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breast cancer prevention by green tea

VIEWS: 2 PAGES: 9

									Breast cancer prevention by

         green tea




               NTR 416

               Yang Li

        Department of Nutrition

              April 25th




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Introduction

 Tea is one of the most consumed beverages worldwide. All tea is produced from the leaves of

Camellia sinensis. Tea is classified as green tea and black tea depending on the processing

method. Green tea is processed from fresh tea leaves which are steamed immediately after

harvest, resulting in minimal oxidation of the naturally occurring polyphenols. Black tea is

processed from dried and crushed leaves, through which indigenous tea polyphenols are oxidized

to other polyphenols. Partially oxidized tea leaves are Oolong tea [1].


 The process of green tea inactivates polyphenol oxidase and other enzymes, preserving the tea

polyphenols known as catechins. The major catechins are (-)-epigallocatechin-3-gallate (EGCG),

(-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), and (-)-epicatechin (EC). EGCG is

the most abundant catechin [2]. In recent years, EGCG has been shown to have anti-tumor effect.

Maryan R. Sartippour et al. [3] observed that green tea extract, including EGCG was effective in

inhibiting breast cancer by suppressing xenograft size and decreasing the tumor vessel density in

mice. Sanjay Gupta et al. [4] claimed that EGCG caused a G0/G1 phase cell cycle arrest and

apoptosis in prostate carcinoma cells. They observed that EGCG-mediated cell cycle

dysregulation and apoptosis was mediated via modulation of cyclin kinase inhibitor (cki)-cyclin-

cyclin-dependent kinase (cdk) machineary. Pro-EGCG was even considered as a potential drug

for cancer prevention and treatment due to its function in proteasome inhibition, growth

suppression, and apoptosis induction [5].


 To investigate the protective effect of EGCG for breast cancer, I begin with several

epidemiological studies to determine the association of green tea/EGCG and breast cancer.

Randomized controlled trials will be reviewed to establish the cause-and-effect relationship. To



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further understand the underlying mechanisms, animal studies and cell culture studies will be

quoted to explain it at the molecular level.


Epidemiological studies


 A meta-analysis conducted by Seely et al. [6] included 7 studies (5 cohort studies and 2 case-

control studies) examining the risk of breast cancer occurrence/recurrence in relation to green tea

consumption. The relative risk (RR) of breast cancer for the highest levels of green tea

consumption, 5 or more cups per day, in cohort studies was 0.89 (95% CI, 0.71-1.1), and in case

control studies, it was 0.44 (95% CI, 0.14-1.31). The RR of cohort studies for breast cancer

recurrence in all stages was 0.75 (95% CI, 0.47-1.19). A subgroup analysis of recurrence in stage

I and II showed a RR of 0.56 (95% CI, 0.38-0.83). Thus, high consumption of green tea may

prevent breast cancer recurrence at early stages.


 Another meta-analysis carried out by Sun CL et al. [7] reviewed 13 papers which examined

populations in eight countries and studies both green tea and black tea. The combined results

from the four studies on green tea indicated a reduced risk of breast cancer for highest versus

non/lowest intake (OR = 0.78, 95% CI = 0.61-0.98). They suggested that green tea but not black

tea consumption is related to a decreased risk of breast cancer. It has been shown that

catechins/EGCG has anti-tumor effect. If the beneficial effect of tea on breast cancer risk

attributes to catechins, lack of risk reduction associated with black tea may be due to the lower

level of catechins in black tea.


 A most recent meta-analysis conducted by Adeyemi A. Ogunleye et al. [8] investigated the

association between green tea consumption and breast cancer risk or recurrence. Nine studies,

including case-control studies and cohort studies, were included in the final analysis. They found


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that higher levels of green tea intake, more than 3 cups per day, were associated with a slightly

reduced risk of breast cancer recurrence (RR = 0.73, 95% CI: 0.56–0.96). However, the studies

of breast cancer incidence did not show consistent results. An analysis of case-control studies

reported an inverse association of green tea consumption and breast cancer, which cohort studies

found no association was observed when they were analyzed separately.

 Even though the combined results showed an inverse association between green tea

consumption and breast cancer risk, some single studies, especially cohort studies, did not show

any association. The inconsistent results were probably due to the confounding factors, different

quantities of tea consumption, and population heterogeneity. Thus, well-designed clinical trials

may clearly demonstrate the cancer-preventive effect of tea consumption.

 However, no randomized controlled trials have been conducted to investigate the protective

effect of green tea for breast cancer to date. It is impossible to establish the cause-and-effect

relationship barely based on the observational results. Thus, it is still uncertain that high intake of

green tea could be potential prevention or treatment for breast cancer.


Molecular mechanisms


 Even though the epidemiological studies indicated controversial results, cell culture studies

have shown the benefits of EGCG in inhibiting tumor cells proliferation and inducing apoptosis

through down-regulation of key proteins and enzymes, and inhibition of signaling pathways.

 1) Anti-proliferation and apoptosis

 EGCG has been shown to suppress cell viability at different time points in human breast

carcinoma MCF-7 cells but had no adverse effect on the growth of normal mammary cells. In

addition, treatment of EGCG for 48 and 72 h markedly increased the percentage of apoptotic

cells (32-51%) [9]. One explanation for it was down-regulation of telomerase because EGCG

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was observed to inhibit telomerase activity in a dose-dependent manner. This inhibition was also

observed at the mRNA level.

 EGCG could also induce cell apoptosis by arresting cells in G0/G1 phase [4]. G1 is between M

(mitosis) and S (synthesis) phases. G1 is a non-growing phase. Progression through the cell cycle

is regulated by cyclin-dependent kinases (CDK) at G1 phase. They are regulated by cyclin

proteins and CDK inhibitors (CDI). They further observed that EGCG-mediated cell cycle

apoptosis was mediated via modulation of CKI-cyclin-CDK machinery. Treatment of EGCG

resulted in up-regulation of WAF1/p21, KIP1/p27, INKa/p16, and INK4c/p18 which are CDK

inhibitors, down-regulation of cyclin D1, cyclin E, CDK2, CDK4, and CDK6 which are cyclin

proteins and CDKs functioning in progressing cell cycle to S phase.

 The similar result was also observed in MCF-7 cells [10]. As MCF-7 cells were exposed to

30µM EGCG over 24 h, a gradual loss of both CDK2 and CDK4 kinase activities occurred.

EGCG also increased expression of CDK inhibitor p21 protein and p27 protein. Thus, tumor

growth was suppressed and induced to apoptosis.

 2) Inhibition of signaling pathways and angiogenesis

 EGCG has also been shown to inhibit the critical transcription factors, activator protein 1 (AP-

1), and nuclear factor κB (NFκB), which are involved in progression of tumors [11, 12]. NFκB

not only regulate cyclin D1 expression, but also induce Bcl-2 and Bcl-XL expression, which

prevent cells from apoptosis.

 Chung JY et al. [13] found that EGCG inhibited MEK1 phosphorylation by decreasing its

association with the kinase RAF1. RAF induces MEK phosphorylation; phosphorylated MEK

induces ERK phosphorylation. Phosphorylated ERK functions in proliferation.




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 A lot of studies have demonstrated the inhibitory effects of EGCG on the epidermal growth

factor receptor (EGFR) signaling pathways. It is shown that EGCG disrupts EGFR signaling and

down-regulates STAT3. EGCG inhibits ligand binding to the EGFR and phosphorylation of

EGFR. This leads to decreased signaling through ERK and STAT3, down-regulation of cyclin

D1, Bcl-2 and Bcl-XL. The net result is decreased proliferation and increased apoptosis (notes

from NTR 621). In addition, to inhibit angiogenesis, EGCG was observed to decrease the levels

of vascular endothelial growth factor (VEGF) at both protein and mRNA levels [14].

 3) antioxidant

 Tea polyphenols are strong antioxidants in vitro [2]. In aged rats, EGCG has been shown to

reduce oxidative stress, lipid peroxidation, and protein carbonylation [15]. So EGCG may act in

the presence of excessive oxidative stress. A human study administered tea catechins (500 mg

per day) to healthy volunteers for 4 weeks and observed decreased plasma oxidized low-density

lipoprotein (LDL) [16]. Thus, tea polyphenols could function as antioxidants though decreasing

oxidative DNA damage.

 EGCG received most of the attention as it can inhibit carcinogenesis via inhibition of

proliferation, induction of apoptosis, and inhibition of signaling pathways. However, the

concentration of EGCG used in the cell culture experiments (20-100 µM) were higher than the

physiological concentrations in human after drinking two or three cups of green tea or in animals

in cancer prevention experiments (< 0.5 µM) [17]. It may not appropriate to extrapolate the

concentrations in cell culture experiments to animals in cancer prevention experiments, and even

to human in prevention studies. Moreover, evidence from cell culture experiments was more

likely to be relevant to treatment rather than prevention.




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 Tea polyphenols, especially EGCG, have anti-tumor effects in different cell models. The

mechanisms are very complicated, including a lot of enzymes and transcription factors. It is

likely that multiple molecular mechanisms, rather than a single receptor or molecular target, are

involved. Even in a single experimental system, multiple molecular targets may be involved.

EGCG may initially bind to the receptors in the membrane, initiating the following signaling

pathways by inhibition of key components that are essential for the proliferation of tumor cells,

or induction apoptosis of the malignant cells. However, it is still a challenge to prove the cellular

and molecular mechanisms in animals and humans because the concentrations used in the cell

culture experiments are much higher than that in animals or humans in physiological state. It has

been shown that EGCG has no adverse effect on normal cells. However, further studies need to

evaluate the efficacy and safety of tea extracts/EGCG when it is considered as an anti-tumor

drug.

Summary


 As discussed in this review, studies in cell models have demonstrated that tea

polyphenols/EGCG could affect many signaling pathways, which result in cancer cell growth

inhibition, apoptosis, inhibition of angiogenesis and metastasis. Tea, as a widely consumed

beverage, may have potential benefits in prevention of human cancer, including breast cancer.

However, its cancer-prevention property has not been observed in human studies consistently.

This is probably due to the low concentrations of tea polyphenols/EGCG in human populations.

To date, no adverse effects of tea polyphenols/EGCG have been reported. Thus, high

consumption of green tea is recommended. But I am not confident to conclude that high

consumption of green tea could prevent human cancer, like breast cancer. Well-designed

prevention studies need to be conducted to establish the cause-and-effect relationship between


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green tea intake and breast cancer risk, the optimal dose of green tea, the potential harmful

effects when combined green tea with other foods and beverages.




References


1.     Yuan, J.M., C. Sun, and L.M. Butler, Chapter 8. Tea and cancer prevention: Epidemiological
       studies. Pharmacol Res, 2011.
2.     Yang, C.S., et al., Cancer prevention by tea: animal studies, molecular mechanisms and human
       relevance. Nature Reviews Cancer, 2009. 9(6): p. 429-439.
3.     Maryam R. Sartippour, D.H., Jiyuan Ma, Qingyi Lu, Vay Liang Go, and Mai Nguyen, Green Tea and
       Its Catechins Inhibit Breast Cancer Xenografts. NUTRITION AND CANCER, 2001. 40(2): p. 149-156.
4.     Sanjay Gupta, T.H., and Hasan Mukhtar, Molecular pathway for ())-epigallocatechin-3-gallate-
       induced cell cycle arrest and apoptosis of human prostate carcinoma cells. Archives of
       Biochemistry and Biophysics, 2003. 410: p. 177-185.
5.     Landis-Piwowar, K.R., et al., A Novel Prodrug of the Green Tea Polyphenol (-)-Epigallocatechin-3-
       Gallate as a Potential Anticancer Agent. Cancer Research, 2007. 67(9): p. 4303-4310.
6.     Seely, D., The Effects of Green Tea Consumption on Incidence of Breast Cancer and Recurrence of
       Breast Cancer: A Systematic Review and Meta-analysis. Integrative Cancer Therapies, 2005. 4(2):
       p. 144-155.
7.     Sun, C.L., Green tea, black tea and breast cancer risk: a meta-analysis of epidemiological studies.
       Carcinogenesis, 2006. 27(7): p. 1310-1315.
8.     Ogunleye, A.A., F. Xue, and K.B. Michels, Green tea consumption and breast cancer risk or
       recurrence: a meta-analysis. Breast Cancer Research and Treatment, 2009. 119(2): p. 477-484.
9.     Mittal, A., et al., EGCG down-regulates telomerase in human breast carcinoma MCF-7 cells,
       leading to suppression of cell viability and induction of apoptosis. Int J Oncol, 2004. 24(3): p. 703-
       10.
10.    Liang, Y.C., et al., Inhibition of cyclin-dependent kinases 2 and 4 activities as well as induction of
       Cdk inhibitors p21 and p27 during growth arrest of human breast carcinoma cells by (-)-
       epigallocatechin-3-gallate. J Cell Biochem, 1999. 75(1): p. 1-12.
11.    Barthelman, M., et al., (-)-Epigallocatechin-3-gallate inhibition of ultraviolet B-induced AP-1
       activity. Carcinogenesis, 1998. 19(12): p. 2201-4.
12.    Lin, Y.L. and J.K. Lin, (-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by
       down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-
       kappaB. Mol Pharmacol, 1997. 52(3): p. 465-72.
13.    Chung, J.Y., et al., Mechanisms of inhibition of the Ras-MAP kinase signaling pathway in 30.7b
       Ras 12 cells by tea polyphenols (-)-epigallocatechin-3-gallate and theaflavin-3,3'-digallate. FASEB
       J, 2001. 15(11): p. 2022-4.
14.    Sartippour, M.R., et al., Green tea inhibits vascular endothelial growth factor (VEGF) induction in
       human breast cancer cells. J Nutr, 2002. 132(8): p. 2307-11.
15.    Senthil Kumaran, V., et al., Repletion of antioxidant status by EGCG and retardation of oxidative
       damage induced macromolecular anomalies in aged rats. Exp Gerontol, 2008. 43(3): p. 176-83.



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16.   Inami, S., et al., Tea catechin consumption reduces circulating oxidized low-density lipoprotein.
      Int Heart J, 2007. 48(6): p. 725-32.
17.   Yang, C.S., et al., Bioavailability issues in studying the health effects of plant polyphenolic
      compounds. Mol Nutr Food Res, 2008. 52 Suppl 1: p. S139-51.




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