Molecular Basis of Breast Cancer Flashcards
Two main gene defects identified in familial breast cancer
BRCA1 and BRCA2
BRCA1 mutations implications
- Increases lifetime risk to 50-80%
- ie not completely penetrant
- Also increases ovarian risk to 40-50%
BRA1 mutation
- Most result in truncated protein
- Mutations occur throughout gene
- 1863 amino acids
Why defects in BRCA1 predispose to cancer?
Knudson two hit hypothesis
- first hit is germline mutation
- second hit is somatic mutation
one copy is ok but when mutation occurs you have no working copy of the gene
What does BRCA1 do?
binds to RAD50-1
DNA repair
BRCA2
- More than 400 mutations reported
- Most result in truncated protein
- Founder effect
- Increases rick of prostate cancer in males and breast cancer in females
implications of a BRCA2 mutation
BRCA2 deficient cells are sensitive to DNA damaging agents
- causes chromosomal defects
Homology directed repair of DNA double strand breaks
BRCA2 recruits RAD51 to sites of DNA damage
BRCA2 promotes nucleation of the RAD51 Filament
BRCA2 stimulates RAD51 - mediated strand exchange and D-loop formation
Other gene defects linked to familial breast cancer
SNPs
TP53
Implications for treatment
- DNA damaging agents
- DNA Double strand breaks
- Replication fork stalling
Synthetic lethality
- Two genetic mutations are independently compatible with life
- BUT together cause mortality
PARP (Poly (ADP-ribose) polymerase)
repairs SS DNA breaks
Oestrogen Receptor (ER) Positive Tumours
• Around 60% of tumours ER Positive
Hormone Therapy
- Eg tamoxifen
- Prodrug
- Antagonist of Oestrogen receptor
- Prevents expression of genes which would otherwise be stimulated by oestrogen
When is hormone therapy used
- Often used prophylactically after surgery for early stage breast cancer
- Common side effect- hot flushes
