Scott: Breast Cancer Genetics Flashcards
breast cancer arises from what layer of tissue
epithelial layer
inner layer
contains ductal and alveolar cells
contain ERa cells and - cells
progenitor cells
luminal layer
outer layer
contains primarily contractile cells
contains stem cells
ALL ERa +
myoepithelial layer
how does normal breast development create conditions for development of breast cancer?
adult tissue has STEM cells and PROGENITOR cells> maintain signaling therapy> proliferation/capacity to grow thorugh lifespan
Normally: ordered progression along pathway> leads from SC to fully differentiated cells
2 key signaling pathways that play a role in dysregulation
estrogen/estrogen receptor a
EGF/EGFR
development of breast cancer requires
GENETIC (germline/somatic) and HOST (diet, hormones, IR) factors
accounts for 5-10% of inherited breast cancer mutations
germine genetic changes (pts have relatives w/ breastcancer)
Most PREVALENT breast cancer genetic susceptiblity factor that accounts for 20% of FAMILIAL breast cancers
BRCA1/2
BRCA1
65% breast cancer
40% ovarian cancer (no early dx)
BRCA2
40% breast cancer
11% ovarian cancer
inheritance of BRCA
AD
how is BRCA1 often INACTIVATED in sporadic tumors
promoter methylation (epigenetic mechanism)
ATM
CHEK2
PALB2
BRIP1
other mutations in DNA repair gens that can lead to 2-3 fold increased risk
Why does inactivation of BRCA1/2 lead to breast cancer susceptibility?
BRCA are needed for DNA repair during homologous recombination
Repair defect in BRCA1/2 mutant cells>
genomic instability>
opportunity of accumulation of somatic cancer causing mutations
recruited as recognition complex after recognition of a break
BRCA1
prepairs ends from repair to create a SINGLE stranded end and recruits repair machinery
BRCA1
promotes new DNA syntehsis and recruits Rad51 to promote strand invasion
BRCA2
leads to luminal progenitor accumulation
mut BRCA1–> required for differentaiation
why are there limited tx options for BRCA1 tumors?
b/c they develop from the luminal progenitor stage they are often TRIPLE NEGATIVE
standard test for BRCA1/2 genetic testing
full gene seq for pt muations, and insertions/deletions in bRCA1/2
accounts for 90% of breast cancers
sporadic cancers (somatic mutations)
Somatic changes
random somatic mutations (microevolution) are inheriited from one cell division to next but it is NOT passed down from parent to child
Initiating event in MOST breast cancers and driving force in both familial and sporadic cancers
somatic genetic changes
oncotype dx
gene expression signature correlated w/ level of relapse/mets
compares expression pattern in normal vs tumor cells> tumors grouped into similar mRNA expression
Microarray
why was it important to identify the 5 clinical subtypes?
diff subtypes have diff gene expression/cells of origin> diff tx/prognosis
high levels of estrogen receptor
best prognosis
luminal A= luminal progenitor
overexpression of HER2
prognosis improved w/ use of TRASTUZUMAB
her 2 amplified= progenitor
triple negative
often BRCA1 inactivated by methylation of promoteor
worst prognosis- no targetd therapy
basal like tumor
*from earliest luminal progenitor
accounts for 65% of breast cancers
ER alpha
how did they figure out that ER signaling was implicated in breast cancer?
blocking ER signaling was HIGHLY effective in treating ER + breast caancer
what controls normal proliferation of luminal cells?
extracellular estrogen
ER binds ERa>
trxn of paracrine GF>
acts on nearby cells>
proliferation
Cells expressing ER PROLIFERATE while cells taht don’t do NOT
how can estrogen exposure increase the risk for cancer in normal tissue?
longer exposure> increased risk/opp to make mutations
what is the role of ER in ER + breast cancers?
Est> binds ER> upregulates FOXA1> allows increased access of ER to DNA for trxn> incrased availibility of promoter for cyclin D> increased trxn of cylcin D> progression through G1/S checkpoint> cell proliferation
assoc w/ a GOOD prognosis b/c can tx w/ selective SERMS/aromatase inhibitors
ER + brast cancer
ER antagonist that reduces breast cancer recurrence and mortality
Tamoxifen
binds to ER and favors interaction w/ co repressors>
BLOCKS ER dep trxn/proliferation
tamoxifen
blocks synthesis of estrogen in NON ovarian tissues but does NOT affect ER
aromatase inhibitors
Genomic amplification of TK receptor>
aggressive ER negative tumor
ERBB2= E
GF receptor family
how is ERBB2 overexpression oncogenic?
ERBB2 dimerization>
domain constantly OPEN>
does NOT require ligand binding>
CELL CYCLE PROCEEDS INDEPENDENTLY OF GROWTH FACTORS
monoclonal Ab that binds extracellular domain of ERBB2>
blocked activity of homodimers
TRastuzumab
increases survival in Her2 overexpressing cancers
trastuzumab
small moleucle inhibitor that BLOCKS kianse active site> EGFR-ERBB2 heterodimer activity
Lapatinib
