Transcript Estrogen Metabolism Role in Oncology

Estrogen Metabolism
Role in Oncology
Tom Archie, MD
SLWRMC Tumor Board
June 19, 2008
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50yo Caucasian Female
Early breast cancer – poorly differentiated
MRI negative for contralateral tumor
Receptor Status:
– Triple Negative (ER, PR, HER2/neu)
• Lumpectomy followed by Taxotere and
Cytoxan
Estrogen Metabolism Testing
• Identify high risk patients for new breast
cancer
• Others: prostate cancer, leukemia, olfactory
tumors, and Parkinson’s Disease (probably more
to come)
• Identify high risk of recurrence in breast
cancer patients (and other cancers)
• Modify risk via modification of estrogen
metabolism balance
• Future: “pre-mammogram” biomarker
Catechol Estrogen Quinones to
DNA Adducts
• Endogenous Estrogens can become
carcinogenic via formation of catechol estrogen
quinones, which react with DNA to form specific
depurinating estrogen-DNA adducts.
• The mutations resulting from these adducts can
lead to cell transformation and the initiation of
breast cancer.
• Irregardless of ER status
• Mechanism: Sheer volume of DNA “apurinic” sites – DNA
repair enzymes make mistakes, leading to single nucleotide
polymorphisms (SNP)
Catechol Estrogen Quinones to
DNA Adducts
• 4-OH-estrone induces DNA Adduct
formation in normal breast epithelium
(MCF-10F cells)
• Saeed M et al. Int J Cancer. 2007 Apr 15;120(8):1821-4.
Human Study of Urinary Estrogen
Metabolites w/ and w/o Breast CA
• Human study comparing healthy controls, breast cancer
patients, and “high risk” patients (as determined by
oncologists in study)
• The levels of the ratios of depurinating DNA adducts to
their respective estrogen metabolites/conjugates were
significantly higher in high-risk women (p < 0.001) and
women with breast cancer (p < 0.001) than in control
subjects.
• This mechanism represents the best understood and
documented initiation step in the formation of any
cancer.
• Gaikwad NW et al. The molecular etiology of breast cancer:
evidence from biomarkers of risk. Int J Cancer. 2008 May
1;122(9):1949-57.
COMT and CE (Catechol Estrogen)
• Quantitatively, the most active CE conjugative pathway
is methylation. CE methylation is catalyzed by COMT
• Catechol-O-methyltransferase (COMT) a classical
phase II enzyme, catalyzes the transfer of methyl groups
from S-adenosyl methionine, the enzyme cofactor, to
hydroxyl groups of a number of catechol substrates,
including the CEs.
• Under normal circumstances, CEs are, for the most
part, promptly O-methylated by COMT to form 2- and 4O-methylethers, which are then excreted.
• While virtually all catechols are substrates for COMT, the
highest affinities for the enzyme are exhibited by the CEs
• Journal of the National Cancer Institute Monographs No. 27, 2000
Low Functioning COMT
and Breast Cancer Risk
• Genetic epidemiology studies have
proposed a possible correlation between
the low activity allele (COMTLL) and
increased breast cancer risk
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Lavigne JA, et al. An association between the allele coding for a low activity
variant of catechol-O-methyltransferase and the risk for breast cancer.
Cancer Res 1997;57:5493–5497.
Huang CS, et al. Breast cancer risk associated with genotype polymorphism
of the estrogen metabolizing genes CYP17, CYP1A1, and COMT: A
multigenic study on cancer susceptibility. Cancer Res 1999;59:4870–4875.
Yim D-S, et al. Relationship between the val158met polymorphism of
catechol O-methyl transferase and breast cancer. Pharmacogenetics
2001;11:1–8.
COMT and Breast Cancer
• COMT protects cells from the genotoxicity and
cytotoxicity of catechol estrogens, by preventing
their conversion to quinones
• Adds methyl group (-CH3) at the -OH site that would
otherwise be oxidized by peroxidase enzymes
• Low activity of COMT leads to higher levels of
depurinating estrogen-DNA adducts that can
induce mutations and initiate cancer.
– MCF-10F (human breast epithelial cells that are ER
neg)
– Estrogen-DNA adducts’ carcinogenicity independent
of ER status
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Zahid M et al. Free Radic Biol Med. 2007 Dec 1;43(11):1534-40.
• Lu F et al.J Steroid Biochem Mol Biol. 2007 ; 105(1-5): 150–158.
Low Functioning COMT Common
• 25% of US Caucasians are homozygous for the
val108/158met polymorphism in the COMT gene
• Lachman HM, et al. Pharmacogenetics 1996;6:243–250.
• Scanlon PD, et al. Science 1979;203:63–65.
• 27% Chinese Americans and 34% Japanese Americans
• Wu A et al. Cancer Res 2003;63: 7526–7529
• Val108/158Met SNP associated with 3-4x
reduction in functional enzymatic rate of COMT.
• Zhu BT. Curr Drug Metab 2002;3: 321–349
E2:E16 Ratio - Breast Cancer Risk
• Prospective Study 10,786 women aged
34-69 with 5 ½ yr followup
• Measured urinary estrogen metabolites
• 144 breast cancer pts w/ 4 matched controls for
each cancer
• Highest quintile E2:E16 ratio
– Premenopausal: OR 0.58 (42% risk red)
– Postmenopausal: OR 1.29 (29% risk inc)
Muti et al. Epidemiology. 2000 Nov;11(6):635-40
Broccoli increases E2:E16 ratio
• Increase E2:E16 ratio 29.5% with broccoli
500gr/day
• Cruciferous vegetables cause the
upregulation of Cyp1A2 (19%) and
Cyp1A1 and inhibit Cyp2E1
– Indole 3 Carbinol (glucocinolate)
– Sulforaphane (isothiocyanate)
– Diindolylmethane (glucocinolate)
– Calcium D Glucarate
Interpretation
• Low 2-Hydroxyestrone/16α-Hydroxyestrone
Ratio
– Premenopausal female
– Increased risk of ongoing carcinogensis leading to
treatment failure
Interpretation
• Poor methylation capacity – she is a “slow methylator”
– 4-Methoxyestrone is undetectable
• 4-Hydroxyestrone is not being methylated adequately.
– 4-Hydroxyestrone level is high.
• This is associated with increased levels of 4-catechol
estrogen DNA adducts, which are strongly associated with
the initiation of breast and prostate cancer.
– COMT is likely genetically slow
• Principal agent for eliminating catechol estrogens
Interpretation
• Interestingly, the methylation of 2OHE is
adequate, whereas methylation of 4OHE
is not
• I find no literature citing methylation
preferences for 2OHE vs. 4OHE
• Fact remains that additional methylation
support is needed
Treatment Goals
• Enhance methylation
• Decrease Cyp1B1 activity
• Increase E2:E16 ratio
– Cruciferous vegetables
Improve Methylation
• Increase substrate for COMT (SAMe)
• Add methyl donors
– Folate, methylcobalamin (B12)
– Trimethylglycine (Betaine)
– Vit B6 (to discourage the accumulation of
homocysteine and encourage the formation of
glutathione via synthesis of cysteine)
• There is no physiological mechanism to suggest
an adverse interaction between methylation and
the metabolism of either taxotere or cytoxan
Improve Methylation
COMT
Cyp1B1 inhibition
(ie: reduction of DNA adducts)
• Reduce xenobiotic pollutant exposure
• N-acetyl Cysteine
• Sulforaphane (glucosinolate from broccoli)
induces quinone reductase, which takes CEQs
back to catechol estrogens, reducing the
potential for the creating of DNA adducts.
– Hwang. J Med Food. 2005 Summer;8(2):198-203
• Glutathione conjugates are not playing much of
a role in protecting against DNA adducts.
Cyp 1B1 Inhibition to decrease
DNA Adduct Formation
• Increased methylation of catechol
estrogens leads to feedback inhibition of
Cyp1B1
– Dawling et al. Cancer Res. 2003 Jun 15;63 (12):3127-32.
Cyp 1B1 Inhibition to decrease
DNA Adduct Formation
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Reduced Lipoic Acid
N-acetyl Cysteine
Resveratrol
Melatonin (minimal but positive effect)
– Zahid M. et al. Inhibition of depurinating estrogen-DNA adduct formation
by natural compounds. Chem Res Toxicol. 2007 Dec;20(12):1947-53.
Epub 2007 Nov
– Chen et al. Resveratrol inhibits TCDD-induced expression of
CYP1A1 and CYP1B1 and catechol estrogen-mediated oxidative
DNA damage in cultured human mammary epithelial cells
Carcinogenesis vol.25 no.10 pp.2005--2013, 2004
doi:10.1093/carcin/bgh183
Synergism b/t Paclitaxel and
Broccoli Glucosinolate
• Diindolylmethane in combination with
paclitaxel synergistically inhibits growth of
Her2 / neu human breast cancer cells
through G2M phase cell-cycle arrest and
induction of apoptosis / necrosis
• McGuire KP, et al. J Surg Res. 2006 May
15;132(2):208-13. Epub 2006 Mar 31.
Broccoli and Antitumor Effects
• Sulforaphane inhibits breast cancer growth
and induces Quinone Reductase
– Hwang. J Med Food. 2005 Summer;8(2):198-203.
• I3C induces Br CA cell cycle arrest
Potential Risk
• Uncertain effect on Cyp3A4
– (60% of drugs)
– Sulforaphane inhibtis
– Diindolylmethane has no effect
• Could affect concentration of these drugs
and theoretically increase adverse drug
events or decrease efficacy
• Taxotere metabolized by Cyp3A4
• Consider avoiding near time of infusion
Prostate CA
• Small study of urine estrogen metabolites in men
with prostate cancer vs. benign urological d/o vs.
healthy controls
• 4-OHE1-DNA Adducts detected at higher levels
in samples from subjects with prostate cancer
and benign urological conditions compared to
healthy males
• This is the first demonstration that CEQ-derived
DNA adducts are present in urine samples from
subjects with prostate cancer.
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Markushkin Y et al. Potential biomarker for early risk assessment of prostate
cancer. Prostate. 2006 Oct 1;66(14):1565-71
Extension to Other Cancers
• This mechanism is also involved in
– Initiation of leukemia by benzene
– Rat olfactory tumors by naphthalene
– Neurodegenerative diseases such as
Parkinson's disease by dopamine.
• Estrogens and Human Diseases. Volume 1089 published November
2006 Ann. N.Y. Acad. Sci. 1089: 286–301 (2006). doi:
10.1196/annals.1386.042
Conclusion
• No human intervention trials on manipulation of estrogen
metabolism in patients w/ active breast cancer
• Epidemiologic studies support cruciferous vegetables
and methyl donors to decrease breast cancer risk
• In vitro studies showing anticancer effects of brassica
• Risk of non-action vs. action?
• Enhance methylation now
• Increase E2:E16 ratio now but reduce likelihood of
possible interaction w/ metabolism of taxotere by
avoiding for 1 week prior and 2 days after administration
of taxotere
• Inhibit Cyp1B1 now
In a word….
One Last Thought
for Future Discussion
Multifocal Angiostatic Therapy
curcmin, artemsia,
mistletoe, ginger
scutellaria,
resveratrol,
grapeseed extract,
green tea, gingko, ginger
squalamine, Vit D
artemsia
silymarin, glycine, mistletoe
curcumin
scutellaria
VEGFR
curcmin,
scutellaria,
cartilege,
silymarin,
green tea
EGCG, silymarin,
quercetin,
resveratrol, soy
isoflavones,
curcumin, EPA
Multifocal
Angiostatic
Therapy
Cu antagonists
bFGFR and TNF-1:
Growth
Factors
NFkB
COX-2
Cu antagonists
VEGF, AKs, bFGF, IL8, MMPs,
TNF-1, heparinases, collagenases
Silymarin,
Glycine, Ginger
green tea
quercetin
magnolia
resveratrol,
soy, curcumin
holy basil
rosemary
ganoderma
licorice Vit E
Anti-COX-2: quercetin,
scutellaria, EPA/DHA, licorice,
ginger, resveratrol, grapeseed
extract, curcumin, salicylates,
garlic, green tea, panax ginseng,
silymarin, bilberry, antioxidants,
boswellia, aloe
Anti- NFkB: poria,
coriolus, ginger,
resveratrol, green tea,
artemsia, quercetin,
carnosol, panax ginseng,
silymarin, salicylates,
curcumin, picentannol,
basil, Cu antagonists
rosemary