understanding estrogen receptors, tamoxifen, and raloxifene
DESCRIPTION
Understanding CancerTRANSCRIPT
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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 [email protected] you have questions about this booklets content, suggestions for new topics, or other feedback, please send an e-mail to [email protected].