Molecular Basis of Breast Cancer

Question 1

What is the inheritance pattern of BRCA-1?

Answer 1

Autosomal dominant

Question 2

What are the risks associated with BRCA1 mutation?

Answer 2

50-80% lifetime risk of breast cancer

40-50% lifetime risk of ovarian cancer

Question 3

What type of mutations are present in BRCA1?

Answer 3

Over 650 different mutations identified throughout gene

Result in truncated (not full length chromosome)

Question 4

Why does a BRCA mutation predispose breast cancer?

Answer 4

A tumour contains 2 copies of the mutated BRCA1 gene
Both genes rarely would spontaneous become mutated
If carrying mutated BRCA already, only need on spontaneous mutation to cause cancer

Question 5

What is the function of BRCA1?

Answer 5

Relocalises to sites of damage and has a caretaker function on damaged genes i.e. repairs damaged DNA

Question 6

What is the function of BRCA2?

Answer 6

Recruits RAD51 to sites of double stranded DNA breaks to allow homologous recombination repair

Question 7

Which population have a high incidence of BRCA2 mutation?

Answer 7

Ashkenazi Jew

Question 8

What risk comes with carrying the BRCA2 mutation?

Answer 8

Increased risk of breast cancer

Increased risk of prostate cancer

Question 9

Summarise the functions of BRCA1 and BRCA2 in the same pathway

Answer 9

BRCA1 - recognises original DNA damage and helps stabilise structure while its being unwound and prepared for repair
BRCA2 - recognises structure and brings RAD51 to site to carry out homologous recombination and repair of damaged DNA

Question 10

Why is the breast susceptible to tumourigenesis due to BRCA1 and BRCA2??

Answer 10

Tissue specific effects
Tissue specific expression of BRCA genes
Responsiveness to hormones, especially oestrogen
Oestrogen metabolism may result in free radical generation

Question 11

How do cells with both BRCA genes manage to survive and allow tumourigenesis to occur?

Answer 11

Cells somehow manage to stabilise genome, as a consequence of mutations in the same or other associated genes (compensating mutations)

Question 12

What usually happens to a cell with 2 BRCA mutations?

Answer 12

Genome is very unstable leading to early cell death

Question 13

Are BRCA genes involved in sporadic breast cancer?

Answer 13

No

Question 14

What is synthetic lethality?

Answer 14

2 genetic mutations may be independently compatible with life, but together they cause mortality

Question 15

What is PARP?

Answer 15

Poly ADP-ribose polymerase

Question 16

What is the function of PARP?

Answer 16

Repairs single stranded DNA breaks via base excision pathway (targets damaged bases)

Question 17

What happens in the base excision pathway involving PARP?

Answer 17

Base is damaged generating a ssDNA break
PARP binds to break and amplifies DNA
PARP recruits other proteins to site to repair damage
PARP falls off when repair is complete

Question 18

What is the link between BRCA and PARP pathways?

Answer 18

If BRCA is mutated, PARP can take over

If PARP is mutated, BRCA can take over

Question 19

How can PARP be used as a therapeutic target?

Answer 19

PARP inhibitors can be given to people with BRCA mutations meaning that neither DNA repair pathway can take place and the cells will die

Question 20

Give an example of a PARP inhibitor

Answer 20

Olaparib

Question 21

How can BRCA mutated cells become resistant to treatment?

Answer 21

BRCA -/- gene may produce a protein that has limited DNA repair function (rather than none at all)
This protein may repair BRCA gene itself resulting in a more active BRCA gene than the original BRCA -/- cells
Drugs that target the fact that BRCA cannot repair DNA will be less effective as BRCA now has small amount of repair function

Question 22

What are the risk factors for sporadic breast cancer?

Answer 22

Early menarche
Late menopause
First child after 30 years of age

Question 23

What is the most common type of sporadic breast cancer?

Answer 23

No special type (ductal)

Question 24

What percentage of breast tumours are oestrogen positive?

Answer 24

60%

Question 25

How can oestrogen cause breast cancer?

Answer 25

Oestrogen receptor binds to DNA and stimulates gene transcription
Oestrogen responsive genes can include those which drive proliferation

Question 26

What is tamoxifen?

Answer 26

Oestrogen receptor antagonist

Question 27

What is a notable side effect of tamoxifen?

Answer 27

Hot flushes

Question 28

When is tamoxifen often used?

Answer 28

As prophylaxis after surgery for early stage breast cancer

Question 29

Which gene is overexpressed in 20-30% of tumours?

Answer 29

HER2 - Human Epidermal Growth Factor Receptor

Question 30

How does a HER2 mutation promote tumourigenesis?

Answer 30

HER2 involved in cell division pathway
Amplification of gene leading to over expression of HER2 protein
More protein means more active pathway

Question 31

What is Trastuzumab (Herceptin)?

Answer 31

Monoclonal antibody to HER2

Question 32

What is the mechanism of Trastuzumab?

Answer 32

Prevents signalling, surpressing growth and angiogenesis, resulting in cell mediated cytotoxicity

Question 33

How does Docetaxel work?

Answer 33

Stabilises microtubules, causing multipolar spindles to form
Normal cells would not continue to divide, however cells with non-functioning checkpoints (cancer cells) would leading to mitotic catastrophe which triggers apoptosis
Normal cells would eventually go on to divide once the drug has worn off