Estrogen, Breast Cancer

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Estrogen, Breast Cancer Treatments

• Yali Gao yali.gao_at_utoronto.ca
• Jadie Lo jadielo_at_gmail.com
• Koren Lui koren.lui_at_utoronto.ca
• Eva Ng eva-ng_at_hotmail.com
• March 10, 2009

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Estrogen

• Steroid chemical messenger
• Primary female sex hormone
• Also present in male (but at much lower levels)
• Two major types of naturally occurring estrogens
  produced and secreted by ovaries
• Estradiol
• Estrone

Estrone
Estradiol
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Role in Breast Development

• Promotes the development of female secondary sex
  characteristics such as breasts
• Readily diffuses into cell membrane and interact
  with estrogen receptor a found in the cytoplasm
• Enters nucleus and turns on estrogen-responsive
  genes to stimulate
• cell proliferation

Estrogen
Estrogen receptor
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Risk in Development of Breast Cancer

• Estrogen may contribute to the risk of breast
  cancer due to
• 1) its role in stimulating breast cell division
• 2) its activity during the critical periods of
  breast growth and development
• 3) its effect on other hormones that stimulate
  breast cell division, and
• 4) its support of the growth of
  estrogen-responsive tumours

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Role in Breast Cancer

• About 1/3 to 2/3 of all breast tumours have
  estrogen receptors and depend on estrogen for
  growth
• DNA error causes uncontrolled proliferation of
  breast cells upon binding of estrogen to its
  receptor
• Estrogen turns into reactive metabolite
  (estradiol 4-OH) and binds to DNA, causing
  depurination mutation

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Treatments

• Surgery mastectomy
• Chemotherapy use high doses of cytotoxic or
  anti-neoplastic drugs at low frequencies (spread
  apart)
• ie cis-platin, methotrexate, topoisomerase
  inhibitors, 5-fluorouracil
• Radiation to generate reactive oxygen species,
  thereby inducing cell damage
• Hormone inhibitor (SERMS- selective estrogen
  receptor modulator)

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Tamoxifen

• Prodrug is metabolized in the liver by cytochrome
  P450 into its reactive metabolite, which has a
  higher affinity for estrogen receptors
• Metabolite acts as antagonist in breast tissues
• Competitive binding to estrogen receptors on
  tumour cells

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Tamoxifen

• Results in inhibition of transcription of
  estrogen-responsive genes and decrease DNA
  synthesis
• Strengthens bone

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Raloxifene

• More recently available anti-estrogen compound
  replacing tamoxifen
• As effective as tamoxifen in reducing the risk of
  breast cancer and strengthening bone
• Showed lower occurrence of uterine cancer

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Aromatase Inhibitors

• Interfere with bodys ability to produce estrogen
  by inhibiting aromatase from catalyzing the final
  step in estrogen synthesis
• Steroidal non-competitive permanent inhibition
• Non-steroidal competitive reversible inhibition
• Extends survival rate and prevents recurrence
• For post-menopausal

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Herceptin

• Monoclonal antibody that targets over-expressed
  HER-2 receptors (in 20-30 of breast cancers)
• Used when cancer has spread after other drug
  treatments
• Inhibit growth factors from stimulating cell
  proliferation and alert immune system to destroy
  cancer cell

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STS Inhibitors

• Steroid sulfatase (STS) hydrolyzes estrone
  sulfate
• Results in precursors for more biologically
  active estrogen and androgens
• STS inhibitor will decrease the elevated levels
  of STS activity in hormone-dependent cancer cells
• Phase I trial results are also encouraging

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Summary

• Estrogen steroid chemical messenger
• Two major types estradiol, estrone
• Primary female sex hormone
• Estrogen Receptor Intracellular nuclear hormone
  receptor
• ER a is found in breast cancer cells
• Role in Breast Cancer
• About 1/3 to 2/3 of all breast tumours have
  estrogen receptors and depend on estrogen for
  growth
• DNA error causes uncontrolled proliferation of
  breast cells upon binding of estrogen to its
  receptor
• Estrogen turns into reactive metabolite
  (estradiol 4-OH) and binds to DNA, causing
  depurination mutation
• Treatments
• Surgery, Chemotherapy, Radiation, Hormone
  inhibitor

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References

• http//envirocancer.cornell.edu/FactSheet/General/
  fs9.estrogen.cfm
• http//www.cancer.gov/cancertopics/factsheet/thera
  py/tamoxifen
• http//www.cancer.ca/Canada-wide/About20cancer/
• types20of20cancer/Causes20of20breast20cancer
  .aspx?sc_langen
• http//www.healthyontario.com/DrugDetails.aspx?bra
  nd_id1060brand_nameTamofen
• American Association for Cancer Research Cancer
  drugs in the pipeline Anonymous. Medical Devices
  Surgical Technology Week. Atlanta Jan 4, 2009.
  pg. 635