Molecular Basis of Breast Cancer Flashcards
What are the main two defects in familial breast cancer?
BRCA-1 and BRCA-2
BRCA-1 Mutation
Increases lifetime risk of breast cancer to 50-80% so it is not completely penetrant. It also increases risk of ovarian cancer to 40-50%. To test for it you need to sequence the whole gene as there is no singular hotspot for mutation and over 650 different mutations identified. Most of these mutations result in a truncated protein. The BRCA-1 gene is responsible for RAD51 binding which is a protein involved in DNA sensitivity and repair. Therefore BRCA-1 is involved in DNA repair which is affected when the gene is mutated.
Knudson Hypothesis
When someone is born with an inherited mutation, they have this mutation in all copies of their DNA and therefore are more likely to develop cancer if a somatic mutation occurs and affects the second copy of the same gene.
Remember that other mutations also need to occur for cancer to occur.
BRCA-2 Mutation
Increases the risk of prostate cancer in males and breast cancer in females. It also requires sequencing of the full gene as there is over 400 mutations which could predispose to cancer (however due to it being such a large gene, there is unknown variance). However, it does have a certain mutation which is more common in the Ashkenazi Jew population. BRCA-2 also is responsible for binding RAD51. BRCA-2 deficient cells are more senstive to double stranded DNA breaks caused by DNA damaging agents. This creates tri/quadradial chromosomes. Usually there is homologous directed repair of these dsDNA breaks (exposure of ssDNA to rejoin with copy of the same undamaged chromatid and restore it).
In a normal cell, this is how BRCA1 and BRCA 2 would restore DNA…
- BRCA-1 recognises there is a break in the DNA and recruits the enzymes needed to expose it.
- BRCA-2 with RAD51 then makes it ready to undergo homologous recombination
Why are breast cells more susceptible to dsDNA breaks?
They have a lot of oestrogen receptors and their metabolites could be responsible for the dsDNA breaks. Initially genomically unstable so the tumour has to stabilise the genome to be able to grow which is why there are also secondary alterations which have to occur to be able to cause cancer and overcome growth arrest.
Men get breast cancer too!!!!!
Particularly with BRCA2 mutation.
Sporadic Breast Cancer
BRCA1 and 2 not usually linked with sporadic and there is not much known about other genes which contribute to both sporadic and familial.
What factors to consider when referring families for genetic counselling?
- Number of family members affected?
- Age of onset? Early more likely to be inherited.
- What generations are affected? Loads of generations?
- Ethnicity? Particularly Ashkenazi Jew.
Risk factor for breast cancer
Early menarche
Managing risk of breast cancer
- More regular screening
- Mammography and MRI (but MRI more false positive)
- More radical - oopherectomy or mastectomy
- Still be ppl who need treatment.
Synthetic Lethality
- Two genetic mutations are independently compatible with life however together cause mortality of the cell.
- BRCA mutation + PARP (poly ADP-ribose polymerase; repairs ssDNA breaks) deficiency = no DNA repair and therefore cell death.
- However resistance to drugs which do this starts to occur over time. Genomic stress leads to repair (reverse mutation), genomic stability, so BRCA could be partially repaired and gives BRCA 2 function.
How do we figure out where sporadic tumour derives from?
- Biopsy
- Immunohistochemistry
- Cells could overexpress oestrogen receptor positive, progesterone receptor positive or HER2/erbB2 positive (or a combination of some/all)
- Lobular or ductal cells? 90% arise from duct cells and then we figure out if it comes from basal cells or lumen of duct?
Hormone Therapy
- Tamoxifen - prodrug (will not work for people who do not have enzyme which will convert it), antagonist of oestrogen receptor, prevents expression of genes which would otherwise be stimulated by oestrohgen. Often used prophylactically after surgery for early stage breast cancer. However adherence is a problem due to hot flush side effect. Only targets cells which overexpress oestrogen receptors.
HER2/erbB2 +ve Tumours
- Epidermal Growth Factor Receptor (HER2/erbB2) is overexpressed in 20-30% of tumours due to gene amplification.
- It binds to cells, dimerises, stimulates tyrosine kinase activity which brings about signal transduction to the nucleus and stimulates cell division.
