9. Molecular Basis of Breast Cancer Flashcards
Which genes defects predispose to breast cancer?
BRCA1 and BRCA2
BRCA1 gene defect, predisposes to which cancers?
Breast and ovarian cancer
What is the BRCA1 gene defect?
Autosomal dominant
Increases lifetime risk of breast cancer to 50-80% i.e. not completely penetrant
Increases ovarian risk to 40-50%
Why do defects in BRCA1 predispose to cancer?
Two-hit hypothesis:
Both copies of tumour suppressor gene disrupted in tumour. Either:
1. May arise in both copies of the gene in the same cell by chance (rare and sporadic)
Orrr….
2. Patient has inherited one defective copy of the gene already. In this situation only need one further mutation to occur by chance and tumour will arise.
Inheritance of the mutation therefore predisposes to disease.
Why do defects in BRCA1 predispose to cancer?
Two-hit hypothesis:
Both copies of tumour suppressor gene disrupted in tumour. Either:
1. May arise in both copies of the gene in the same cell by chance (rare and sporadic)
Orrr….
2. Patient has inherited one defective copy of the gene already. In this situation only need one further mutation to occur by chance and tumour will arise.
Inheritance of the mutation therefore predisposes to disease.
What is the role of BRCA1?
In the DNA damage response. Relocalises to the site of damage, therefore acting as a caretaker instead of a gatekeeper.
BRCA2 gene defects?
Increase risk of prostate cancer in males and breast cancer in females.
Is a larger gene so more likely to have variants of unknown significance such as: Missense, intronic and small in frame deletions/insertions
BRCA1 deficient cells are sensitive to…
DNA damaging agents.
Cells from Tr/Tr mice are more sensitive to DNA damagingW agents where damage has to be repaired via DNA DS repair pathway.
What is the process of DNA double strand breaks?
Homology directed repair of DNA double strand breaks:
Structure unwound to reveal SS section. Then there is a cofrmation of D-loop strcuture. where damaged DNA becoems intercalated with undamaged DNA of replicated chromosome (during S phase, i.e. doubling). Intercalated produces repair template which restores wild type helix
Role of BRCA2 and DNA damage response?
- BRCA2 recruits Rad51 to sites of DNA damage
- BRCA2 promotes nucleation of the Rad51 filament
- BRCA2 stimulates Rad51-mediated strand exchange with D-loop formation
D-loop formation is the initial stage when the damage strand and template are brought together. Key in DNA DS break repairs.
What does breast cancer evolve from BRCA1/2 gene defects instead of other sites?
Tissue specific effects that promote tumourigenesis. Tissue specific expression of BRCA genes.
Responsiveness to hormones, especially oestrogen.
Bi-allelic loss of BRCA usually detrimental (chromosome instability).
Must be compensating mutations that allows BRCA-/- cells to grow out and evolve into full blown tumours.
Process of screening for breast cancer?
Screening= MRI detected 2X tumours than mammography, BUT high false +rate 11% cf 5% with mammography
Options to manage risk of breast cancer
Mastectomy
Oophorectomy
Tamoxifen
What is synthetic lethality?
When two genetic mutations are independently compatible with life
BUT together cause mortality
Can be used in cancer treatment to selectively kill cancer cells which already have a gene mutation in one pathway.
Role of PARP?
Repairs SS DNA breaks by base excision repair (BER)
It is recruits to damage base of DNA where is amplifies then recruits other factors in order to repair section.
Two pathways for DNA repair?
Homologous recombination pathway (relies on BRCA gene)
Base excision repair (relies on PARP)
Need at least 1 on order to repair DNA damage
How do cancer cells develop resistance?
Chromosomes appear organised and stable
Due to ability to express close resemblance to BRCA2 gene.
BRCA-/- cells are deficient at DNA repair BUT can still do some albeit badly. Sometimes that repair results in a BRCA2 gene which has more function than the original cells so become resistant to drug.
Clues for sporadic breast cancer?
Early menarche
Late menopause
First child at 30yrs+
What is the origin for breast cancer?
Cells in the ducts, either basal cells or cells lining the lumen
How prevalent are oestrogen positive tumours in the breast?
60%
Mechanism of oestrogen positive tumours?
Receptor is in the nucleus. Oestrogen responsive genes can include those which drive proliferation.
What hormone therapy is available for breast cancer?
E.g. Tamoxifen
What is tamoxifen?
Hormone therapy for breast cancer
Prodrug
Antagonist of oestrogen receptor so… prevents expression of genes which would otherwise be stimulated by oestrogen
Often uses prophylactically after surgery for early stage breast cancer.
Side effect: Hot flushes
Different molecular bases for breast cancer?
Oestrogen receptor positive
Epidermal growth factor receptor 2 positive
Prevalence of Epidermal growth factor receptor 2 positive breast cancers?
20-30% of tumours.
Action of trastuzimab (Herceptin)?
‘Humanised’ monoclonal antibody to HER2
It prevents the signalling, so suppresses growth and angiogenesis
Humanised= The mouse part recognises the antigen and the human part protects it from the host immune system
Role of docetaxel in treating breast cancer?
Stabilises microtubles so leads to mitotic catastrophe.
So the chromosomes cannot segregate –> Apoptosis
