Molecular Basis of Breast Cancer Flashcards
What is the inheritance pattern of BRCA-1?
Autosomal dominant
What are the risks associated with BRCA1 mutation?
50-80% lifetime risk of breast cancer
40-50% lifetime risk of ovarian cancer
What type of mutations are present in BRCA1?
Over 650 different mutations identified throughout gene
Result in truncated (not full length chromosome)
Why does a BRCA mutation predispose breast cancer?
A tumour contains 2 copies of the mutated BRCA1 gene
Both genes rarely would spontaneous become mutated
If carrying mutated BRCA already, only need on spontaneous mutation to cause cancer
What is the function of BRCA1?
Relocalises to sites of damage and has a caretaker function on damaged genes i.e. repairs damaged DNA
What is the function of BRCA2?
Recruits RAD51 to sites of double stranded DNA breaks to allow homologous recombination repair
Which population have a high incidence of BRCA2 mutation?
Ashkenazi Jew
What risk comes with carrying the BRCA2 mutation?
Increased risk of breast cancer
Increased risk of prostate cancer
Summarise the functions of BRCA1 and BRCA2 in the same pathway
BRCA1 - recognises original DNA damage and helps stabilise structure while its being unwound and prepared for repair
BRCA2 - recognises structure and brings RAD51 to site to carry out homologous recombination and repair of damaged DNA
Why is the breast susceptible to tumourigenesis due to BRCA1 and BRCA2??
Tissue specific effects
Tissue specific expression of BRCA genes
Responsiveness to hormones, especially oestrogen
Oestrogen metabolism may result in free radical generation
How do cells with both BRCA genes manage to survive and allow tumourigenesis to occur?
Cells somehow manage to stabilise genome, as a consequence of mutations in the same or other associated genes (compensating mutations)
What usually happens to a cell with 2 BRCA mutations?
Genome is very unstable leading to early cell death
Are BRCA genes involved in sporadic breast cancer?
No
What is synthetic lethality?
2 genetic mutations may be independently compatible with life, but together they cause mortality
What is PARP?
Poly ADP-ribose polymerase
What is the function of PARP?
Repairs single stranded DNA breaks via base excision pathway (targets damaged bases)
What happens in the base excision pathway involving PARP?
Base is damaged generating a ssDNA break
PARP binds to break and amplifies DNA
PARP recruits other proteins to site to repair damage
PARP falls off when repair is complete
What is the link between BRCA and PARP pathways?
If BRCA is mutated, PARP can take over
If PARP is mutated, BRCA can take over
How can PARP be used as a therapeutic target?
PARP inhibitors can be given to people with BRCA mutations meaning that neither DNA repair pathway can take place and the cells will die
Give an example of a PARP inhibitor
Olaparib
How can BRCA mutated cells become resistant to treatment?
BRCA -/- gene may produce a protein that has limited DNA repair function (rather than none at all)
This protein may repair BRCA gene itself resulting in a more active BRCA gene than the original BRCA -/- cells
Drugs that target the fact that BRCA cannot repair DNA will be less effective as BRCA now has small amount of repair function
What are the risk factors for sporadic breast cancer?
Early menarche
Late menopause
First child after 30 years of age
What is the most common type of sporadic breast cancer?
No special type (ductal)
What percentage of breast tumours are oestrogen positive?
60%
How can oestrogen cause breast cancer?
Oestrogen receptor binds to DNA and stimulates gene transcription
Oestrogen responsive genes can include those which drive proliferation
What is tamoxifen?
Oestrogen receptor antagonist
What is a notable side effect of tamoxifen?
Hot flushes
When is tamoxifen often used?
As prophylaxis after surgery for early stage breast cancer
Which gene is overexpressed in 20-30% of tumours?
HER2 - Human Epidermal Growth Factor Receptor
How does a HER2 mutation promote tumourigenesis?
HER2 involved in cell division pathway
Amplification of gene leading to over expression of HER2 protein
More protein means more active pathway
What is Trastuzumab (Herceptin)?
Monoclonal antibody to HER2
What is the mechanism of Trastuzumab?
Prevents signalling, surpressing growth and angiogenesis, resulting in cell mediated cytotoxicity
How does Docetaxel work?
Stabilises microtubules, causing multipolar spindles to form
Normal cells would not continue to divide, however cells with non-functioning checkpoints (cancer cells) would leading to mitotic catastrophe which triggers apoptosis
Normal cells would eventually go on to divide once the drug has worn off
