Breast Cancer Genetics- Scott

Question 1

What are the two key signaling pathways in the development of breast cancer?

Answer 1

Estrogen/ER alpha

EGF/EGFR Family

Question 2

How are BRCA1 and BRCA2 inherited?

Answer 2

Autosomal Dominant - inheritance of a single copy confers susceptibility

Question 3

BRCA1 is often inactivated in sporadic tumors… through what mechanism?

Answer 3

Epigenetic mechanism - promoter methylation

Question 4

What do the BRCA1 and BRCA2 genes encode?

Answer 4

Essential components of homologous recombination DNA repair machinery

• repairs double stranded DNA breaks
• failure to repair leads to genomic instability
• Genomic instability creates conditions for oncogenic somatic mutations to arise

Question 5

What is required for differentiation at the luminal progenitor stage?

Answer 5

BRCA1

Question 6

Why do BRCA1 mutations usually result in “basal like” tumors?

Answer 6

BRCA1 is necessary for differentiation at the luminal progenitor cell stage

Accumulation of progenitor cells

**OFTEN TRIPLE NEG.

Question 7

What is the difference between germline and somatic mutations?

Answer 7

Germline- inherited

Somatic - oncogenesis is initiated by somatic genetic and epigenetic changes
*Not passed down from parent to child

Somatic mutations result in dysregulated proliferation

Question 8

What protein does BRCA2 recruit during the homologous recombination DNA repair?

Answer 8

Rad51

Question 9

Why are somatic mutations important for cancer?

Answer 9

1. They are the initiating event in sporadic cancers

2. They drive the development of sporadic AND familial cancers through microevolution

Question 10

What is microevolution?

Answer 10

Random somatic mutations that result in dysregulated proliferation and inappropriate survival are selected for

Question 11

What can increase your risk for breast cancer?

Answer 11

Increased life time exposure to estrogen:

> 30 yrs old at first pregnancy
Late menopause
Early Menarche
No Breastfeeding

Question 12

What two classes of drugs can be used to treat ER+ breast cancer?

Answer 12

SERMs

Aromatase Inhibitors

Question 13

Describe general estrogen receptor signaling

Answer 13

Estrogen binds ER (steroid hormone receptor)
Translocated to the nucleus
Dimerizes
Acts as TF for proliferation and survival

Question 14

Describe the difference in ER pathway between normal and tumor breast tissue

Answer 14

Normal tissue- ER+ is TF for other growth factors (amphiregulin) that promote growth of neighboring cells

*ER+ cells DO NOT proliferate

Cancer Tissue- ER is TF for growth directly (Cyclin D & other regulators)

*ER+ cells DO proliferate

Question 15

How are ER+ tumor cells different form normal ER+ cells?

Answer 15

1. Increase in the number of cells expressing ER

2. Change in which genes are regulated by ER binding

Question 16

In breast cancer are there any mutations or amplifications of genes encoding estrogen or estrogen receptor?

Answer 16

Nope!

Question 17

What TF binds closed chromatin and opens it, allowing for ER to bind to it?

Answer 17

FOXA1

Question 18

What transition does Cyclin D1 regulate in the cell cycle?

Answer 18

G1 to S Transition

Question 19

Are high levels of ER associated with a good prognosis?

Answer 19

YES!

Can treat with SERM or aromatase inhibitors

Question 20

What type of receptor is ERBB2? Does it require a ligand to dimerize?

Answer 20

Tyrosine Kinase

• *Dimerization domain is constitutively open
• *DOES NOT require ligand binding for activation

Dimerization initiates cell signaling pathways the promote G1 to S progression

Question 21

Trastuzumab

Answer 21

Monoclonal Ab that binds extracellular domain of ERBB2 (blocks homodimers)

Question 22

Lapatinib

Answer 22

Blocks kinase active site, prevents heterodimer activity