Estrogen actions and breast cancer

1. Understanding Cancer and Related Topics
Understanding Estrogen Receptors,
Tamoxifen, and Raloxifene
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Developed by:
Lewis J. Kleinsmith, Ph.D.
Donna Kerrigan, M.S.
Jeanne Kelly
Brian Hollen
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).

2. What Are Estrogens?
O
Estrone
Estradiol
Steroid ring system
OH
HO
HO

3. Brain
Estrogen Target Tissues
Bone
Uterus
Liver
Heart
Breast

4. Estrogen Receptors
Estrogen target cell
(e.g., breast, uterine
lining, liver, etc.)
Estrogen
receptor
Tamoxifen
Estrogen
Non-target cell
(contains no
estrogen receptor)

5. 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

6. 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

7. Estrogen-Induced
Stimulation of Cell Proliferation
High estrogen concentration
Breast or uterine cell

8. Estrogen and Cancer
Uterus
Increases cancer risk
Beneficial effects Harmful effects
Breast
Programs milk production
Liver and heart
Controls cholesterol
Uterus
Prepares for fetus
Bone
Preserves strength
Breast
Increases cancer risk

9. Estrogen and Breast Cancer
High
estrogen
The Menstrual Cycle
Days
4 14 28
Breast cell death
Breast cell proliferation
Low
estrogen

10. Cancer Arises From
DNA Mutations in Cells
Last DNA mutation from:
• heredity
or
• radiation or chemicals
or
• spontaneous errors
during DNA duplication
DNA mutations
Normal cell Uncontrolled proliferation

11. Estrogen-Induced Proliferation
of Existing Mutant Cells
Mutant breast cells
(caused by error,
inheritance, and/or
environmental factors)
Estrogen stimulation

12. Estrogen-Induced Proliferation and
Spontaneous New Mutations
Normal breast cell
Increased proliferation
Estrogen stimulation
Mistake in DNA duplication

13. Estrogen and Uterine Cancer
2. Estrogen can increase the
chances of developing new,
spontaneous mutations.
Estrogen action on the uterus
Normal uterine cell
Spontaneous
mutation
1. Estrogen can stimulate
the division of existing
mutant uterine cells.

14. 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

15. SERMs
SERM
Uterine
receptor
activated
Estrogen receptor
in uterine cell
Uterine cell proliferation
Breast receptor
not activated
Estrogen
receptor in
breast cell
No breast cell
proliferation

16. 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

17. Tamoxifen and Breast Cancer Treatment
Breast cancer
surgically removed
Reduced risk
of cancer
recurrence
Treatment with
tamoxifen

18. Estrogen Receptor-Negative
Breast Cancer
Estrogen
Estrogen receptor-
negative breast cancer
Estrogen receptor-
positive breast cancer
Cell proliferation
• Not controlled by estrogen
• Not inhibited by tamoxifen
Cell proliferation
• Controlled by estrogen
• Inhibited by tamoxifen
Estrogen receptor
Tamoxifen inhibits

19. 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

20. 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

21. 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

22. 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

23. 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)

24. 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

25. Raloxifene and the
Prevention of Osteoporosis
O
OH
CL-
HN+
HO S
O

26. Raloxifene and
Risk 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

27. We would like to hear from you . . .
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