Molecular Basis of Breast Cancer Flashcards
What percentage of breast cancers are familial?
5 - 10%
What percentage of cancers are breast?
10%
What are the 2 main genes identified which are thought to increase breast cancer risk?
BRCA1 and BRCA2
By how much does BRCA1 increase risk of breast cancer?
50 - 80%
By how much does BRCA1 increase risk of ovarian cancer?
40 - 50%
How is BRCA1 inherited?
autosomal dominant
How many amino acids does BRCA1 affect?
1863
What do gene defects in BRCA1 usually result in for the protein?
Truncated protein
What does BRCA1 and BRCA2 bind to?
RAD51 particularly
What does BRCA1 do?
- Repairs DNA (moves to site of damage)
- Caretaker
What does BRCA2 increase the risk of in males?
Prostate cancer
What does BRCA2 do?`
Involved in DNA damge response
How do BRCA2 and Rad51 interact?
- BRCA2 recruits Rad51 to site of DNA damage
- BRCA2 promotes nucleation of the Rad51 filament
- BRCA2 stimulates Rad51 mediated strand exchange and D-loop formation
- Stimulates homologues recombination and repair
- Repairs DNA double strand breaks
Why is breast tissue specifically sensitive to BRCA1 and 2 mutations?
- Breats tissue is sensitive to hormones (estrogens)
- As estrogen is metabolisesd metabolites may cause DNA damge
What ethnic background is particularly susceptible to BRCA2 mutations?
Ashkenazi jews
What is Synthetic lethality?
When a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not
What are risk factors for sporadic breast cancer?
- Early menarche
- Late menopause
- First child after 30 years of age
What percent of tumours come from the ducts?
90%
What proteins signal that breast cancer is luminal?
ER +ve, PR+/-, HER2+/-
What will Basal-lie breast cancers have molecularly?
Triple -ve (ER, PR, HER2)
What percentage of breast cacners are estrogen receptor positive?
60%
“What does the estrogen allow the estrogen receptor to do?
Binds to the receptor allowing it to bind to transcription factors
Describe Tamoxifen?
- Prodrug
- Competitive antagonist of estrogen receptor so used in ER +ve BCs
- Prevents expression of genes which would otherwise be stimulated by estrogen
- Used prophylactically after surgery for early stage breast cancer
What is a common side effect of tamoxifen?
Hot flushes
What percentage of Breast cancers have epidermal growth factor receptor 2 over-expressed? (HER2/erbB2)
20-30% (gene amplification)
Where is the estrogen receptor located?
Nucleus
Where is HER2/erbB2 located?
Cell membrane (tyrosine kinase so acts as a dimer - signal transduction)
What is the monoclonal antibody called that inhibits HER2?
Trastuzumab (Herceptin)
What is an aneuploid tumour?
- Chromosomes do not seperate properly between 2 cells (nondisjunction)
- When mitotic checkpoint fails
What drug is used to treat aneuploid BC as a result of mitotic checkpoint failure ?
Docetaxel (Taxotere)
What does docetaxel do?
- Stabilises microtubular network
- Stops aberrant, multipolar spindles