breast cancer and estrogen · pdf filedavid t. zava, phd founder, ceo, chief research...
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David T. Zava, PhD Founder, CEO, Chief Research Scientist ZRT Laboratory
Breast Cancer And
Estrogen Metabolism
COPYRIGHT 2002
E ER
XENOESTROGENS (eg, DDT)
POLLUTANTS
XENOBIOTICS (eg, PCBs)
ESTROGENS (E1, E2)
PROGESTERONE
PROLACTIN
SHBG
THYROID
MELATONIN
CORTISOL
17B-HSD TYPE II (E1→E2) E1-SULFATASE (E1-S04 →E1) AROMATASE (A →E1)
BREAST STROMA
IMMUNE CYTOKINES SYSTEM TH1 ↓ TH2 ↑
DHEA
ADRENAL GLAND
STRESS
Emotional Physical Surgical
OVARIAN DYSFUNCTION
HEAVY METALS
ZINC SMOKING
POOR DIET (refined carbohydrates)
INSULIN
OBESITY
INSULIN RESISTANCE
TESTOSTERONE
(AROMATASE) LH/FSH
POLYCYSTIC OVARIES
ERT HRT
HORMONAL RISK FACTORS FOR BREAST CANCER THE ESTROGEN MATRIX
Vitamin D3
Iodine (I2)
2-OH-E1(E2)
E2 E1-S04 E1
16-OH-E1 4-OH-E1(E2)
4-QUINONE-E1(E2) 2-QUINONE-E1(E2) PROTEIN BINDING
DNA ADDUCT FORMATION
DNA ADDUCT FORMATION
NO FURTHER EFFECT
DNA REPAIR DNA DAMAGE MUTATION
CANCER
Sulfotransferase
Sulfatase
17 ß-HSD-Type II
17ß-HSD-Type I
E1 = ESTRONE
E2 =ESTRADIOL
E3 = ESTRIOL
E3
GST-GSH conjugation of 2- & 4-Quinone E1(E2)
COMT-Methylation of 2- & 4-OH –E1(E2)
INACTIVE ESTROGEN
METABOLITES
ESTROGEN METABOLISM AND BREAST CANCER RISK
Cyp-1A1
2-MeO-E1(E2)
4-MeO-E1(E2)
2-GS-E1(E2)
4-GS-E1(E2)
ESTROGENS
The Angel of Life
Or
The Angel of Death
2-OH-E1(E2)
E2 E1-S04 E1
16-OH-E1 4-OH-E1(E2)
4-QUINONE-E1(E2) 2-QUINONE-E1(E2) PROTEIN BINDING
DNA ADDUCT FORMATION
DNA ADDUCT FORMATION
NO FURTHER EFFECT
DNA REPAIR DNA DAMAGE MUTATION
CANCER
Sulfotransferase
Sulfatase
17 ß-HSD-Type II
17ß-HSD-Type I
E1 = ESTRONE
E2 =ESTRADIOL
E3 = ESTRIOL
E3
GST-GSH conjugation of 2- & 4-Quinone E1(E2)
COMT-Methylation of 2- & 4-OH –E1(E2)
INACTIVE ESTROGEN
METABOLITES
ESTROGEN METABOLISM AND BREAST CANCER RISK
Cyp-1A1
2-MeO-E1(E2)
4-MeO-E1(E2)
2-GS-E1(E2)
4-GS-E1(E2)
Different types of body fluids commonly
used for testing hormones
Serum and Plasma (Venipuncture)
Urine (Liquid and Dry)
Saliva
Capillary Blood (Finger Stick Dried Blood Spots)
Dried Urine Test
Steroid Hormone Metabolite Testing by GC-MS/MS and LC-MS/MS
Potentially Harmful
Harmful
Safe Beneficial
Chinese-US (ZRT) Urine Steroid Hormone
Metabolite Breast Cancer Study
Eric Shi, PhD, MD, David Zava, PhD et.al. 37 Chinese premenopausal breast cancer patients-newly diagnosed, no Tx 42 Healthy age-matched controls Morning spot urine collections on filter paper-dried-shipped to ZRT at ambient temperature Steroids extracted from filter paper, SPE, enzyme hydrolyzed, liquid extracted, dried, derivatized, analyzed by GC-MS/MS.
Internal Research Results on Estrogen Metabolites and
Breast Cancer (to be published)
- 4-OH-Estrogens higher in breast cancer patients than controls - Selenium low in controls and breast cancer patients but statistically lower in patients
Potentially Harmful
Harmful
Safe Beneficial
2-OH-E1(E2)
E2 E1-S04 E1
16-OH-E1 4-OH-E1(E2)
4-QUINONE-E1(E2) 2-QUINONE-E1(E2) PROTEIN BINDING
DNA ADDUCT FORMATION
DNA ADDUCT FORMATION
NO FURTHER EFFECT
DNA REPAIR DNA DAMAGE MUTATION
CANCER
Sulfotransferase
Sulfatase
17 ß-HSD-Type II
17ß-HSD-Type I
E1 = ESTRONE
E2 =ESTRADIOL
E3 = ESTRIOL
E3
GST-GSH conjugation of 2- & 4-Quinone E1(E2)
COMT-Methylation of 2- & 4-OH –E1(E2)
INACTIVE ESTROGEN
METABOLITES
ESTROGEN METABOLISM AND BREAST CANCER RISK
Cyp-1A1
2-MeO-E1(E2)
4-MeO-E1(E2)
2-GS-E1(E2)
4-GS-E1(E2)
2-OH-E1(E2)
E2 E1-S04 E1
16-OH-E1 4-OH-E1(E2)
4-QUINONE-E1(E2) 2-QUINONE-E1(E2) PROTEIN BINDING
DNA ADDUCT FORMATION
DNA ADDUCT FORMATION
NO FURTHER EFFECT
DNA REPAIR DNA DAMAGE MUTATION
CANCER
Sulfotransferase
Sulfatase
17 ß-HSD-Type II
17ß-HSD-Type I
E1 = ESTRONE
E2 =ESTRADIOL
E3 = ESTRIOL
E3
GSH Transferase
COMT
INACTIVE ESTROGEN
METABOLITES
ESTROGEN METABOLISM AND BREAST CANCER RISK
Cyp-1A1
2-MeO-E1(E2)
4-MeO-E1(E2)
2-GS-E1(E2)
4-GS-E1(E2)
STRESS-BREAST CANCER
and
Cortisol-Melatonin-Estrogen
E ER
XENOESTROGENS (eg, DDT)
POLLUTANTS
XENOBIOTICS (eg, PCBs)
ESTROGENS (E1, E2)
PROGESTERONE
PROLACTIN
SHBG
THYROID
MELATONIN
CORTISOL
17B-HSD TYPE I (E1→E2) E1-SULFATASE (E1-S04 →E1) AROMATASE (A →E1)
BREAST STROMA
IMMUNE CYTOKINES SYSTEM TH1 ↓ TH2 ↑
DHEA
ADRENAL GLAND
STRESS
Emotional Physical Surgical
OVARIAN DYSFUNCTION
CADMIUM
ZINC SMOKING
POOR DIET (refined carbohydrates)
INSULIN
OBESITY
INSULIN RESISTANCE
TESTOSTERONE
(AROMATASE) LH/FSH
POLYCYSTIC OVARIES
ERT HRT
HORMONAL RISK FACTORS FOR BREAST CANCER THE ESTROGEN MATRIX
Vitamin D3
Iodine (I2)
Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D. Diurnal Cortisol Rhythm as a Predictor of Breast Cancer Survival. JNCI 92: 994-1000, 2000.
Normal Profile: Cortisol high morning, low night Breast Cancer Profile: Flat Diurnal Cortisol, high at night
Normal
Cancer
Normal Healthy Adult: Cortisol and Melatonin
Circadian Rhythm
Typical Cancer Patient: Cortisol and Melatonin
Circadian Rhythm
E ER
XENOESTROGENS (eg, DDT)
POLLUTANTS
XENOBIOTICS (eg, PCBs)
ESTROGENS (E1, E2)
PROGESTERONE
PROLACTIN
SHBG
THYROID
MELATONIN
CORTISOL
17B-HSD TYPE II (E1→E2) E1-SULFATASE (E1-S04 →E1) AROMATASE (A →E1)
BREAST STROMA
IMMUNE CYTOKINES SYSTEM TH1 ↓ TH2 ↑
DHEA
ADRENAL GLAND
STRESS
Emotional Physical Surgical
OVARIAN DYSFUNCTION
HEAVY METALS
ZINC SMOKING
POOR DIET (refined carbohydrates)
INSULIN
OBESITY
INSULIN RESISTANCE
TESTOSTERONE
(AROMATASE) LH/FSH
POLYCYSTIC OVARIES
ERT HRT
HORMONAL RISK FACTORS FOR BREAST CANCER THE ESTROGEN MATRIX
Vitamin D3
Iodine (I2)
TYPICAL URINARY HORMONE PROFILE IN BREAST CANCER PATIENTS
ESTRADIOL & ESTRONE
4-OH-E1 & 4-OH-E2 RATIO 4-MeO-E1/4-OH-E1
PREGNANEDIOL RATIO PREGNANE/PREGNENE
TESTOSTERONE & DHT EPI-TESTOSTERONE
DHEA DIURNAL CORTISOL (FLAT)
DIURNAL MELATONIN
TYPICAL SALIVARY AND BLOOD (DBS) HORMONE PROFILE IN BREAST CANCER
PATIENTS
ESTRADIOL & ESTRONE PROGESTERONE
RATIO PROGESTERONE/ESTRADIOL TESTOSTERONE
DHEA(S) DIURNAL CORTISOL (FLAT)
Simple life style changes to reduce risk of developing
breast cancer:
Eat right-lots of organic vegetables Avoid pollutants Exercise Get adequate sleep in a dark room If hormone deficient: take necessary
hormones to create balance Find ways to reduce stress(ors)