Botanical Influences on Estrogen Metabolism - a literature review in the field of complementary cancer care
©
Chanchal Cabrera Msc, MNIMH, AHG
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Incidence
of breast cancer
Breast cancer is the most
common form of cancer among women in Europe, North and South America and
Australasia; approximately 1 in 10 women in Western countries will
develop breast cancer during their lifetime [i].
It is estimated that the disease will affect five million women
worldwide over the next decade, and the incidence of breast cancer is
increasing on average by about 1% per year in industrialized countries
and at a greater rate in developing countries. [ii]
Breast cancer is the
second leading cause of death among American women [iii] and by the year 2000 it
was estimated that 1 billion women worldwide would have breast cancer. [iv]
180,000 new cases of
breast cancer are expected to be diagnosed in the USA in 2001.[v]
Figures compiled by the World Health Organization over the past
40 years show a steady increase in both the incidence and the death rate
from breast cancer and only in the past 5 years has this been see to
come down.
Table 1
Incidence
of breast cancer morbidity and mortality in UK, USA and Australia 1955
- 1997
|
year
|
Australia
*
|
No. deaths
|
Deaths
**
|
UK*
|
No. of deaths
|
Deaths
**
|
USA*
|
No. of deaths
|
Deaths
**
|
|
1955
|
9
|
1107
|
120.3
|
50
|
9595
|
188.3
|
164
|
21,945
|
133.6
|
|
1960
|
10
|
1151
|
112.0
|
52
|
10,267
|
196.0
|
179
|
23,970
|
133.7
|
|
1965
|
11
|
1285
|
113.3
|
54
|
10,957
|
201.3
|
193
|
27,048
|
139.6
|
|
1970
|
12
|
1497
|
119.4
|
55
|
12,121
|
217.5
|
204
|
29, 917
|
146.5
|
|
1975
|
13
|
1656
|
120.2
|
56
|
13,081
|
233.8
|
215
|
32,435
|
150.5
|
|
1980
|
14
|
1803
|
123.4
|
56
|
13,671
|
242.8
|
227
|
35,641
|
156.9
|
|
1985
|
15
|
2195
|
139.3
|
56
|
15.073
|
266.7
|
239
|
40,093
|
167.9
|
|
1990
|
17
|
2421
|
141.9
|
57
|
15,179
|
266.4
|
256
|
43,391
|
169.7
|
|
1995
|
18
|
2598
|
143.8
|
58
|
14,114
|
240.8
|
263
|
43,844
|
166.9
|
|
1997
|
-
|
-
|
-
|
59
|
13,399
|
227.1
|
268
|
41,943
|
156.7
|
*population in millions
**per million
Source: World Health
Organization
Although not
confirmed it is thought that the recent decline in incidence and
mortality may be due to several factors including but not limited to
earlier detection, increased knowledge by the patients of contributory
and protective dietary factors and the use of modern
endocrine-modulating drugs. However, these statistics must be viewed
critically in light of the fact that each country may apply different
criteria to the diagnosis of cancer and that these criteria may change
over time.
Etiology of
breast cancer
Although the specific
etiology of breast cancer remains unknown, a number of factors are
recognized which increase a woman's risk of developing the disease.
Genetic predisposition, or family history of breast cancer, is known to
be responsible for 5% of all cases [vi].
The breast cancer gene BRCA1 confers a 59% risk of developing breast
cancer by the age of 50 as compared to only 2% risk in the non-gene
carrying population.[vii]
Up to 75% of women with breast cancer have no significant family
history of the disease. However, the variation in incidence throughout
populations, and changes relating to population migration and adoption
of altered lifestyles, all point to the critical importance of
non-genetic determinants. Such factors include early menarche [viii],
late menopause [ix], late age at birth of
first child or nulliparity, a history of benign breast disease, breast
density [x], environmental exposures
especially to xeno-estrogens [xi]
[xii],
and diet. [xiii]
[xiv]
[xv]
[xvi]
[xvii]
[xviii]
[xix]
Dietary
modification with the introduction of soy products, curcumin,
cruciferous vegetables and low fat could be beneficial in reducing the
risk of developing cancer and possibly the effects of DDT. [xx]
The
National Cancer Institute has estimated that only 18% of American adults
consume the recommended amount (5 - 7 servings) of fruit and
vegetables daily, and much of what is consumed comprises French fries,
potato chips, tomato sauce and other processed foodstuffs of dubious
nutritional value. There is also evidence that hormones play a major
role in the etiology of breast cancer, with the risk of developing
malignancies related to the cumulative exposure of the breast to
estrogen and progesterone, which stimulate the growth of tumor cells.[xxi]
Estrogen receptors are expressed in approximately 35-55% of all
breast tumors but up to 80-90% of tumors from women older than 55 years.
[xxii]
A bewildering number of
factors play into the formation, development and progression of breast
cancer and many of them offer opportunity for intervention. Of these
processes, the estrogen signaling specifically is the focus of the
present research proposal. Other mechanisms are mentioned for
completeness. (see chart 1)
1)
Hormonal (estrogen) signaling may be
modulated by regulating the formation, function and excretion of
estrogens.
2)
Angio-genesis and consequent metastasis may be inhibited in many ways:
* Signal
transduction pathways may be modulated by inhibiting a variety of growth
factors [xxiii]
[xxiv]
[xxv]
[xxvi]
Epidermal Growth Factor (EGF), Fibroblast Growth Factors (FGF),
Transforming Growth Factor (TGF), Platelet-Derived Growth Factor (PDGF),
Insulin-Like Growth factors(ILGF), Protein Tyrosine Kinase (PTK),
Protein Kinase C (PKC), tumor suppressor genes, Vascular Endothelial
Growth Factor (VEGF) and reticular activating system (RAS).
*
Angio-genesis may also be inhibited by regulating the process of
inflammation that the tumor uses to promote angiogenesis. [xxvii]
[xxviii]
[xxix]
[xxx]
[xxxi]
This is achieved through several mechanisms including
cyclo-oxygenase 2 (COX 2), 5, 12 & 15 lipoxygenase (LOX), platelet
aggregation and Hydroxyl-3-methylgutaryl coenzyme A reductase
(HMG CoA reductase) and by chelating copper from the system. Many
compounds exert anti-inflammatory and chemo-protective effects,
including Curcumin from Turmeric. [xxxii]
[xxxiii]
3)
Urokinase type plasminogen activator (uPA) and matrix
metalloproteinease (MMP) are two families of enzyme modulators that
tumor cells use to alter the extra-cellular fluid matrix
(ECF) such that they can spread more easily. Their expression is
regulated by oncogenes, tumor promoters and growth factors. In health
their expression is prevented by specific inhibitors in the matrix. [xxxiv]
[xxxv]
Stabilizing the ECF, which is a form of connective tissue, can
reduce cancer spread. The use of glycosaminoglycans (GAGS) as a
nutritional supplementation has shown promise in treating cancer for
this reason. [xxxvi]
4)
Cell adhesion molecules (CAM) are cell receptors that control
intra-cellular and inter- cellular communication. CAMs regulate organ
architecture, cell migration, cell differentiation, apoptosis
(programmed cell death), mitosis, platelet aggregation and the activity
of the immune system. There are 4 main classes of CAMs: cadherins,
integrins, cell surface lectins and Immuno-globulin Super Family Cell
Adhesion Molecules (ISCAMs). [xxxvii]
Allopathic
interventions - an overview
At the time of diagnosis,
approximately 50% of patients will be diagnosed with early breast
cancer. This proportion is increasing as a consequence of the
introduction of early detection programs. Surgery remains the primary
treatment for early breast cancer, and the frequency of radical
mastectomy has been replaced by breast conserving surgery. After
surgery, other therapeutic modalities such as radiation, chemotherapy or
endocrine therapy may be given in the adjuvant setting. Surgical cure
rates vary for patients with early breast cancer; the US figure is
approximately 40%, and there are no definitive means to predict those
who will be cured and those who will have recurrent disease.[xxxviii]
Breast cancer research has
developed at a rapid pace over the last decades. Age, race, tumor size,
histological tumor type, axillary nodal status, standardized
pathological grade, and hormone-receptor status are accepted as
established prognostic and/or predictive factors for selection of
systemic adjuvant treatment of breast cancer. The role of other
promising new factors, such as p53 mutations, HER-2 status, plasminogen
activator system, histological evidence of vascular invasion, and
quantitative parameters of angiogenesis are currently or will soon be
determined in prospective studies. Treatment options to date have raised
almost as many questions as they have provided answers and research
today is focusing more and more on natural substances and synthetic
analogues as mechanisms for cell function alteration. [xxxix]
Estrogen receptor site modulation and Aromatase inhibition
Since 1896, when Sir
George Beatson demonstrated that ovariectomy induced regression of
mammary tumors in women, the aim of endocrine breast cancer therapy has
been to selectively deprive the body of estrogen. Ovariectomy
accomplished this by removing the gland that is the predominant source
of estrogens in premenopausal women. Since the avoidance of such surgery
is preferable, emphasis is devoted to the pharmacological inhibitors of
estrogen production.
Substantial evidence
supports the concept that estrogens cause breast cancer in animals and
in women but the precise mechanism is unknown.
How
estrogen might cause breast cancer
-
Estrogens stimulate proliferation of breast cells and thus
statistically increase the chances for genetic mutations.
-
Estrogen metabolism generates oxygen-free radicals and quinones
which produce both stable and unstable DNA adducts and result in genetic
mutations which accumulate and could ultimately cause cancer.
-
In situ synthesis of
estrogen due to the over-expression of intra-cellular aromatase. [xl]
Like other steroid
hormones, the two circulating estrogens (estrone and estradiol) are
produced from cholesterol. The process of transformation from
cholesterol through pregnenolone, progesterone and androstenedione to
testosterone largely occurs in the liver and adrenal glands.
Testosterone then travels to distant tissues, notably adipose tissue and
the skin, where it is converted by the action of aromatase into
estrogens. There are many possible points of pharmacological
intereference in this process. In particular, aromatase inhibition has
shown great potential, as has
interference in the binding of testosterone or estrogen to target
tissues through competitive inhibition mechanisms. One
study of several naturally occurring and synthetic flavones found
inhibition of the aromatization of androstenedione and testosterone to
estrogens by several compounds including chrysin, apigenin, Quercitin
and flavones. Chrysin was a potent competitive inhibitor and induced
spectral changes in the aromatase cytochrome P-450 indicative of
substrate displacement. The authors conclude that flavones may thus
compete with steroids in their interaction with certain mono-oxygenases
and thereby alter steroid hormone metabolism. [xli]
Inhibiting the enzymes
that are involved at earlier steps in the branching pathway of
steroidogenesis could have an undesirable impact on the production of
other physiologically important hormones such as aldosterone and
cortisol. Aromatase is a cytochrome P450 enzyme, with both an iron (heme)-containing
and a steroid-binding site. Since aromatase catalyzes the last step in
estrogen production, it makes an ideal target for the development of
selective and potent inhibitors.
Two
mechanisms for inhibiting aromatase
1)
Occupying the steroid-binding site of the enzyme with a compound
such as formestane (Lentaron)
2)
Binding the iron with nitrogen-containing compounds such as
aminoglutethimide (Orimeten), the oldest aromatase inhibitor.
Aminoglutethimide was one
of the earliest pharmaceutical agents to inhibit adrenal steroid
biosynthesis and block the conversion of cholesterol to pregnenolone,
therefore reducing levels of adrenal androgens, which are a source of
estrogens in both pre-menopausal and postmenopausal women.
Aminoglutethimide has produced anti-tumor response rates of 35% in
unselected patients, most of whom have undergone prior therapy with
either chemotherapy or hormonal manipulation. Although aminoglutethimide
has long been used to treat advanced breast cancer, its aromatase
inhibition is not selective. Consequently, aminoglutethimide also binds
to and thereby inhibits several other cytochrome P450 enzymes in the
steroidogenesis pathway. Aminoglutethimide does have the known side
effect of impaired mineralo-corticoid and gluco-corticoid activity. [xlii]
An ideal aromatase inhibitor would fit the catalytic site of
aromatase optimally and would thus interact only with aromatase. The
affinity of letrozole (Femara) for the heme group of aromatase makes it
a selective and potent inhibitor. In fact, studies show that Femara has
little effect on the other adrenal steroids, and is the most selective
aromatase inhibitor available today. [xliii]
Flavone
and isoflavone phytoestrogens are plant chemicals and are known to be
competitive inhibitors of cytochrome P450 aromatase with respect to the
androgen substrate. [xliv]
In one study the flavonoids
catechin, daidzein, equol, genistein, beta-naphthoflavone (BNF),
quercetin and rutin exerted no effect on aromatase activity. Eleven
flavonoid compounds were compared with aminoglutethimide (AG) for their
abilities to inhibit aromatase enzyme activity. Three
naturally-occurring flavonoids, chrysin, flavone, and genistein
4'-methyl ether (Biochanin A) showed I50 values of 4.6, 68, and 113
microM, respectively, while AG showed an I50 value of 7.4 microM.
Kinetic analyses showed that both AG and the flavonoids acted as
competitive inhibitors of aromatase. Chrysin,
the most potent of the naturally-occurring flavonoids, was similar in
potency and effectiveness to AG. [xlv]
[xlvi]
Metabolism of
estrogens
Estrogen is a steroid
hormone, manufactured in the body from cholesterol by way of
pregnenolone, progesterone, androstenedione and testosterone. The final
step in the pathway is conducted in the ovaries, adrenal glands and
skin. Exogenous estrogens may contribute to the total load although the
extent to which this is significant is unproven.[xlvii]
[xlviii]
Xeno-hormones
may work bi-functionally, through genetic or hormonal paths, depending
on the periods and extent of exposure.
Xeno-hormones can modify DNA structure or function. Two distinct
mechanisms can influence the potential for aberrant cell growth:
compounds can directly bind with endogenous hormone or growth factor
receptors affecting cell proliferation or compounds can modify breast
cell proliferation altering the formation of hormone metabolites that
influence epithelial-stromal interaction and growth regulation.
Beneficial xeno-hormones,
such as indole-3-carbinol, genistein, and other bioflavonoids, may
reduce aberrant breast cell proliferation, and influence the rate of DNA
repair or apoptosis and thereby influence the genetic or hormonal
micro-environments. [xlix]
[l]
Estrogen is comprised of
three main types: Estrone, Estradiol and Estriol, with Estrone
conferring the least cell-proliferant activity and Estriol conferring
the most. Estrogen manufactured and active in peripheral tissues and
organs eventually ends up in the liver where it is metabolized for
excretion. Hydroxylation reactions in phase I detoxification yields
either 16alpha hydroxyestrone (16alpha-OH), 4 hydroestrone (4-OH) or 2
hydroxyestrone (2-OH). (see
charts 2 & 4).
16alpha-OH goes on to be
reduced and form Estriol which is the most cell proliferant of the 3
endogenous estrogens although each of the estrogens are capable of
binding to target tissues. All three hydroxyestrones can be excreted via
glucuronidation, methylation or sulfation and are eliminated in bile and
urine. However, studies suggest that elevated 2:OH : 16alpha -OH
ratio is protective in breast cancer. In the presence of certain
critical co-factors, (L-methionine, B12, B6, S-adenosyl methionine, S-adenosyl
homocysteine, choline, folate, magnesium) 4-OH is cycled into 2-OH in
the liver. In the absence of these co-factors, and in the absence of
adequate levels of anti-oxidants, then 4-OH may oxidize into toxic
quinines. Unavailability or deficiency of glutathione-S-transferases,
the family of iso-enzymes that act as intra-cellular anti-oxidants,
permits the onwards formation quinoones into toxic mercapturates. [li]
In this study we shall research the extent to which 2-OH
formation can be promoted using specific botanical extracts and
nutritional supplies. The therapeutic intent is to promote estrogen
clearance.
(See charts 2 - 5)
Botanical & nutritional intervention in breast cancer development
and progression
Much recent research has
focused on the influence of a variety of naturally occurring substances
or their synthetic analogues. Phyto-estrogens, many of them flavonoids
in nature, as well as other flavonoids, lignans, catechins, progestins
and essential fatty acids have been investigated and many have shown
significant promise in reducing the occurance and spread of breast
cancer. An extensive literature review
revealed thousands of supportive citations for the idea of
supplementing the diet with specific botanicals and nutritional
supplements and a few inconclusive or dismissive.
In many cases the results
of research have demonstrated variable results according to dose or
potency of test material. At low concentrations, genistein and
coumestrol significantly enhanced E2-induced and tyrosine kinase-mediated
DNA synthesis; at high concentrations, inhibition was observed.
Differing effects are observed with other compounds. [lii]
Opportunities
to inhibit estrogen formation
-
Inhibition of the sulphotransferases that sulphate both
estrogenic steroids and a variety of environmental chemicals, including
dietary pro-carcinogens. Circulating steroid sulphates are thought to be
the major source of estradiol in post-menopausal breast tumors and
sulphation is a key step in the activation of some dietary pro-carcinogens.[liii]
-
The enzyme 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD
5) converts estradiol (the more active form) to estrone (the less active
form). Inhibition of reductive and oxidative activities of 17beta-HSD 5
is seen in the presence of many dietary compounds, especially
zearalenone, coumestrol, quercetin and
biochanin A. Inhibitor
potency increases with an increasing number of hydroxylations in the
flavonoids molecule.[liv]
-
Inhibition of aromatase through use of lignans and flavonoids.[lv]
[lvi]
Wine
has been shown to contain phytochemicals that are capable of suppressing
aromatase. Red wine was shown to be much more effective than white wine
in the suppression of aromatase activity. [lvii]
In another study, among several flavonoids tested, only
7-methoxyflavanone and 7,8-dihydroxyflavone at high concentrations (50
microM) possessed anti-estrogenic and anti-proliferative activities.
These results suggest that two hydroxyls (in positions 7 and 8) or
7-methoxy substitutes are essential for the anti-estrogenic activity of
flavonoids. However, the authors emphasize that flavonoids at high
concentrations appear to exert their anti-proliferative activity through
other estrogen receptor-independent mechanisms as well. [lviii]
Opportunities
to inhibit estrogen function
-
Human
estrogen receptors (ER) exist as two subtypes, ER alpha and ER beta,
which differ in the C-terminal ligand-binding domain and in the
N-terminal transactivation domain. Competition with estrogens at
the receptor site of the target tissue can modulate estrogen activity at
the functional level. Several
lignans and the isoflavonoids daidzein and equol were found to compete
with estradiol for binding to the rat uterine type II estrogen binding
site. [lix]
Some phytoestrogens such as coumestrol, genistein, apigenin,
naringenin, and kaempferol compete stronger with E2 for binding to ER
beta than to ER alpha [lx]
and the effect of this on clinical outcomes has yet to be investigated.
The compound Indole-3-carbinol (I3C), extracted from cabbage, and its
more metabolically available and active form, diindolyl-methane (DIM)
have received much attention recently as potent mechanisms for
influencing estrogen function at the receptor site. DIM is a major in
vivo product of I3C, and can inhibit the proliferation of both
estrogen-dependent and -independent breast tumor cells. It is an
antagonist of estrogen receptor function and a weak agonist of aryl
hydrocarbon (Ah) receptor function. [lxi]
[lxii]
[lxiii]
-
Green
tea extract inhibited protein kinase C activation by teleocidin, a tumor
promoter, as did (-)-epigallocatechin gallate (EGCG), the main
physiologically active polyphenol in green tea extract. In addition,
EGCG and green tea extract showed inhibitory effects on the growth of
lung and mammary cancer cell lines with similar potencies. An experiment
using the estrogen-dependent MCF-7 cell line showed the mechanisms of
action of these compounds to be inhibiting the interaction of estrogen
with its receptors. The authors suggest that EGCG and compounds in green
tea extracts may block the interaction of tumor
promoters, hormones and growth factors with their receptors. [lxiv]
-
Inihibition
of estrogen activity through other mechanisms: several flavonoids,
including kaempferide, apigenin, and flavone, are distinct, in that
their anti-estrogenic activity does not appear to correlate with binding
to ER, and therefore their suppression of estrogen-mediated gene
trans-activation and proliferation may occur independent of direct
antagonism of the receptor. It is suggested that receptor
binding-independent anti-estrogenic chemicals may function through
alternate signaling pathways as indirect ER modulators in a receptor-
and cell type-specific manner.[lxv]
-
Research
with coumestrol, genistein, biochanin A, apigenin, luteolin, kaempferol,
and enterolactone showed conflicting
results. Induction of DNA synthesis in estrogen-dependent cell lines but
not in estrogen-independent cell lines is consistent with an estrogenic
effect of these compounds. Inhibition of estrogen-dependent and
-independent breast cancer cells at high concentrations suggests
additional mechanisms independent of the estrogen receptor. [lxvi]
One interesting piece of research found that genistein and
curcumin together exerted a significantly greater effect than the
individual substances given in isolation. [lxvii]
[lxviii]
-
Stimulation
of SHBG synthesis. Maintenance or elevation of plasma Sex Hormone Binding Globulin (SHBG) which carries
testosterone and estrogen and makes it unavailable for initiating
biological mechanisms. Isoflavones and lignans support SHBG formation
and function. [lxix]
[lxx]
[lxxi]
Opportunities to increase estrogen excretion and
elimination
-
Estrogen
is metabolized along three pathways to form the 2-hydroxylated, the 4
hydroxylated and the 16alpha-hydroxylated metabolites. Based on proposed
differences in biological activities, the ratio of
2-hydroxyestrogen:16alpha-hydroxyestrone (2:16alpha-OHE1), has been used
as a biomarker for breast cancer risk. Women with an elevated
2:16alpha-OHE1 ratio are hypothesized to be at a decreased risk of
breast cancer. Flaxseed, the most significant source of plant lignans,
and wheat bran, an excellent source of dietary fiber, have both been
shown to have chemo-protective benefits. In one study urinary excretion
of 2-hydroxyestrogen and 16alpha-hydroxyestrone, as well as their ratio,
2:16alpha-OHE1, were measured by enzyme immunoassay. Flaxseed
supplementation significantly increased the urinary 2:16alpha-OHE1 ratio
(P = 0.034), but wheat bran had no effect. [lxxii]
In another study flaxseed supplementation significantly increased
urinary 2-OHEstrogen excretion (p < 0.0005) and the urinary 2/16
alpha-OHE1 ratio (p < 0.05) in a linear, dose-response fashion. There
were no significant differences in urinary 16 alpha-OHE1 excretion.
These results suggest that flaxseed may have chemo-protective effects in
postmenopausal women. [lxxiii]
Soluble fiber such as is found in fruits, vegetables and certain
grains including oats, undergoes
metabolism in the small and large intestine and has an appreciable
effect on modifying carcinogens in the colon. Insoluble fiber such as is
found in wheat and rice bran, does not alter carcinogenic metabolites
but does give bulk to the stool, thus diluting potential toxins and
speeding the transit time and hence reducing toxin exposure overall. [lxxiv]
-
Rat
studies have demonstrated that administration of green tea stimulated
liver microsomal glucuronidation of estrone and estradiol by
as much as 37%. Enzyme kinetic analysis indicates that the
inhibition of estrone glucuronidation by 10 microM (-)-epigallocatechin
gallate was competitive while inhibition by 50 microM (-)-epigallocatechin
gallate was noncompetitive. Similarly, several flavonoids (naringenin,
hesperetin, kaempferol, quercetin, rutin, flavone, alpha-naphthoflavone
and beta-naphthoflavone) also inhibited rat liver microsomal
glucuronidation of estrone and estradiol to varying degrees. Naringenin
and hesperetin displayed the strongest inhibitory effects. These two
hydroxylated flavonoids had a competitive mechanism of enzyme inhibition
for estrone glucuronidation at a 10 microM inhibitor concentration and a
predominantly noncompetitive mechanism of inhibition at a 50 microM
inhibitor concentration. [lxxv]
[lxxvi]
Research into chrysin-induced UDP-glucuronosyltransferase
(UGT) activity and expression in human intestinal cell lines,
demonstrated that flavonoids may be important for the glucuronidation
and detoxification of cells. [lxxvii]
-
Potential exists to promote the preferential excretion of
2-OH through the use of several compounds, notably Indole-3-carbinol
(IC3) or its more potent and bio-available metabolite,
Di-indolyl-methane (DIM). Similar effects can be obtained with flax,
kudzu and soya. Supplementation with L-methionine, S-adenosyl-methionine
(SAM), vitamin B12, helps the inter-conversion of 2-OH and 4-OH in the
liver. 4-OH may convert
into quinones which are potentially carcinogenic and need lots of free
radical quenching. Anti-oxidants can inhibit the formation of these
compound.
-
-
Maintain or elevate plasma Sex Hormone Binding Globulin which has
been correlated to increased urinary
excretion of 16 alpha-hydroxyestrone and estriol. [lxxviii]
High intakes of caffeinated coffee, green tea, and total caffeine
were commonly correlated with increasing sex hormone-binding globulin
after controlling for potential confounders. Although the effect of
caffeine cannot be distinguished from effects of coffee and green tea,
consumption of caffeine-containing beverages appeared to favorably alter
hormone levels associated with the risk of developing breast cancer.[lxxix]
-
Unquenched quinines become mercapturates.
Formation and excretion of these products is mediated by
glutathione-s-transferase (GST) which can be supported by
supplementation with glutathione, selenium and N-acetyl-cysteine (NAC). Reduced
glutathione and N-acetylcysteine can inhibit both apoptosis and necrosis
of several cell types, suggesting a critical role for reactive oxygen
species (ROS) in cell death. [lxxx]
[lxxxi]
However, research into the effects of NAC is equivocal and more
investigation is called for [lxxxii]. Recent
research has indicated that certain GST genotypes may have greater
susceptibility to malignant changes than others [lxxxiii]
and in future this may be used as a clinical test to evaluate the need
or potential benefit from supplementation with GST or its pre-cursors.
-
An enzyme in the bowel called glucuronidase can de-conjugate
estrogen waste metabolites and allow them to be re-absorbed in an
oxidized and highly reactive form. [lxxxiv]
[lxxxv]
.
-
The body of evidence suggests that supplementation of the diet
with potent botanical and nutritional extracts provides positive health
benefits.
Other mechanisms of
reducing mammary tumorigenesis
As described in the
section on the etiology of breast cancer, many factors play into the
formation, development and progression of breast cancer and many of them
offer opportunity for intervention. The research study we are proposing
will look exclusively at estrogen metabolism, but it is interesting to
note how many other mechanisms are advantageously influenced by
flavonoids and lignans.
-
Reduction
of Insulin-Like Growth Factor I (IGF1) levels which are associated with
abnormal cell turnover. Reduced plasma levels of IGF1 are inversely
related to urinary lignan excretion after supplementation with flaxseed.[lxxxvi]
Both the oil and the seed have been investigated. Flaxseed, a
rich source of lignan precursor secoisolariciresinol-diglycoside (S.D.)
and alpha-linolenic acid (ALA), has been shown to be protective at the
early promotion stage of carcinogenesis. Reduction in tumor size is due
in part to the lignans. The effect of flaxseed oil may also be related
to its high ALA content. The S.D. in flaxseed appears to be beneficial
throughout the promotional phase of carcinogenesis whereas the oil
component is more effective at the stage when tumors have already been
established. [lxxxvii]
-
Involvement
of non-hormonal mechanisms such as may be triggered by lignans. Research
with rats into the lignan hydroxymatairesinol (HMR) from Norway Spruce,
the most abundant single component of spruce lignans, has demonstrated
that it is metabolized to enterolactone (ENL) as the major metabolite in
rats after oral administration. HMR decreased the number of growing
tumors and increased the proportion of regressing and stabilized tumors.
HMR (50 mg/kg body wt) did not exert estrogenic or anti-estrogenic
activity. Neither ENL nor enterodiol showed estrogenic or
anti-estrogenic activity via a classical alpha- or beta-type estrogen
receptor-mediated pathway. HMR was an effective antioxidant in vitro. [lxxxviii]
-
Many
flavonoids are strongly anti-oxidant and this may reduce tumorigenesis
by inhibiting DNA damage and promoting DNA repair. Regulation of cell
protein content and inhibition of protein,
DNA and RNA synthesis has been demonstrated by quercitin. [lxxxix]
Novel
1H-cyclopenta[b]benzofuran lignans
extracted from Aglaia elliptica are potent cytostatic inhibitors
of protein biosynthesis and are capable of delaying tumor growth in an in
vivo model. [xc]
-
Increased intracellular reduced glutathione (GSH) content
and hence quenching of free radicals and inhibition of oxidative
damage has been demonstrated by quercitin and myricetin. [xci]
-
Investigation
into a number of naturally occurring chemo-preventive agents such as
curcumin, quercetin, auraptene, 1'-acetoxychavicol acetate (ACA) and
indole-3-carbinol showed generation of apoptosis as well as inhibition
of cell proliferation. [xcii]
-
Progestins may also exert direct anti-estrogenic action by
increasing the oxidative activity of 17 beta-hydroxy-steroid-dehydrogenase,
thereby facilitating the conversion of estradiol (the more active form)
to estrone (the less active form). Progestins may exert additional
anti-estrogenic effects by suppressing estrogen receptor levels. They
also cause estrogen deprivation indirectly through suppression of
pituitary ACTH secretion, resulting in reduced production of adrenal
androgen precursors. Aromatase inhibition in pre-menopausal women
interrupts estrogen biosynthesis; the reflex rise in FSH then stimulates
production of new aromatase enzyme, and the LH increment results in
enhanced ovarian steroidogenesis, counteracting the inhibitory action of
aromatase-blocking drugs on the ovary. [xciii]
-
Dihydrobenzofuran
lignans (2-phenyl-dihydrobenzofuran derivatives) constitute a new group
of anti-mitotic and potential anti-tumor agents that inhibit tubulin
polymerization. A dimerization product of caffeic acid methyl ester,
showed promising activity. It inhibited mitosis at micromolar
concentrations in cell culture through a relatively weak interaction at
the colchicine binding site of tubulin.
[xciv]
-
Reduction
of the highly proliferative terminal end bud (TEB) structures in the
developing mammary gland by differentiation to alveolar buds (ABs) and
lobules has been suggested to be protective against mammary cancer and
may be achieved through the ingestion of flaxseed and exposure to
protective lignans. Research
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early puberty onset and lengthened cycles due to prolonged estrus. This
increased exposure to endogenous estrogens and stimulated mammary gland
differentiation, as indicated by fewer TEBs and more ABs. [xcv]
-
Two
citrus flavonoids, hesperetin and naringenin, found in oranges and
grapefruit, respectively, and four non-citrus flavonoids, baicalein,
galangin, genistein, and quercetin, showed inhibitory effects on
proliferation and growth of a human breast carcinoma cell line. The most
potent single flavonoids was baicalein and the addition of quercitin to
any of the other flavonoids increased their potency. Although tumor
incidence and tumor burden (grams of tumor/rat) were somewhat variable
in the different groups, rats given orange juice had a smaller tumor
burden than controls, and they grew better than any of the other groups.
[xcvi]
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In vitro, anti-proliferative effects of different
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various experimental animal tumor models, different PAs showed a greater
anti-tumor activity than tamoxifen
Combination treatment of different PAs, or progesterone receptor
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Inhibition of cyclin-dependent kinases has been demonstrated
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Both
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