a

R

Understanding Cancer and Related Topics

Understanding Estrogen Receptors, Tamoxifen, and Raloxifene

This Booklet describes the hormone Estrogen and its receptor. Explains the relationship of Estrogen and its receptor to Breast Cancer and the risks and benefits of reducing cancer risk with drugs called antiestrogens and selective estrogen receptor molecules (SERMs)

Developed by:Lewis J. Kleinsmith, Ph.D.Donna Kerrigan, M.S.Jeanne KellyBrian Hollen

What Are Estrogens?

O

Estrone

Estradiol

Steroid ring system

OH

HO

HO

Brain

Estrogen Target Tissues

Bone

Uterus

Liver

Heart Breast

Estrogen Receptors

Estrogen target cell(e.g., breast, uterine

lining, liver, etc.)

Estrogen receptor

Tamoxifen

Estrogen

Non-target cell(contains no

estrogen receptor)

Estrogen Receptors Trigger Gene Activation

Estrogen molecule

Specific proteins

Messenger RNAs

Gene activated

Change in cell behavior (e.g., increased proliferation)

Estrogen response elements

Coactivators

DNA molecule

Nucleus

Cytoplasm

Estrogen receptor

Estrogen-Induced Changes in Cell Behavior

Messenger RNAs

Gene activated

Estrogen response elements

Coactivators

DNA molecule

Nucleus

Cytoplasm

Estrogen receptor

Estrogen molecule

New proteins lower LDL

Liver cell

New proteins raise HDL

Estrogen-Induced Stimulation of Cell Proliferation

High estrogen concentration

Breast or uterine cell

Estrogen and Cancer

UterusIncreases cancer risk

Beneficial effects Harmful effects

BreastPrograms milk production

Liver and heartControls cholesterol

UterusPrepares for fetus

BonePreserves strength

BreastIncreases cancer risk

Estrogen and Breast Cancer

Highestrogen

The Menstrual CycleDays

4 14 28

Breast cell deathBreast cell proliferation

Lowestrogen

Cancer Arises From DNA Mutations in Cells

Last DNA mutation from:• heredity

or• radiation or chemicals

or• spontaneous errors

during DNA duplication

DNA mutationsNormal cell Uncontrolled proliferation

Estrogen-Induced Proliferation of Existing Mutant Cells

Mutant breast cells(caused by error, inheritance, and/or environmental factors)

Estrogen stimulation

Estrogen-Induced Proliferation andSpontaneous New Mutations

Normal breast cell

Increased proliferation

Estrogen stimulation

Mistake in DNA duplication

Estrogen and Uterine Cancer

2. Estrogen can increase the chances of developing new, spontaneous mutations.

Estrogen action on the UterusNormal uterine cell

Spontaneous mutation

1. Estrogen can stimulate the division of existing mutant uterine cells.

Antiestrogens

Estrogen receptor

Binding to DNA

Estrogen receptor

Coactivator binds

Genes are activated

Estrogen

Coactivator cannot bind to antiestrogen-bound receptor

No gene activation

Antiestrogen

Binding to DNA

SERMsSERM

Uterine receptor activated

Estrogen receptor in uterine cell

Uterine cell proliferation

Breast receptor not activated

Estrogen receptor in breast cell

No breast cell proliferation

Tamoxifen and Cancer

Estrogen molecule binds

to estrogen receptor

Tamoxifen receptor

cannot bind to cooactivators

Tamoxifen receptor does

not acquire changed

shape

Tamoxifen molecule binds

to estrogen receptor

Estrogen receptor binds

to cooactivators

Estrogen receptor acquires

changed shape

Tamoxifen and Breast Cancer Treatment

Breast cancer surgically removed

Reduced risk of cancer

recurrence

Treatment with tamoxifen

Estrogen Receptor-Negative Breast Cancer

Estrogen

Estrogen receptor-negative breast cancer

Estrogen receptor-positive (er+) breast cancer

Cell proliferation• Not controlled by estrogen• Not inhibited by tamoxifen

Cell proliferation• Controlled by estrogen• Inhibited by tamoxifen

Estrogen receptor

Tamoxifen inhibits

Tamoxifen and Breast Cancer Prevention

Cumulative

number of cases

(per 1000 women)

Placebo

Tamoxifen

0 1 2 3 4 5 6

40

30

20

10

0

Invasive Breast Cancer rates in Women at High Risk

Years

Tamoxifen as a Cause of Uterine Cancer

Decreased cancer risk

Tamoxifen Estrogen

Uterine receptor activated

Estrogen receptor in uterine endometrial cell

Endometrial cell proliferation

Breast receptor not activated

Estrogen receptor in breast cell

blocked

No breast cell proliferation

Increased cancer risk

The Need for Better SERMs

Bad effects• Increases uterine cancer risk• Increases blood clot risk

Tamoxifen

Good effects• Reduces breast cancer risk• Lowers LDL cholesterol• Strengthens bones

Estrogen Replacement During Menopause

Good effects• Strengthens bones• Lowers LDL cholesterol• Raises HDL cholesterol• Reduces menopausal

symptoms (e.g., hot flashes)

Estrogen

Bad effects• Increases breast cancer risk• Increases uterine cancer risk• Increases blood clot risk

Estrogen Plus Progesterone Replacement

Bad effects• Increases invasive breast

cancer risk• Increases heart attacks• Increases strokes• Increases blood clots

Estrogen plus Progesterone reported effects

Good effects• Strengthens bones• Decreases colon

cancer risk• Reduces menopausal

symptoms (e.g., hot flashes)

Search for the Perfect SERM

The “ideal” SERM would:• Strengthen bones• Lower LDL cholesterol and

raise HDL cholesterol• Relieve hot flashes• Reduce breast cancer risk• Reduce uterine cancer risk

Raloxifene and the Prevention of Osteoporosis

O

OH

CL-

HN+

HO S

O

Raloxifene andRisk of Invasive Breast Cancer

Raloxifene

Bad effects• No relief for hot flashes• No reduction of LCIS• No reduction of DCIS

Good effects• Strengthens bones• Lowers LDL cholesterol• Reduces risk for

invasive breast cancer• Fewer uterine cancers

than tamoxifen• Fewer blood clots than

tamoxifen

We would like to hear from you . . .If you enjoyed this booklet please let us know by contacting Stacy Martello at stacy@fightpink.org.If you have questions about this booklets content, suggestions for new topics, or other feedback, please send an e-mail to kerrigad@mail.nih.gov.