Tea contains polyphenols like catechins that may reduce cancer risk. Epidemiological studies on tea consumption and cancer have mixed results. Animal studies show tea frequently inhibits tumors in organs like the colon, esophagus, liver, and lungs. Tea's anticancer effects may be due to its ability to reduce oxidative stress, induce cell death, inhibit angiogenesis and cell proliferation, and interfere with DNA methylation.

1. Tea and Tea Polyphenols in Cancer Prevention Sharon Ross, PhD, MPH [email_address] Nutritional Science Research Group, Division of Cancer Prevention

2. 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 O OR 2 HO OH OH R 1 HO

3. Increased Concentration of Catechins Following Black Tea Consumption Plasma Levels (nmol/L) Urinary Excretion (nmol/h) Fecal Excretion (  mol) Epigallocatechin Epicatechin Epigallocatechin Gallate Epicatechin Gallate Warden BA, et al. J Nutr 2001;131:1731-1737

5. Recent Epidemiological Studies of Tea And Gastric/Stomach Cancer Country (Tea type) Study Type Risk/Association Reference China (green tea) India (unknown) Japan (green tea) Japan (green tea) Japan (green tea) China (unknown**) Japan (green tea) Japan (green tea) Case- control Case- control Prospective cohort Prospective cohort Prospective cohort Nested case- control Prospective cohort Nested case- control Decrease Decrease No association No association* No association Decrease Decrease*** No association Setiawan 2001 Rao 2002 Tsubono 2001 Hoshiyama 2002 Fujino 2002 Sun 2002 Sasazuki 2004 Hoshiyama 2004 * Deaths **Urinary polyphenols/metabolites ***distal gastric, women only

8. Tea and Cancer Prevention Camellia Sinensis Yang, CS. Personal Communication Skin Liver Colon Oral Esophagus Lung Stomach Prostate Mammary

9. Results of Animal Studies With Tea Number of Studies Yang CS. Personal Communication 1 10 Lung 3 6 Breast 0 1 Prostate 0 1 Bladder 0 7 Liver 3 10 Intestine/Colon 0 5 (Fore)stomach 1 3 Esophagus 0 2 Oral 5 13 Skin Not Protective Protective Organ Site

10. Lung Tumorigenesis Model in A/J Mice Yang CS. Personal Communication Tea given during the initiation stage -2 0 16 weeks tea water 1 NNK Tea given during the post-initiation stage water tea 0 16 weeks 1 NNK Tea given after lung adenoma formation water tea 0 16 weeks 52 weeks NNK -2  Tumors  Tumors  Tumors

11. The TRAMP Mouse Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) animal model that express the oncogene SV40 T antigen specifically in the epithelium of the prostate. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Gupta et al. PNAS 2001;98:10350-10355. 100 50 0 30 Weeks 24 18 12 6 metastasis neoplasia hyperplasia puberty TRAMP: A Model for Prostate Cancer Progression Greenberg et al. (Found on TRAMP webpage)

12. Reactive Oxygen Species Endoplasmic Reticulum Mitochondrion O 2 H 2 0 2 OH Damage DNA, RNA Oxidize Proteins (enzymes, histones) Oxidize Lipids Activate Cell Suicide TEA X

13. Biological Activities of Tea Polyphenols Induce Phase I and Phase II enzymes Inhibit cell proliferation and induce apoptosis Several effects on cell signaling pathways (e.g., cyclooxygenase) Inhibit angiogenesis and invasion Inhibit DNA methyltransferase activity

14. NF-  B Metastasis (MMPs, cell adhesion molecules, cell surface proteases) Angiogenesis (Cox-2, NOS, VEGF) Proliferation (c- myc , cyclin D1, gro cytokines [IL-2, -6]) Oncoproteins (Her-2/neu, Ras) IKK activation CK2 induction I  B I  B Activation and Roles of NF-  B in Oncogenesis Altered cytokine production NF-  B nfkb gene amplif., rearrangement Survival (Bcl-x L , A1/Bfl-1, IEX-1L, IAP1, IAP2) Mutations in I  B genes Co-acting factors (AP-1, AhR, c/EBP, p300) Modifications (phosphorylation, acetylation) EGCG [Proteasome] DEX Sonenshein GE. Personal Communication

15. Tea Polyphenol Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase Activity Cancer Res. 63(22): 2003

17. Identification of Genes Affected by EGCG Treatment in D3-1 Breast Cancer Cells 24 h samples Sonenshein GE. Personal Communication 1 2 3 4 1 2 3 4 0.37 0.36 0.42 0.61 0.17 0.25 0.39 0.3 0.91 1.32 0.46 0.48 0.4 0.94 0.57 0.46 0.79 0.80 0.46 0.48 0.36 0.51 0.36 0.3 0.57 0.91 0.51 0.46 0.27 0.58 0.48 0.45 0.70 0.90 1.01 0.85 0.41 0.93 0.52 0.48 0.74 0.93 0.46 0.64 0.31 0.56 0.44 0.37 0.95 1.37 0.56 0.69 0.2 0.55 0.26 0.23 0.65 0.77 0.73 0.72 0.4 0.67 0.62 0.49 0.57 0.67 1.51 0.01 0.09 0.46 0.13 0.11 1.05 0.84 0.93 1.09 1.04 0.95 0.61 0.69 0.70 1.02 0.36 0.59 0.17 0.6 0.25 0.21 0.92 0.80 1.00 0.31 0.46 0.74 0.47 0.42 0.85 0.95 0.57 0.53 0.5 0.84 0.52 0.45 0.97 1.13 0.49 0.43 0.43 0.85 0.45 0.37 0.87 1.08 0.49 0.84 0.55 0.91 0.65 0.5 0.89 1.00 0.35 0.37 0.43 0.82 0.52 0.46 0.87 1.06 0.51 0.49 0.36 0.81 0.66 0.47 0.92 0.85 0.57 0.59 0.43 0.72 0.52 0.43 0.87 0.87 0.34 0.53 0.48 0.75 0.47 0.44 0.79 0.91 1.42 2.03 0.39 0.84 0.56 0.5 2.31 2.12 0.49 0.53 0.75 0.91 1 0.5 1.31 1.51 0.95 1.00 1.9 2.05 2.43 2.36 1.25 1.43 1.62 1.43 2.08 1.88 2.17 2.22 1.26 1.44 1.37 2.14 1.88 2.01 2.02 2.6 1.21 1.24 1.08 1.45 1.93 1.53 1.6 1.56 1.32 1.75 0.94 1.22 1.5 2.3 0.71 0.78 2 hours 7 hours 1 2 3 4 0.14 0.36 0.31 0.5 0.003 0.17 0.55 0.37 0.44 0.005 0.32 0.64 0.3 0.35 0.005 0.24 0.44 0.49 0.47 0.002 0.33 0.62 0.32 0.45 0.004 0.28 0.52 0.48 0.48 0.002 0.28 0.73 0.39 0.45 0.011 0.31 0.52 0.47 0.6 0.003 0.08 0.47 0.4 1 0.075 0.65 0.46 0.47 0.45 0.002 0.2 0.63 0.28 1 0.082 0.44 0.76 0.43 0.49 0.009 0.4 0.79 0.43 0.52 0.014 0.37 0.83 0.45 0.5 0.020 0.36 1.02 0.38 0.43 0.065 0.4 0.77 0.49 0.57 0.011 0.39 0.85 0.51 0.55 0.022 0.5 0.73 0.57 0.65 0.004 0.94 0.75 0.67 0.63 0.035 0.71 0.83 0.72 0.81 0.005 1.03 0.91 0.54 0.6 0.148 1.7 1.51 1.39 1.37 0.007 1.84 1.53 1.47 1.44 0.008 1.82 1.56 1.77 1.75 0.001 2.11 2.69 2.11 2.08 0.003 5.27 2.31 2.22 2.96 0.054 p value 24 hours UNIQID AND GENE NAME AI003699 LIM and SH3 protein 1 AA099134 Hypoxia up-regulated 1 AA181307 aryl hydrocarbon receptor AA520985 rab3 GTPase-activating protein AA488674 myeloid cell leukemia sequence 1 H50344 tight junction protein 1 AA464532 thrombospondin 1a2 AA053886 SREBP 2 AA995560 protein tyrosine phosphatase AA872383 metallothionein 1E (functional) AI031571 epithelial cell transforming sequence R45056 Human clone 23721 mRNA sequence AA151214 Ras-GTPase activating protein N69204 chromosome segregation 1 W69399 H1 histone family, member 0 AI865149 karyopherin alpha 6 R59621 LanC (bacterial lantibiotic synthetase c H92201 nucleosome assembly protein 1-like 4 AA773461 chord domain-containing protein 1 W46972 solute carrier family 20 AA598794 connective tissue growth factor AA916325 aldo-keto reductase family 1,C3 AI924357 aldo-keto reductase family 1,C2 R93124 aldo-keto reductase family 1,C1 AI023541 carbonic anhydrase IX T54298 PPAR(gamma) angiopoietin related

19. Summary Green, black and oolong teas are differentiated by tea manufacturing processes Teas are rich in polyphenols, e.g., catechins, theaflavins, thearubigens Epidemiological studies show inconsistent evidence for the association between tea consumption and reduced risk of cancer Preclinically, tea frequently inhibits colon, esophageal, liver, lung and skin tumorigenesis Tea and tea polyphenols may have multiple sites of action