Breast Cancer

And
Estrogen Metabolism
David T. Zava, PhD
Founder, CEO, Chief Research Scientist
ZRT Laboratory

COPYRIGHT
2002

HORMONAL RISK FACTORS FOR BREAST CANCER

THE ESTROGEN MATRIX
OVARIAN
DYSFUNCTION

POLYCYSTIC
OVARIES

XENOBIOTICS
(eg, PCBs)

POLLUTANTS

ESTROGENS

ERT
HRT

(E1, E2)

XENOESTROGENS
(eg, DDT)

PROGESTERONE

E
ER

SHBG

Emotional
Physical
Surgical

ADRENAL
GLAND

INSULIN

(refined carbohydrates)

MELATONIN

DHEA

LH/FSH

Iodine (I2)

POOR DIET

THYROID

CORTISOL

(AROMATASE)

Vitamin D3

PROLACTIN

STRESS

TESTOSTERONE

17B-HSD TYPE II (E1E2)

E1-SULFATASE (E1-S04 E1)
AROMATASE
(A E1)

ZINC
BREAST STROMA
IMMUNE CYTOKINES
SYSTEM TH1 TH2

HEAVY
METALS

INSULIN
RESISTANCE
OBESITY

SMOKING

ESTROGEN METABOLISM AND BREAST CANCER RISK

Sulfotransferase

E1-S04

E1
Sulfatase

INACTIVE
ESTROGEN
METABOLITES

2-MeO-E1(E2)
4-MeO-E1(E2)
2-GS-E1(E2)
4-GS-E1(E2)

E2

17-HSD-Type I
Cyp-1A1

4-OH-E1(E2)

2-OH-E1(E2)

16-OH-E1

E3

COMT-Methylation of 2- & 4-OH E1(E2)

4-QUINONE-E1(E2)

2-QUINONE-E1(E2)

PROTEIN
BINDING

GST-GSH conjugation of 2- & 4-Quinone E1(E2)

DNA ADDUCT
FORMATION

CANCER

17 -HSD-Type II

DNA DAMAGE
MUTATION

DNA ADDUCT
FORMATION
DNA REPAIR

NO FURTHER
EFFECT
E1 = ESTRONE
E2 =ESTRADIOL
E3 = ESTRIOL

ESTROGENS
The Angel of Life
Or
The Angel of Death

ESTROGEN METABOLISM AND BREAST CANCER RISK

Sulfotransferase

E1-S04

E1
Sulfatase

INACTIVE
ESTROGEN
METABOLITES

2-MeO-E1(E2)
4-MeO-E1(E2)
2-GS-E1(E2)
4-GS-E1(E2)

E2

17-HSD-Type I
Cyp-1A1

4-OH-E1(E2)

2-OH-E1(E2)

16-OH-E1

E3

COMT-Methylation of 2- & 4-OH E1(E2)

4-QUINONE-E1(E2)

2-QUINONE-E1(E2)

PROTEIN
BINDING

GST-GSH conjugation of 2- & 4-Quinone E1(E2)

DNA ADDUCT
FORMATION

CANCER

17 -HSD-Type II

DNA DAMAGE
MUTATION

DNA ADDUCT
FORMATION
DNA REPAIR

NO FURTHER
EFFECT
E1 = ESTRONE
E2 =ESTRADIOL
E3 = ESTRIOL

Different types of body fluids commonly

used for testing hormones

Serum and Plasma (Venipuncture)

Urine (Liquid and Dry)

Dried
Urine Test

Saliva

Capillary Blood
(Finger Stick Dried Blood Spots)

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 GCMS/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

ESTROGEN METABOLISM AND BREAST CANCER RISK

Sulfotransferase

E1-S04

E1
Sulfatase

INACTIVE
ESTROGEN
METABOLITES

2-MeO-E1(E2)
4-MeO-E1(E2)
2-GS-E1(E2)
4-GS-E1(E2)

E2

17-HSD-Type I
Cyp-1A1

4-OH-E1(E2)

2-OH-E1(E2)

16-OH-E1

E3

COMT-Methylation of 2- & 4-OH E1(E2)

4-QUINONE-E1(E2)

2-QUINONE-E1(E2)

PROTEIN
BINDING

GST-GSH conjugation of 2- & 4-Quinone E1(E2)

DNA ADDUCT
FORMATION

CANCER

17 -HSD-Type II

DNA DAMAGE
MUTATION

DNA ADDUCT
FORMATION
DNA REPAIR

NO FURTHER
EFFECT
E1 = ESTRONE
E2 =ESTRADIOL
E3 = ESTRIOL

ESTROGEN METABOLISM AND BREAST CANCER RISK

Sulfotransferase

E1-S04

E1
Sulfatase

INACTIVE
ESTROGEN
METABOLITES

2-MeO-E1(E2)
4-MeO-E1(E2)
2-GS-E1(E2)
4-GS-E1(E2)

E2

17-HSD-Type I
Cyp-1A1

4-OH-E1(E2)

16-OH-E1

2-OH-E1(E2)

E3

COMT

4-QUINONE-E1(E2)

2-QUINONE-E1(E2)

PROTEIN
BINDING

GSH Transferase

DNA ADDUCT
FORMATION

CANCER

17 -HSD-Type II

DNA DAMAGE
MUTATION

DNA ADDUCT
FORMATION
DNA REPAIR

NO FURTHER
EFFECT
E1 = ESTRONE
E2 =ESTRADIOL
E3 = ESTRIOL

STRESS-BREAST CANCER
and
Cortisol-Melatonin-Estrogen

HORMONAL RISK FACTORS FOR BREAST CANCER

THE ESTROGEN MATRIX
OVARIAN
DYSFUNCTION

POLYCYSTIC
OVARIES

XENOBIOTICS
(eg, PCBs)

ESTROGENS

ERT
HRT

POLLUTANTS

(E1, E2)

XENOESTROGENS
PROGESTERONE

PROLACTIN
SHBG
STRESS
Emotional
Physical
Surgical

(AROMATASE)

MELATONIN

E
ER

Iodine (I2)
INSULIN
POOR DIET

(refined carbohydrates)
17B-HSD TYPE I (E1E2)
E1-SULFATASE (E1-S04 E1)
AROMATASE
(A E1)

ZINC
BREAST STROMA
CADMIUM

DHEA

LH/FSH

Vitamin D3

THYROID

CORTISOL
ADRENAL
GLAND

(eg, DDT)

TESTOSTERONE

IMMUNE CYTOKINES
SYSTEM TH1 TH2

INSULIN
RESISTANCE
OBESITY

SMOKING

Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D.

Diurnal Cortisol Rhythm as a Predictor of Breast

Cancer Survival. JNCI 92: 994-1000, 2000.

Cancer

Normal

Normal Profile: Cortisol high morning, low night

Breast Cancer Profile: Flat Diurnal Cortisol, high at night

Normal Healthy Adult:

Cortisol and Melatonin
Circadian Rhythm

Typical Cancer Patient:

Cortisol and Melatonin
Circadian Rhythm

HORMONAL RISK FACTORS FOR BREAST CANCER

THE ESTROGEN MATRIX
OVARIAN
DYSFUNCTION

POLYCYSTIC
OVARIES

XENOBIOTICS
(eg, PCBs)

POLLUTANTS

ESTROGENS

ERT
HRT

(E1, E2)

XENOESTROGENS
(eg, DDT)

PROGESTERONE

E
ER

SHBG

Emotional
Physical
Surgical

ADRENAL
GLAND

INSULIN

(refined carbohydrates)

MELATONIN

DHEA

LH/FSH

Iodine (I2)

POOR DIET

THYROID

CORTISOL

(AROMATASE)

Vitamin D3

PROLACTIN

STRESS

TESTOSTERONE

17B-HSD TYPE II (E1E2)

E1-SULFATASE (E1-S04 E1)
AROMATASE
(A E1)

ZINC
BREAST STROMA
IMMUNE CYTOKINES
SYSTEM TH1 TH2

HEAVY
METALS

INSULIN
RESISTANCE
OBESITY

SMOKING

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)