The Correlation Between Green Tea Consumption with Risk of Breast

Cancer in Adult Women

Author :
Tara Wandhita Usman
03009250

Faculty of Medicine
Trisakti University
Jakarta 2012

ABSTRACT

The purpose of this review is to explore the correlation of green tea intake, was
inversely associated with risk of breast cancer. A number of epidemiologic and clinical trials
studies, both casecontrol and cohort in design, have examined the possible association
between tea intake and breast cancer development in humans.
The inverse relationship noted with greater tea consumption (three cups a per day)
among younger women (ages up to 50 years) was consistent for in situ and invasive breast
cancer, although stratified results were based on small numbers. No significant relationships
according to tea consumption were observed in older women, regardless of breast cancer
subtype.
A major focus of cancer prevention clinical trials has been on modulation of
hormones and nutritional modifications using natural or synthetic bioactive food components
for breast cancer. Breast cancer prevention clinical trials have investigated the role of
estrogen antagonists with agents such as tamoxifen, raloxifene, and newer agents such as
aromatase inhibitors and bioactive food components.
In summary that regular drinking of green tea was associated with a slightly decreased
risk for breast cancer in young women, but not in women ages 51 to 65 years old. The current
epidemiologic literature supports the hypothesis that green tea protects against breast cancer.

Keyword : Green Tea, Breast Cancer, Catechins, Tamoxifen. Women.

INTRODUCTION

Tea, a product made up from leaf and bud of the plant Camellia sinensis, is the second
most consumed beverage in the world, well ahead of coffee, beer, wine and carbonated soft
drinks

(1,2)

. Depending on the manufacturing process, teas are classified into three major

types: non-fermented green tea; semi-fermented oolong ; and fermented black and red.
Black tea is consumed principally in Europe, North America and North Africa (except
Morocco) while green tea is widely drunk in China, Japan, Korea and Morocco; oolong tea is
popular in China and Taiwan (3,4).

Breast cancer is the most common cancer in women worldwide, comprising 16% of
all female cancers. It is estimated that 519.000 women died in 2004 due to breast cancer, and
although breast cancer is thought to be a disease of the developed world, a majority (69%) of
all breast cancer deaths occurs in developing countries (WHO Global Burden of Disease,
2004). Incidence rates vary greatly worldwide, with age standardized rates as high as 99.4 per
100.000 in North America. Eastern Europe, South America, Southern Africa, and Western
Asia have moderate incidence rates, but these are increasing. The lowest incidence rates are
found in most African countries but here breast cancer incidence rates are also increasing. (5)

GREEN TEA COMPOSITION

The chemical composition of green tea is complex: proteins (15-20% dry weight),
whose enzymes constitute an important fraction; amino acids (1-4% dry weight) such as
theanine or 5-N-ethylglutamine, glutamic acid, tryptophan, glycine, serine, aspartic acid,
tyrosine, valine, leucine, threonine, arginine, and lysine; carbohydrates (5-7% dry weight)
such as cellulose, pectins, glucose, fructose, and sucrose; minerals and trace elements (5%
dry weight) such as calcium, magnesium, chromium, manganese, iron, copper, zinc,
molybdenum, selenium, sodium, phosphorus, cobalt, strontium, nickel, potassium, fluorine,
and aluminum; and trace amounts of lipids (linoleic and -linolenic acids), sterols
(stigmasterol), vitamins (B, C, E), xanthic bases (caffeine, theophylline), pigments
(chlorophyll, carotenoids), and volatile compounds (aldehydes, alcohols, esters, lactones,
hydrocarbons).
Fresh leaves contain, on average, 3-4% of alkaloids known as methylxanthines, such
as caffeine, theobromine, and theophylline. In addition, there are phenolic acids such as gallic
acids and characteristic amino acid such as theanine present (6).
Green tea contains polyphenols, which include flavanols, flavandiols, flavonoids, and
phenolic acids; these compounds may account for up to 30% of the dry weight. Most of the
green tea polyphenols (GTPs) are flavonols, commonly known as catechins. Products derived
from green tea are mainly extracts of green tea in liquid or powder form that vary in the
proportion of polyphenols (45-90%) and caffeine content (0.4-10%).
The major flavonoids of green tea are various catechins, which are found in greater
amounts in green tea than in black or Oolong tea (7). There are four kinds of catechins mainly
find in green tea: epicatechin, epigallocatechin, epicatechin-3-gallate, and EGCG (8).

Fig. 1. Chemical structure of gallic acid and four major catechins in green tea. GA,
gallic acid; EGCG, (-)-epigallocatechin-3-gallate; EGC, (-)-epigallocatechin; ECG,
(-)-epicatehin-3-gallate; EC, (-)-epicatechin.

GREEN TEA AND HUMAN HEALTH

Green tea has been considered a medicine and a healthful beverage since ancient
times. The traditional Chinese medicine has recommended this plant for headaches, body
aches and pains, digestion, depression, detoxification, as an energizer and, in general, to
prolong life. Green tea leaves contain three main components which act upon human health:
xanthic bases (caffeine and theophylline), essential oils and especially, polyphenolic
compounds. Caffeine acts mainly upon the central nervous system, stimulating wakefulness,
facilitating ideas association and decreasing the sensation of fatigue. Some of the effects
caused by caffeine are influenced by theophylline tea content. Theophylline induces
psychoactive activity, it also has a slightly inotrope and vasodilator effect, and a much higher
diuretic effect than caffeine. However, its most interesting effects can be seen at the
bronchopulmonar and respiratory level. Theophylline causes a non-specific relaxation on the
bronchial smooth muscle, and respiratory stimulation is also observed. Essential oils are in a

great extent volatile and they evaporate from the beverage after some time, thus it is not very
convenient to overextend the brewing time.
However, green tea has received a great deal of attention especially due to its content
of polyphenols, which are strong antioxidants and present important biological properties. In
recent years, the health benefits of consuming green tea, including the prevention of
cardiovascular diseases, the anti-inflammatory, antiarthritic, antibacterial, antiangiogenic,
antioxidative, antiviral, neuroprotective, prevention of cancer, and cholesterol-lowering
effects of green tea. Among all GTP, catechins and gallic acid have been especially
considered to be the main players in the beneficial effects on human health.
On the one hand, epidemiological studies have suggested that high consumption of
green tea protects against the development of chronic active gastritis and decreases the risk of
stomach cancer; in addition, the ingestion of green tea before fasting protects the intestinal
mucosa against atrophy (9).

RISK FACTORS OF BREAST CANCER

Factors that are associated with an increased risk of breast cancer include: Being
female, Increasing age, family or personal history of breast cancer, inherited genes (genetics),
radiation exposure, obesity, beginning your period at a younger age, beginning menopause at
an older age, having your first child at an older age, postmenopausal hormone therapy and
drinking alcohol (10).

A risk factor is anything that makes it more likely you'll get a particular disease. But
having one or even several risk factors doesn't necessarily mean you'll develop cancer
many women who develop breast cancer have no known risk factors other than simply being
women .

EPIDEMIOLOGIC STUDIES
In three epidemiological studies involving a total of 18.000 participants,

(11,12,13)

there was indicated that green tea consumption protects against breast cancer. The first
epidemiologic observations in Shanghai, China suggested that regular drinking of green tea
was associated with a slightly decreased risk for breast cancer. (breastca) This observation
was subsequently confirmed on Asian -(Chinese-,Japanese-,and Filipino-) American women
in Los Angeles County, that reported a significant inverse relationship between intake and
particularly intake of green tea and risk of breast cancer (examined the interrelationships
between tea intake, COMT genotype, and breast cancer risk)

(12)

In brief, cases were women with a first primary breast cancer diagnosis identified
from population-based cancer registries in Wisconsin, Massachusetts, and New Hampshire, a
total of 5,059 cases and 4,486 controls were included in the present analysis, of whom 98%
were Caucasian. (13)

All models included terms for referent age (in 5-year categories) and study site
(Wisconsin, Massachusetts, or New Hampshire). As considered potential confounding by
established breast cancer risk factors including menopausal status/age at menopause,
parity/age at first birth, body mass index, recency of postmenopausal hormone use, education,
alcohol consumption, physical activity, history of benign breast disease, and history of
screening mammogram in the 5 years before the reference age. (13)

Tests for linear trend were done by including an ordinal variable for cups per day (0,
<1, 1<2, 2<3, 3 or more) in logistic regression models that also included terms for age and
state of residence, and in multivariate models, all other covariates. (13)

As the result inverse association was limited to younger women (ages 50 years and
younger) : those reporting three or more cups per day 5 years prior to the interview had a
37% reduced breast cancer risk when compared with women reporting no tea consumption
and the test for trend with increasing cups per day was statistically significant. No similar
inverse association was observed in women ages 51 to 65 years or in older women. (13)

When examined according to breast cancer subtypes, the inverse relationship noted
with greater tea consumption (three cups a per day) among younger women (ages up to 50
years) was consistent for in situ and invasive breast cancer, although stratified results were
based on small numbers. No significant relationships according to tea consumption were
observed in older women, regardless of breast cancer subtype. (13)

CLINICAL TRIALS
Breast cancer prevention clinical trials
Breast cancer is the most commonly diagnosed cancer and the second most common
cause of cancer deaths among American women. Breast cancer risk generally is associated
with exposure to estrogens and the presence of estrogen receptors (ER) and progesterone
receptors on the relevant cancer cells. Risk factors such as obesity for postmenopausal breast
cancer may work through hormonal mechanisms, and there also are genetic predispositions
(i.e., BRCA mutations). Approximately 70% of breast cancer tumors are ER+ and respond to
estrogen by increasing growth. An initial strategy for designing clinical trials to prevent
breast cancer or its recurrence has been to reduce the amount of estrogen reaching breast
tissue by blocking ERs with selective estrogen receptor modulators (SERM), such as
tamoxifen and raloxifene. Clinical trials on breast cancer are using a variety of agents

SERMs, aromatase inhibitors (AI), and bioactive food componentsto reduce breast cancer
risk by altering hormonal influences or through various other biological pathways and
mechanisms. (14)
Tamoxifen and Raloxifene trials.

In the clinic, endocrine therapy is an important intervention for women with breast
cancers that express ER, and treatment with tamoxifen has enhanced patient survival

(15).

Early breast cancer prevention trials investigated tamoxifen to reduce breast cancer risk, and
.

results were encouraging, but some adverse effects occurred (16)

The Breast Cancer Prevention Trial (BCPT), conducted by the National Surgical
Adjuvant Bowel and Breast Project (NSABP), was the first large-scale prevention trial
conducted by NCI. At about the time BCPT was reporting results, publication of results from
the Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis trial indicated that
raloxifene reduced the incidence of breast cancer (a secondary end point) by 74% without an
associated increased risk for endometrial cancer. Participants in MORE, unlike participants in
BCPT, were not at high risk for breast cancer. As seen in BCPT with tamoxifen, raloxifene
was effective in reducing ER+ breast tumors (90%) but not ER breast tumors. Although
both are classified as SERMs, tamoxifen and raloxifene are chemically and mechanistically
distinct compounds that act through different mechanisms to block estrogens actions. (14)

Given the encouraging results of the BCPT and the MORE, the NSABP designed a
trialStudy of Tamoxifen and Raloxifene (STAR)to compare raloxifene and tamoxifen in
19,000 high-risk postmenopausal women, ages 35 and older, in a randomized, double-blind,
placebo trial. The STAR trial, funded by the NCI and supported by the Community Clinical
Oncology Program (CCOP), an NCI mechanism to improve accrual to NCI-sponsored

clinical trials with the involvement of community-based physicians, will assess the
occurrence of noninvasive breast cancer, endometrial cancer, and cardiovascular events, with
potential side effects of raloxifene and tamoxifen targeted as secondary end points. Results
are expected by 2006. (14)
Bioactive food components and breast cancer trials.

Bioactive food components, such as soy isoflavones, perillyl alcohol, green tea
polyphenols, and naringenin (found in grapefruit) are being tested in NCI-sponsored phase I,
II, or III chemoprevention trials for breast cancer.

Flavonoids in green tea are among the dietary factors that may play a role in cancer
protection and have been shown to have potent antioxidant effects. Green tea has also been
found to block certain steps in carcinogenesis.
Recently, green tea was reported to inhibit angiogenesis using both in vitro and in
vivo assays. That suggested that green tea reduces levels of two important angiogenic factors,
VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor), as well
as aFGF (acidic fibroblast growth factor) in breast cancer. Others have noted effects of green
tea on additional angiogenesis-related molecules, including IL-8 (interleukin-8), urokinase,
matrix metalloproteinases (MMP-2 and MMP-9), PDGF (platelet derived growth factor) and
TNF- (tumor necrosis factor). Angiogenesis is a crucial process in malignancy and may
account for, in part, the cancer-preventive effect of green tea in vivo. (14)
Further understanding of the interactions between green tea and ER signaling is
crucial for the use of this natural product to treat or prevent ER-positive breast cancers, which
represent the majority of primary breast tumors. The results of these experiments offer some
new insight, and will help in the design of future preclinical and human trials. (14)

 In vitro proliferation studies

The in vitro assays showed that individually, green tea or tamoxifen inhibited
proliferation of human ER-positive MCF-7 breast cancer cells. When tested tamoxifen at a
lower dose (nm) than the standard in vitro dose (m), in order to better detect potential
synergy. The combination of green tea and tamoxifen was more effective than either agent
given alone. The CI calculations for 0.510 g/ml green tea and 0.510 nm tamoxifen
combinations consistently showed CI values <1, indicating synergism. We saw similar effects
in two other ER-positive human breast cancer cells, ZR75 and T47D. (15)

MECHANISM OF GREEN TEA AS ANTI CARCINOGENIC

There has been extensive in vitro research regarding the possible cancer prevention
mechanisms by green tea extracts and their polyphenols using human breast cancer cell lines.
These studies suggested that multiple mechanisms are involved, including induction of
apoptosis and cell cycle arrest, down-regulation of telomerase, inhibition of vascular
endothelial growth factor and suppression of aromatase activity. And also have demonstrated
cancer preventive properties in carcinogen induced or transplanted mammary tumors in
experimental animal studies. Green tea extracts or catechins fed to rodents after
administration of chemical carcinogens decreased the size and multiplicity of mammary
tumors (17).
There has been extensive research into the possible anti carcinogenic mechanisms of
tea and its polyphenols, and many of these mechanistic studies relate specifically to the
catechins. In experimental studies involving breast cancer cell lines, EGCG, the major
catechin in green tea, has been shown to suppress cell viability and induce apoptosis by down
regulation of telomerase, and to inhibit angiogenesis by reducing expression of vascular
endothelial growth factor in a dose-dependent manner. Epigallocatechin, another major

catechin in green tea, also has strong effects in inducing apoptosis and inhibiting growth of
breast cancer cells in vitro.

CONCLUSION
On the basis of currently available evidence, regular drinking of green tea was
associated with a slightly decreased risk for breast cancer. Risk of breast cancer was
influenced significantly by intake of green tea and particularly of the intake. Tea catechins
appeared to reduce breast cancer risk in this study of Asian-American women.

The results among younger women were consistent regardless of breast cancer
subtypes defined by breast cancer stage (invasive and in situ) and histology (ductal and
lobular), although the number of younger women consuming large quantities of tea (three or
more cups per day) was limited in all analyses. Our results provide some support for the
hypothesis that regular tea consumption, particularly at moderately high levels, might reduce
breast cancer risk in younger women. No similar inverse association was observed in women
ages 51 to 65 years or in older women.

In summary, the current epidemiologic literature supports the hypothesis that green
tea protects against breast cancer.

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