Transcript Document

BPA and Breast Cancer
Background Research
Hormone receptors receive
growth signals from the hormones
estrogen and progesterone.
Breast
Cancer
~75% of breast cancers are ER+,
and about 65% are both ER+ and
PR+.
~ 20-30% have too many HER2
receptors (human epidermal
growth factor receptor).
HER2 receives signals that
stimulate tumor growth. The more
HER2 receptors, the more
aggressive the cancer.
About 0% of breast
cancers are triple negative.
Estrogen Receptor
Estrogen Receptors
http://www.bio.cmu.edu/Courses/BiochemMols/ER/#ERchime
Hall et al. 2001. J. Biol. Chem., 276: 36869-36872
ER effects on different cell types
Estrogens can activate growth
factor receptor signaling
Levin ER. Mol.Endocrinol. 2003;17:309-17
GPR30????
MCF-7 has a higher ratio of ERalpha: ERbeta
MDA-MB-231 has only ERbeta
Estrogen
and Related
Molecules
Bisphenol-A (BPA)
1) Polycarbonate plastic
– Baby bottles, toys
– Automobiles, CDs, DVDs1
2) Epoxy resins
– Lining of metal cans
– To prevent corrosion of metal cans
– Food cans, Water bottles
Bisphenol-A (BPA) Facts
• United States- over 2 billion lbs/year1
• Globally- over 6 billion lbs/year1
• “One of the highest volume chemicals
produced worldwide”2
• BPA levels detected in
human fluids and tissues2
How does BPA get into human body??
Polycarbonate Synthesis
H 3C
H 3C C H 33
C H 3Phosgene
Ester bond
HH3 CC C
CH
H3
3
3
O
C
HO
HO
OH
O
HOO
O
OH
H
OH
H 3C
CH3
H 3C
Ester bond
O
CH3
O
O
C
RO
O
O
OR
O
O
H 2O
Heat- up to 55x faste
H 3C
H 3C C H 3
CH3
H 3C C H 3
Ester bond
O
H RO
O
H 3C
CH3
O
C
O
O
OHO
O
HO
O
OR
OH
H 2O
Bisphenol-A (BPA) leaching from polycarbonate.
Routes of exposure to BPA
• Ingestion (most of the time)
– BPA leaches into contents of
plastic products.
– Extremely small amount of exposure, (“lowdose”)
but widespread and continuous.
• Transdermal (skin) exposure
• Inhalation
The Problem: BPA and Health Risks
• BPA shows endocrine disrupting effects.
• Associated with:
– Breast, prostate cancer
– Impaired reproductive functions
– Adverse developmental effects, brain
The Problem: BPA and Health
Risks
• “Xenoestrogen”
– Mimics endogenous estrogen
– Binds estrogen receptors (ERs)
Mechanism of Action
Estrogen Receptor (ER)
Free BPA
BPA
Nucleus
Phospholipid bilayer
The Effect of Estrogenic
Compounds such as BPA
23
Effects of BPA
EXTRA SLIDES
Estrogen has multiple effects
Phytoestrogens
Aherne and O’Brien, 2002. Nutrition 18:75-81.
Benassayag, et al., 2002. J. Chromatogr.B
777:233-248.
Comparison of binding affinities and
transactivation of estrogen and phytoestrogens
Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414
Dietary Sources of Phytoestrogens
Pytoestrogens in humans
• Phytoestrogens have weaker estrogenic activity compared
to circulating estrogens (17-b-estradiol or estrone).
• Phytoestrogens can bind sex steroid binding protein (SBP)
and a-feroprotein (AFP) and be circulated.
• Dietary phytoestrogens are metabolised by intestinal
bacteria, absorbed, conjugated in the liver (by
sulfotransferases and UDP-glucoronyosyl transferases),
circulated in plasma and excreted in urine.
• Phytoestrogen levels are higher in fluid collected from
breast and prostatic ducts compared with serum or
plasma.
• Urinary isoflavonoid excretions range from about 0.3-30
mM/day.
• Urinary secretions of vegetarians may contain 1000 times
higher phytoetsrogens than total urinary steroid estrogens.
• Phytoestrogens demonstrate inhibitory effects at 0.5-50mM
which are similar to levels in urine.
Soy Phytoestrogens
• Genistein, daidzein, coumesterol, and equol bind to and
transactivate both ER a and b (0.1-10mM)
• Genistetin has a higher affinity for ERb.
• Soy PEs effect cell cycle progression, growth, and
differentiation. Have antioxidant and anti-angiogenic
activities.
• Genistein affects cellular function via inhibition of 17 betasteroid oxidoreductase (an enzyme necessary for
conversion of androgens to E2).
• Inhibits aromatase.
• Effects cycloxygenase, lipoxygenase, Cholesterol 7a
hydroxylase.
• Modulates the activity of topoisomerase II.
• Modulates enzymes involved in phosphoinositide (PI)
turnover.
• Modulates TGF-β signaling cascades
• Increases epidermal growth factor (EGF) and EGFR levels.
y
m
s
:
4
'
,
5
,
7
T
r
i
h
y
d
r
o
x
y
i
s
o
f
Genistein
4',5,7-Trihydroxyisoflavone
• Both estrogenic and anti-estrogenic
effects
• Inhibitor of tyrosine kinases
• 20-fold higher binding affinity for ER-b
than ER-a (Makela et al. 1999)
Phytoestrogens in Human Health
•
•
•
•
•
•
Cancer preventive
Post-menopausal supplement
Prevention of osteoporosis
Cardiovascular health
Fertility
Breast enhancement
References: Kurzer, 2003. J. Nutr. 133: 1983S-1986S.
Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.
Cancer preventive
• Benefits to human breast and uterine cancer
controversial.
• Genistein can be carcinogenic in uterine cancer at
neonatal exposure.
• Cancer protective in animal studies, especially when
exposed during breast development.
• Isoflavonoids and lignans stimulate proliferation of ER+
breast cancer cells.
• Inhibit cell growth at high concentrations and in ERa (-)
breast cancer cells.
• Therefore, ER b may have cancer protective effect.
• Anti-angiogenic effects of genistein, daidzein, and
biochanin A may contribute to antitumor activity.
• Anti-oxidants in vitro and in vivo.
Post-menopausal therapy
• In 2002, the Women’s Health Initiative
(WHI) trial of estrogen/progestin therapy
was halted midtrial due to high incidence
of breast cancer and cardiovascular
disease.
• Consumption of 30mg/d soy isoflavones
may reduce hot flashes by 30-50%.
Prevention of osteoporosis
• Isoflavone intake increases bone
mineral density.
• Can be useful in preventing postmenopausal osteoporosis.
• Diets rich in phytoestrogens can
protect long-term bone loss (Setchell &
Lydeking-Olsen, 2003. Am. J. Clin. Nutr. 78:593S609S)
.
Cardiovascular health
• Average intake of 47g/day soy protein results
in 9% decrease in total cholesterol,13%
decrease in LDL cholesterol, and a trend
towards HDL cholesterol.
• Flavanoids decrease platelet aggregation.
• Genistein-induced inhibition of growth factor
activity can interfere with platelet and thrombin
action.
Effects on fertility (premenopausal)
• Interferes with menstrual cycle (delay)
Reduced LH and FSH and progesterone.
• Male rodents exposed to PEs in early life:
impaired semen quality, congenital
malformations, testicular cancer
(coumesterol, delay in mating)
Red wine phytoestrogens:
Resveratrol, quercetin, and anthocyanins
• Antioxidant, anti-apoptosis, anti-inflammatory, anti-cancer, and
anti-invasive.
• Reduces Cu-induced LDL oxidation by binding to LDL via a glycosidic
ether bond. Increases HDL cholesterol. Inhibits platelet activation.
• Ameliorates neuronal damage due to ethanol consumption. Probably
via antioxidant effect. Minimizes effects of NOS activity by ehtanol.
Inhibits ethanol-induced arachidonic acid release and cycloxygenase
activity.
Anti-ageing role?
• inhibitory effects on cancer initiation, growth promotion progression
and angiogenesis in model systems.
• The anti-proliferative activity of resveratrol is mediated by p38-MAPKs
via p53 mediated inhibition. Resveratrol may inhibit apoptosis induced by
oxidized lipoproteins through inhibition of NF-kB and AP-1 pathways.
• Resveratrol inhibits protein kinase C, Akt, and FAK activities in ER a (+)
breast cancer cells.