Molecular Basis of Breast Cancer

Question 1

What are the 2 main gene defects involved in familial breast cancer?

Answer 1

• BRCA 1

- BRCA 2

Question 2

Describe BRCA 1 mutations

Answer 2

• increases lifetime risk of breast cancer to 50-80%
• ie. not completely penetrant (as it increases risk of cancer not the cancer itself)
• increases risk of ovarian cancer as well

Question 3

Why do defects in BRCA1 predispose to cancer?

Answer 3

2 hit hypothesis

Question 4

What is the role of the BRCA1 and BCRA2 genes?

Answer 4

involved in DNA repair and protecting the genome

Question 5

Why do defects in BRCA2 predispose to cancer?

Answer 5

cells which only have one working copy of the gene are slightly more susceptible to DNA damaging agents

Question 6

Describe the repair of a DNA strand break

Answer 6

• double strand DNA break
• removal of some bases which allow single strand of DNA to recognise its partner in the undamaged copy
• allows a pair to occur and normal helix to be generated

Question 7

Describe the role that BRCA2 has in DNA damage response

Answer 7

• recruits RAD-51 to the single strand of DNA

- facilitates the formation of the unique structure required for DNA repair (D loop formation)

Question 8

Why are the cells of the breast susceptible to cancer?

Answer 8

• tissue is very sensitive to hormones like oestrogen

- something in the process of breaking down oestrogen can result in DNA damage

Question 9

What factors would you consider in referral for genetic counselling?

Answer 9

• number of family members affected
• what generations
• age of onset
• ethnic background

Question 10

What is a protein important in single strand DNA breaks?

Answer 10

• PARP
• binds to damaged base
• facilitates assembly of proteins to repair damage

Question 11

What are some implications for treatment?

Answer 11

• DNA damaging agents
• DNA double strand breaks
• replication fork stalling

Question 12

Describe synthetic lethality

Answer 12

when 2 genetic mutations are compatible with life if occurring independently but if together then causes mortality

Question 13

If a breast tumour is oestrogen receptor positive what treatment can you use?

Answer 13

• tamoxifen (anti-estrogen drug)

- prevents expression of genes which would normally stimulate oestrogen

Question 14

What drug would you use for breast tumours which are positive for epidermal growth factor receptor 2?

Answer 14

• trastuzumab (herceptin)
• monoclonal antibody which binds to HER2 preventing signalling
• suppresses growth and angiogenesis