBSP pickled jalapenos3 TBSP olive oil4 TBSP tahini

4 TBSP fresh cilantro1 TBSP cumin

1 tsp pepper flakessalt and pepper to taste

Cut tempeh into 1” cubes and place in a steamer: cook 15 minutes. Drain and allow to cool.

Combine all ingredients in a food processor. Blend until smooth and creamy. Garnish with additional jalapeño slices and cilantro sprigs.

Brigitta BorregoChef at Nutritional Solutions 2008-2011

Tempeh

BUTYRATE

Summer Winter

‣HDAC inhibitor

‣DNMT inhibitor

Summer

action of GI floraon soluble fiber

carb restrictionβ-OH-butyrate

Assembleor VETO4

MicroRNA REGULATE

assembly

Once a gene is unwrapped & unzipped, its proteins can be assembled...or blocked by miRNA

Dee

per

Det

ails

EMBO Mol Med 2012;4:143-59.Dee

per

Det

ails

mRNA

miRNA

microRNA

blocks

protein

assembly

Green teaCurcuminSoy foodsCrucif vegFolate

Mol Carcinog 2012;51:213-30. • Genes Nutr, 2011;6(2):93–108. • Pharm Res, 2010 Jun;27(6):1027-41.

Vitamins A/DResveratrolEllagic acidOmega-3sButryate

Cancer Prev Res (Phila) 2010;3:62-72.

↓miRNAsmodulation of genes relating to

cell proliferation, apoptosis, p53 function, differentiation, Ras activation, NF-kappaB

and angiogenesis

↑miRNAs

Dee

per

Det

ails

Mol Carcinog 2012;51:213-30.

Gene Pathways in Cancer

www.genome.jp/kegg/pathway

HDAC

Dee

per

Det

ails

HATS

PromoterHYPER-

methylationGlobal DNA

HYPO-methylation

VSVS

Putting it allTogether

&

✦ 70% reduced expression of her2neu

✦ 34% reduction in ki-67 (rate of cancer cell division and growth)

✦ 30% increase in apoptosis

Post-menopausal BrCa pts

Muffin with 25 g (2 TBSP) flaxseed meal vs “placebo” muffin x 4-5 weeks

Compare tumor baseline (biopsy) and subsequent lumpectomy

Her2neu

Clin Cancer Ther, 2005 May 15;11:3828-35.

‣Hormone-refractory prostate cancer cells

‣Genistein+quercetin+EGCG (2.5 microM) suppress growth and synergistically alter gene expression

Anticancer Res 2009;29:4025-32.

EGCG

EGCGGenisteinQuercetin

NFkßswitch off

ModifyHistones

wrap/unwrapMethylation

zip/unzipmicroRNA

veto

spicesturmeric

basilmint

rosemarygarlic

parsleythymesage

saffron

green teacurcumin

cruciferous vegsoy foods berries

red/purple grapescitrusgarlic

brazil nutsbutyrate

leafy greens beets

green tea/coffeecruciferous veg

soy foods berries/grapes

applesbrazil nutstomatoesbutyrate

green teacurcumin

cruciferous vegsoy foods

leafy greensomega-3 fats

butyrateraspberries

walnuts

Plain SteamedBroccoli

NFkßswitch off

Modify Histoneswrap/unwrap

Methylation zip/unzip

microRNAveto

BasilBroccoliRebecca Katz

Cancer Fighting Kitchen

in t

he k

itch

en

in t

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en Asian Cabbage Crunch3 cups red cabbage, shredded

3 cups Napa cabbage, shredded

1 cup red bell pepper, thinly sliced

2 TBSP fresh mint, finely chopped

1/4 cup fresh cilantro or fresh basil, finely chopped

3 scallions thinly sliced

1 cup of fresh or frozen shelled edamame (optional)

½ cup Sesame Miso Dressing (p. 187)

1 TBSP black sesame seeds

In a large bowl, combine the cabbages, red bell pepper, mint, and cilantro and scallions. Add the dressing and toss until well combined. Top with black sesame seeds. Allow the salad to sit for a few minutes so the flavors have a chance to penetrate the cabbage.

Rebecca Katz, The Longevity Cookbook, p. 87.

NFkßswitch off ✔

Modify Histoneswrap/unwrap ✔Methylation

zip/unzip ✔microRNA

veto ✔

in t

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enSmoked Salmon Nori Rolls

8 Nori Sheets1 cup Edamame Wasabi Spread (p. 172)

4 oz of Smoked Wild Salmon, spritzed with lime juice

16 pieces of cucumber, thinly sliced lengthwise

16 pieces of thinly sliced red bell pepper16 pieces of thinly sliced avocado

24 fresh mint leaves24 fresh cilantro leaves

Place the sheet of nori on a work surface with the rough side facing up. Carefully spread 2 tablespoons of the edamame wasabi mixture leaving 1½ inches between the mixture and the bottom edge of the nori that’s facing you. Place one piece of the salmon, 2 slices of cucumber, 2 slices of red bell pepper, 2 slices of avocado about 1 ½ inches from the bottom edge. Top with 3 mint leaves and 3 cilantro leaves. Begin to start rolling the nori, compressing the ingredients gently, away from your body to make a compact roll. Moisten your finger with warm water and run it along the inside edge of the flap that remains at the top of the roll, then press the moistened edge against the roll to seal. Repeat with the remaining ingredients. Cut the rolls in half on the diagonal with a sharp serrated knife before serving. Serves 4.

Rebecca Katz, The Longevity Kitchen, p. 140.

PATTERNof the

DIET

Not just individual foods...

NFkß & Diet Patternin Colorectal Cancer Patients

Clin Nutr, 2010 Feb;29(1):42-6.

↑ refined carbs↑ omega 6:3 ratio

(≅26:1)↑ alcohol

↑ omega 6:3 ratio (≅6:1)

↑ fiber↑ selenium↑ vitamin E↑ flavonoids↑ β-carotene↑ isoflavones

High NFkßHigh histological aggressiveness

Low NFkßLow histological aggressiveness

‣Prostate cancer patients not electing surgery, radiation, hormone therapy

‣Gene expression compared after 3 mo on diet

‣Expression of 500+ genes modified

‣Oncogenes were down-regulated

PNAS, 2008 Jun 17;105(24):8369-74.

Diet Alters Gene Expression B

EFO

RE

AFT

ER

Ketogenic diet ad lib (no decrease blood glucose cf control SD)

Analyzed genes across entire mouse genome

Compare gene expression profile tumor & contralateral normal brain

Brain AreaBrain Area

TUMOR Contralateral Non-Tumor

KetogenicDiet

StandardDiet

What’s the Effect of Ketogenic Diet on Gene Expression?

?

Reversion to NormalGene Expression Profile

Epilepsy Res, 2012 Jul;100(3):327-37.

‣COX-2 gene expression reduced to non-tumor levels in KD

‣↓ IGF-1 expression to levels seen in normal brain

‣Genes coding for GPx ↑ in normal but not tumor (effect reversed in standard diet)

What dothese 2DIETS have in common?

Low-fat Plant-based Diet

High-fatKetogenicDiet

45.3lbs/yr

Reduceintake SUGAR

GeneInstability

Antiapoptosis Inflammation

‣↑ IGF-1‣p53‣Bax/Bcl ratio

‣↑ ROS ‣↓/↑ GPx

‣↑ IL-6‣↑ TNF-α

‣↑ VEGF‣↑ PAI-1‣↑ free E₂

Angiogenesis

InsulinResistance

Exp Diabetes Res 2012:789174. Am J Pathol, 2006 Nov;169(5):1505-22.

p53Activity

of p53

StemCells

MalignantBehavior

Differentiation

Cell Cycle 2012 Dec 1;11(23):4436-46.

miR-145miR-34s

High Glycemic Load FoodsBread, white

Bread, whole wheatCereal

OatmealCrackersMuffinsBagels

CookiesPancakes Waffles

Soda popFruit JuiceDried fruits

Candy

ChipsSugarHoney

Flour, whiteFlour, whole wheat

CornCornmeal

PastaPotatoes

Potato chipsPretzels

Rice, whiteRice, brown

Fat-free foods

www.nutritiondata.comwww.glycemicindex.comin

the

kit

chen

5g=

INSTEAD OF THISINSTEAD OF THIS TRY THISTRY THIS

Food (1 cup serving) GL Food

(1 cup serving) GL

White flourWhole wheat

flour

7644

Almond Flour 0White flourWhole wheat

flour

7644 Coconut Flour 0

Corn, sweet yellow 35 Baby Corn 5

Hamburger bun 18

Rice paper wrap 4

Hamburger bun 18 Portobello

mushrooms 3Hamburger bun 18

Romaine lettuce “wrap” 0in

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INSTEAD OF THISINSTEAD OF THIS TRY THISTRY THIS

Food (1 cup serving) GL Food

(1 cup serving) GL

Brown rice 22 Cauliflower rice 2

Pasta noodles 22

Spaghetti squash 2

Pasta noodles 22 Zucchini

“noodles” 1Pasta noodles 22

Miracle noodles 0

Mashed potatoes 16 Mashed

cauliflower 4in t

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Case Reports

&

Cas

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epor

t ‣Dx: Feb 2006 Oligoastrocytoma III, L temporal

‣J.D., 39 yo male athlete, 6‘2” 172#

‣Tumor profiling pathology reports run 9/4/06, 4/27/07 and 9/17/07

Cas

e R

epor

t

p53 wild Survivin IL-6

NormalBaseline

p53cruciferous veggies ad lib

selenium 200mcg/dlow glycemic diet

Survivinmix toco E 400iu + 3 g vit C

milk thistle 400mg HS

IL-6

culinary spices ad lib↓ omega-6 intake / ↑ omega-3

boswellia 300mg x 3 TIDcurcumin 500mg TID resveratrol 100mg/d

feverfew @0.7% parth. 250mg/dfish oil 3g/d

OA III, p53, IL-6, survivin

Cas

e R

epor

t

p53 wild Survivin IL-6

NormalBaselineFollow-up

Cas

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t

‣Dx: Lynch Syndrome [TCC 12/08; CRC ’08; BrCa ’97; Endometrial ’90]

‣B.P., 61 yo female 6‘2” 145#

Baseline> 6 wks> 4 mo

VEGF

98

150

190

A1c6.8%

A1c5.6%

Lynch Syndrome VEGF

FOOD is a "language"translated by our bodiesas the dance of gene expression.When we eat we are silencing oncogenes and awakening tumor suppressor genes. With every bite of food, meal after meal, cancer patients can leverage their power as Epigenetic Engineers tore-engineer their health.

Diet, nutrients, phytochemicals, and cancer metastasissuppressor genes

Gary G. Meadows

# Springer Science+Business Media, LLC (outside the USA) 2012

Abstract The major factor in the morbidity and mortality ofcancer patients is metastasis. There exists a relative lack ofspecific therapeutic approaches to control metastasis, andthis is a fruitful area for investigation. A healthy diet andlifestyle not only can inhibit tumorigenesis but also can havea major impact on cancer progression and survival. Manychemicals found in edible plants are known to inhibit meta-static progression of cancer. While the mechanisms under-lying antimetastatic activity of some phytochemicals arebeing delineated, the impact of diet, dietary components,and various phytochemicals on metastasis suppressor genesis underexplored. Epigenetic regulation of metastasis sup-pressor genes promises to be a potentially important mech-anism by which dietary components can impact cancermetastasis since many dietary constituents are known tomodulate gene expression. The review addresses this areaof research as well as the current state of knowledge regard-ing the impact of diet, dietary components, and phytochem-icals on metastasis suppressor genes.

Keywords Cancer . Dietary . Nutrients . Phytochemicals .

Metastasis suppressor . Epigenetics

AbbreviationsBRMS Breast cancer metastasis suppressorCTGF Connective tissue growth factorDHA Docosahexaenoic acidDLC Deleted in colon cancerEGCG Epigallocatechin-3-gallate

EGF Epidermal growth factorEGFR Epidermal growth factor receptorEPA Eicosapentaenoic acidIFN InterferonKAI1 Kangai 1MALL Mal-likeMAPK Mitogen activated protein kinaseMKK Mitogen-activated protein kinase kinasemiR Micro RNANDRG N-myc downstream-regulated geneNM23 Nonmetastatic gene 23PDCD Programmed cell deathPEBP Phosphatidylethanolamine binding proteinPTEN Phosphatase and tensin homologRASSF Ras-associated domain familyRECK Reversion-inducing-cysteine-rich protein with

kazal motifsRhoGDI2 Rho GDP-dissociation inhibitor 2RKIP Raf-1 kinase inhibitor proteinSNRP Small nucleolar ribonucleoproteinTIMP Tissue inhibitor of metalloproteinaseTRAMP Transgenic adenocarcinoma of the mouse

prostate

1 Introduction

A major contributor to cancer mortality is the metastaticspread of cancer. While diet, nutrients, and specific naturalphytochemicals in plant-based foods such as fruits, vegeta-bles, and spices are known to inhibit metastasis, most stud-ies have to do with cancer prevention and inhibition ofprimary tumor growth. This review concerns the effect ofdiet and natural substances on metastasis suppressor genes,

G. G. Meadows (*)Department of Pharmaceutical Sciences, College of Pharmacy,Washington State University,P. O. Box 646510, Pullman, WA 99164-6510, USAe-mail: meadows@wsu.edu

Cancer Metastasis RevDOI 10.1007/s10555-012-9369-5Further

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