Wk6 BRCA Genetics Flashcards
Which epithilial layer contains ER-a positive cells?
Luminal layer
Two key signaling pathways:
- ER-a
2. EGFR
How many copies of mutated BRCA 1 are needed for increased succeptibility:
one – inherited autosomal dominant
What is the normal function of BRCA 1/2?
DNA repair
– repairs double strand breaks
failure to repair creates conditions for somatic mutations
Gene required for differentiation:
BRCA 1
Why are there limited treatment options for BRCA 1 mutation cancers:
often “triple negative”
low ER, low PR, low ERBB2
% of breast cancers that are sporadic?
90%
**not passed down from mother to child
Driving force in BOTH famillial and sporadic cancers:
Somatic genetic changes
Two most prevalent types of cancer:
ER-a positive (~65%)
HER2 (~25%)
Read slide
slide 17
INdirect control of luminal cell proliferation?
normal ER-a function
–promotes transcription of growth factors
–cells expressing ER do not proliferate – neighboring cells do
Cyclin D1?
stimulated by Estrogen in ER positive CA cells
How are ER+ tumor cells different than normal cells?
more cells expressing ER
different genes regulated by ER binding
How does ER promote transcription of a different set of genes in breast cancer?
overexpression of:
FOXA1
opens closed chromatin
FOXA1
key regulator of G1/S transition
Cyclin D1
Prognosis for CA with high levels of ER?
good —- lots of drug targets
Tx 1st line for ER+
Tamoxifen — an ER antagonist
***inhibits ER’s promotion of transcription
Removes estrogen from the cancer equation completely:
Aromatase inhibitors
What type of receptor is HER2 (aka ERBB2 or Neu)?
tyrosine kinase
What does HER2 do?
promotes proliferation when activated
MOre aggerssive, HER2 or ER+?
HER2
What is the mechanism of HER2 overexpression in oncogenesis?
dimerization can occur by mass action in the absence of a ligand binding
**cell cycle can proceed independant of external growth factors
Tx for HER2 CA?
Trastuzumab — blocks homodimer –> heterodimer
Lapatinib —- blocks kinase active site
