Presentation on theme: "Estrogen Metabolism Role in Oncology"— Presentation transcript:
1Estrogen Metabolism Role in Oncology Tom Archie, MDSLWRMC Tumor BoardJune 19, 2008
2Early breast cancer – poorly differentiated 50yo Caucasian FemaleEarly breast cancer – poorly differentiatedMRI negative for contralateral tumorReceptor Status:Triple Negative (ER, PR, HER2/neu)Lumpectomy followed by Taxotere and Cytoxan
3Estrogen Metabolism Testing Identify high risk patients for new breast cancerOthers: 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 balanceFuture: “pre-mammogram” biomarker
5Catechol 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 statusMechanism: Sheer volume of DNA “apurinic” sites – DNA repair enzymes make mistakes, leading to single nucleotide polymorphisms (SNP)
6Catechol 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 Apr 15;120(8):
7Human 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 May 1;122(9):
9COMT and CE (Catechol Estrogen) Quantitatively, the most active CE conjugative pathway is methylation. CE methylation is catalyzed by COMTCatechol-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 4-O-methylethers, which are then excreted.While virtually all catechols are substrates for COMT, the highest affinities for the enzyme are exhibited by the CEsJournal of the National Cancer Institute Monographs No. 27, 2000
10Low Functioning COMT and Breast Cancer Risk Genetic epidemiology studies have proposed a possible correlation between the low activity allele (COMTLL) and increased breast cancer riskLavigne 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.
11COMT and Breast CancerCOMT protects cells from the genotoxicity and cytotoxicity of catechol estrogens, by preventing their conversion to quinonesAdds methyl group (-CH3) at the -OH site that would otherwise be oxidized by peroxidase enzymesLow 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 statusZahid M et al. Free Radic Biol Med Dec 1;43(11):Lu F et al.J Steroid Biochem Mol Biol ; 105(1-5): 150–158.
12Low Functioning COMT Common 25% of US Caucasians are homozygous for the val108/158met polymorphism in the COMT geneLachman HM, et al. Pharmacogenetics 1996;6:243–250.Scanlon PD, et al. Science 1979;203:63–65.27% Chinese Americans and 34% Japanese AmericansWu A et al. Cancer Res 2003;63: 7526–7529Val108/158Met SNP associated with 3-4x reduction in functional enzymatic rate of COMT.Zhu BT. Curr Drug Metab 2002;3: 321–349
13E2:E16 Ratio - Breast Cancer Risk Prospective Study 10,786 women aged with 5 ½ yr followupMeasured urinary estrogen metabolites144 breast cancer pts w/ 4 matched controls for each cancerHighest quintile E2:E16 ratioPremenopausal: OR 0.58 (42% risk red)Postmenopausal: OR 1.29 (29% risk inc)Muti et al. Epidemiology Nov;11(6):635-40
14Broccoli increases E2:E16 ratio Increase E2:E16 ratio 29.5% with broccoli 500gr/dayCruciferous vegetables cause the upregulation of Cyp1A2 (19%) and Cyp1A1 and inhibit Cyp2E1Indole 3 Carbinol (glucocinolate)Sulforaphane (isothiocyanate)Diindolylmethane (glucocinolate)Calcium D Glucarate
16Interpretation Low 2-Hydroxyestrone/16α-Hydroxyestrone Ratio Premenopausal femaleIncreased risk of ongoing carcinogensis leading to treatment failure
17Interpretation Poor methylation capacity – she is a “slow methylator” 4-Methoxyestrone is undetectable4-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 slowPrincipal agent for eliminating catechol estrogens
18InterpretationInterestingly, the methylation of 2OHE is adequate, whereas methylation of 4OHE is notI find no literature citing methylation preferences for 2OHE vs. 4OHEFact remains that additional methylation support is needed
20Improve Methylation Increase substrate for COMT (SAMe) Add methyl donorsFolate, 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
22Cyp1B1 inhibition (ie: reduction of DNA adducts) Reduce xenobiotic pollutant exposureN-acetyl CysteineSulforaphane (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 Summer;8(2):Glutathione conjugates are not playing much of a role in protecting against DNA adducts.
23Cyp 1B1 Inhibition to decrease DNA Adduct Formation Increased methylation of catechol estrogens leads to feedback inhibition of Cyp1B1Dawling et al. Cancer Res Jun 15;63 (12):
24Cyp 1B1 Inhibition to decrease DNA Adduct Formation Reduced Lipoic AcidN-acetyl CysteineResveratrolMelatonin (minimal but positive effect)Zahid M. et al. Inhibition of depurinating estrogen-DNA adduct formation by natural compounds. Chem Res Toxicol Dec;20(12): Epub 2007 NovChen 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 , 2004doi: /carcin/bgh183
25Synergism 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 / necrosisMcGuire KP, et al. J Surg Res May 15;132(2): Epub 2006 Mar 31.
26Broccoli and Antitumor Effects Sulforaphane inhibits breast cancer growth and induces Quinone ReductaseHwang. J Med Food Summer;8(2):I3C induces Br CA cell cycle arrest
27Potential Risk Uncertain effect on Cyp3A4 (60% of drugs)Sulforaphane inhibtisDiindolylmethane has no effectCould affect concentration of these drugs and theoretically increase adverse drug events or decrease efficacyTaxotere metabolized by Cyp3A4Consider avoiding near time of infusion
28Prostate CASmall study of urine estrogen metabolites in men with prostate cancer vs. benign urological d/o vs. healthy controls4-OHE1-DNA Adducts detected at higher levels in samples from subjects with prostate cancer and benign urological conditions compared to healthy malesThis is the first demonstration that CEQ-derived DNA adducts are present in urine samples from subjects with prostate cancer.Markushkin Y et al. Potential biomarker for early risk assessment of prostate cancer. Prostate Oct 1;66(14):
29Extension to Other Cancers This mechanism is also involved inInitiation of leukemia by benzeneRat olfactory tumors by naphthaleneNeurodegenerative 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: /annals
30ConclusionNo human intervention trials on manipulation of estrogen metabolism in patients w/ active breast cancerEpidemiologic studies support cruciferous vegetables and methyl donors to decrease breast cancer riskIn vitro studies showing anticancer effects of brassicaRisk of non-action vs. action?Enhance methylation nowIncrease 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 taxotereInhibit Cyp1B1 now