Wk6 BRCA Genetics

Question 1

Which epithilial layer contains ER-a positive cells?

Answer 1

Luminal layer

Question 2

Two key signaling pathways:

Answer 2

1. ER-a

2. EGFR

Question 3

How many copies of mutated BRCA 1 are needed for increased succeptibility:

Answer 3

one – inherited autosomal dominant

Question 4

What is the normal function of BRCA 1/2?

Answer 4

DNA repair

– repairs double strand breaks

failure to repair creates conditions for somatic mutations

Question 5

Gene required for differentiation:

Answer 5

BRCA 1

Question 6

Why are there limited treatment options for BRCA 1 mutation cancers:

Answer 6

often “triple negative”

low ER, low PR, low ERBB2

Question 7

% of breast cancers that are sporadic?

Answer 7

90%

**not passed down from mother to child

Question 8

Driving force in BOTH famillial and sporadic cancers:

Answer 8

Somatic genetic changes

Question 9

Two most prevalent types of cancer:

Answer 9

ER-a positive (~65%)

HER2 (~25%)

Question 10

Read slide

Answer 10

slide 17

Question 11

INdirect control of luminal cell proliferation?

Answer 11

normal ER-a function

–promotes transcription of growth factors

–cells expressing ER do not proliferate – neighboring cells do

Question 12

Cyclin D1?

Answer 12

stimulated by Estrogen in ER positive CA cells

Question 13

How are ER+ tumor cells different than normal cells?

Answer 13

more cells expressing ER

different genes regulated by ER binding

Question 14

How does ER promote transcription of a different set of genes in breast cancer?

Answer 14

overexpression of:

FOXA1

Question 15

opens closed chromatin

Answer 15

FOXA1

Question 16

key regulator of G1/S transition

Answer 16

Cyclin D1

Question 17

Prognosis for CA with high levels of ER?

Answer 17

good —- lots of drug targets

Question 18

Tx 1st line for ER+

Answer 18

Tamoxifen — an ER antagonist

***inhibits ER’s promotion of transcription

Question 19

Removes estrogen from the cancer equation completely:

Answer 19

Aromatase inhibitors

Question 20

What type of receptor is HER2 (aka ERBB2 or Neu)?

Answer 20

tyrosine kinase

Question 21

What does HER2 do?

Answer 21

promotes proliferation when activated

Question 22

MOre aggerssive, HER2 or ER+?

Answer 22

HER2

Question 23

What is the mechanism of HER2 overexpression in oncogenesis?

Answer 23

dimerization can occur by mass action in the absence of a ligand binding

**cell cycle can proceed independant of external growth factors

Question 24

Tx for HER2 CA?

Answer 24

Trastuzumab — blocks homodimer –> heterodimer

Lapatinib —- blocks kinase active site

Question 25

Basal-like CA?

Answer 25

often triple neg

often BRCA 1 inactivation mutation