Molecular Basis of Breast Cancer

Question 1

What percentage of breast cancers are familial?

Answer 1

5 - 10%

Question 2

What percentage of cancers are breast?

Answer 2

10%

Question 3

What are the 2 main genes identified which are thought to increase breast cancer risk?

Answer 3

BRCA1 and BRCA2

Question 4

By how much does BRCA1 increase risk of breast cancer?

Answer 4

50 - 80%

Question 5

By how much does BRCA1 increase risk of ovarian cancer?

Answer 5

40 - 50%

Question 6

How is BRCA1 inherited?

Answer 6

autosomal dominant

Question 7

How many amino acids does BRCA1 affect?

Answer 7

1863

Question 8

What do gene defects in BRCA1 usually result in for the protein?

Answer 8

Truncated protein

Question 9

What does BRCA1 and BRCA2 bind to?

Answer 9

RAD51 particularly

Question 10

What does BRCA1 do?

Answer 10

• Repairs DNA (moves to site of damage)

- Caretaker

Question 11

What does BRCA2 increase the risk of in males?

Answer 11

Prostate cancer

Question 12

What does BRCA2 do?`

Answer 12

Involved in DNA damge response

Question 13

How do BRCA2 and Rad51 interact?

Answer 13

• BRCA2 recruits Rad51 to site of DNA damage
• BRCA2 promotes nucleation of the Rad51 filament
• BRCA2 stimulates Rad51 mediated strand exchange and D-loop formation
• Stimulates homologues recombination and repair
• Repairs DNA double strand breaks

Question 14

Why is breast tissue specifically sensitive to BRCA1 and 2 mutations?

Answer 14

• Breats tissue is sensitive to hormones (estrogens)

- As estrogen is metabolisesd metabolites may cause DNA damge

Question 15

What ethnic background is particularly susceptible to BRCA2 mutations?

Answer 15

Ashkenazi jews

Question 16

What is Synthetic lethality?

Answer 16

When a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not

Question 17

What are risk factors for sporadic breast cancer?

Answer 17

• Early menarche
• Late menopause
• First child after 30 years of age

Question 18

What percent of tumours come from the ducts?

Answer 18

90%

Question 19

What proteins signal that breast cancer is luminal?

Answer 19

ER +ve, PR+/-, HER2+/-

Question 20

What will Basal-lie breast cancers have molecularly?

Answer 20

Triple -ve (ER, PR, HER2)

Question 21

What percentage of breast cacners are estrogen receptor positive?

Answer 21

60%

Question 22

“What does the estrogen allow the estrogen receptor to do?

Answer 22

Binds to the receptor allowing it to bind to transcription factors

Question 23

Describe Tamoxifen?

Answer 23

• Prodrug
• Competitive antagonist of estrogen receptor so used in ER +ve BCs
• Prevents expression of genes which would otherwise be stimulated by estrogen
• Used prophylactically after surgery for early stage breast cancer

Question 24

What is a common side effect of tamoxifen?

Answer 24

Hot flushes

Question 25

What percentage of Breast cancers have epidermal growth factor receptor 2 over-expressed? (HER2/erbB2)

Answer 25

20-30% (gene amplification)

Question 26

Where is the estrogen receptor located?

Answer 26

Nucleus

Question 27

Where is HER2/erbB2 located?

Answer 27

Cell membrane (tyrosine kinase so acts as a dimer - signal transduction)

Question 28

What is the monoclonal antibody called that inhibits HER2?

Answer 28

Trastuzumab (Herceptin)

Question 29

What is an aneuploid tumour?

Answer 29

• Chromosomes do not seperate properly between 2 cells (nondisjunction)
• When mitotic checkpoint fails

Question 30

What drug is used to treat aneuploid BC as a result of mitotic checkpoint failure ?

Answer 30

Docetaxel (Taxotere)

Question 31

What does docetaxel do?

Answer 31

• Stabilises microtubular network

- Stops aberrant, multipolar spindles