St A - Molecular Basis of Breast Cancer Flashcards
What are the two main gene defects identified in familial breast cancer?
BRCA1 and BRCA2
What is the increase in risk with BRCA1 mutations?
Increases lifetime risk of BC to 50-80%. Increases ovarian risk to 40-50%
Why do defects in BRCA1 predispose to cancer?
The normal function is to act as a tumour suppressor gene (repairs double strand DNA breaks) and so when you inherit a BRCA1 mutation if the is a somatic mutation by chance then person lacks both normal BRCA1 copies.
Mutations in BRCA2 increases risk of what?
Prostate cancer in males and breast cancer in females
Cells deficient in BRCA2 are?…
Sensitive to DNA damaging agents as the normal function of BRCA2 is to repair DNA damage
How do BRCA1 and BRCA2 repair DNA?
BRCA1 guides repair machinery to broken DNA then BRCA2 recruits a protein called RAD51
Why is the breast prone to developing cancers
Tissue is sensitive to hormone changes such as oestrogen and the breakdown of oestrogen can damage DNA
What are some implications for treatment?
DNA damaging agents, DNA double strand breaks and replication fork stalling
What is synthetic lethality?
Where two genetic mutations are independently compatible with life but if occur together then cause mortality
What is the function of PARP?
It repairs single strand DNA breaks
What occurs if a cell has a BRCA mutation and a PARP deficiency?
This is an example of synthetic lethality. If both these mutations are present then the cell cannot undergo homologous recombination repair (due to BRCA mutation) and it cannot undergo base excision repair (due to PARP deficiency) so results in cell death
If a tumour is oestrogen receptor positive then what treatment can be used?
Tamoxifen - antagonist of oestrogen receptor. It prevents expression of genes which would otherwise be stimulated by oestrogen
What treatment can be used in tumours which test positive for epidermal growth factor receptor 2?
Trastuzumab (herceptin) - it is a monoclonal antibody which binds to HER2 to prevent signalling, therefore suppresses growth and angiogenesis
Explain how molecular analysis of tumours can influence treatment choice
As mentioned, if you can test a tumour to see if it is positive for either oestrogen receptors or for HER2 then you can used different target treatments
