Breast Cancer Genetics Flashcards
The epithelium consists of luminal cells and myoepithelial cells. Which layer contains the progenitor cells?
the luminal cells
but th emyoepithleial cells also contain stem cells
Why is it important that adult breast epithelial cells maintain the capacity for proliferation?
they have to go repeated rounds of regulated, hormone-dependent proliferation and involution at different stages of the life cycle
How is that capacity maintained?
the adult tissue contains stem cellsa nd progenitor cells which allows for proliferation throughout the lifetime
WHat are the two main key signalling pathways essential for normal breast development?
estrogen on ERalpha
EGF on the EGFR family
Are initiating mutations enough to cause breast cancer?
no - you need subsequent mutations (all somatic typically)
Germline genetic changes can contribute to breast cancer initiation. Familial aggregations studies suggest that ___% are due to inherited breast cancer mutations.
5-10%
What is the most common gene mutation in familial breast cancer?
BRCA1 and BRCA2
BrCA1 breast CA risk =?
ovarian CA risk = ?
65%
40%
How about for BRCA2?
breast cancer - 40%
ovarian - 11%
Inheritence of susceptibility is antosomal -_____
dominant
BRCA1 is often inactivated in sporadic tumors by what?
epigenetic mechanisms
so you don’t have to have the germline mutatuion
What does BRCA do under normal contision?
they are essential parts of the homologous recombination machinery to repair double-straded DNA breaks
failure of repair leads to genomic instability, which leads to further ongoenic mutations to arise.
So do the BRCA mutations cause cancer in and of themselves?
no - they create conditions that allow for more mutations that then cause the cancer
Why does BRCA1 have a little higher risk? And why does this limit treatment options?
BRCA1 is also important for differentiation at the luminal progenitor stage
this is a problem in mutation because those cells, if they do become cancerous, can be especially dangerous because they don’t have any receptors at that point - harder to treat
What type of sporadic tumors will resemble those of BRCA1 mutations?
basal-like sporadic tumors
often triple negative as well, making them harder to treat
How many different varians have been identified in BRCA1?
over 1500!
BRCA1/2 account for only 40% of familial breast cancer cases. What are some other genetic issues that can lead to problems?
ATM CHEK2 NBS1 RAD51 PTEN and lots more...but are not in the standard tests because their contribution is so small
How did we identify molecules subtypes of breast cancer?
microarray analysis to compare gene expression between normal and tumor tissues
allowed us to group tumors based on similar mRNA expression patterns
Connecting this microarray analysis to clinical outcome data allowed for development of what?
allowed us to develop oncotype Dx to determine how a tumor will act based on its genetics
What are the 5 subtypes of breast cancer based on these results?
claudin low (normal breast-like - arise from stem cells)
basal - earliest luminal progenitor
her2-amplified
Luminal B
Luminal A
Which subtype has the best prognosis?
luminal A - because it has the highest levels of estrogen receptor (developed from late luminal progenitor) and can be treated with Tamoxifen or aromatase inhibitors
What has the second best prognosis?
her2-amplified, so can be treated with trastuzumab
this actually had one of the worst prognosis before trastuzumab!
What percentage of breast cancers are ERalpha positive?
65%
What percentage have Her2 overexpression?
25%
Describe estrogen receptor signaling under normal conditions?
steroid hormone that acts as a transcription factor for genes that promote proliferation and cell survival (growth factors, etc)
The ER is expressed in a minority of luminal epithelial cells, but those calls don’t actually proliferate! so how does it promote growth?
it promotes expression of PARACRINE growth factors that will on neighboring cells
Describe how ER signalling can change in cancer?
cancers have more cells that are ERalpha positive.
furthermore, estrogen will cause proliferation in both the ER expressing cells and the nearby cells
What is the most improtant cell cycle regulator that is promoted by estrogen?
cyclin D1 - so you lose that checkpoint
Some tumor cells have dysregulated ER signalling, but the ER receptors are normal. What mutation is going on here?
defect in some other part of the signalling pathway
overexpression of FOXA1
Describe what happens with FOXA1.
ER can’t bind to closed chromatin
but FOXA1 can bidnt o closed chromatin at select site and open it to allow for ER binding
one of these sites is the promoter for cyclin D1
How does tamoxifen binding to ER block transcription?
Tamoxifen binding favors interactions with co-repressors, not co-activators
What are the two other HER2 names?
ERBB2
Neu (the name in mice)
ERBB2 is a member of what receptor family?
EGF receptor family
Members of the EGF receptor family are what kind of receptors?
tyrosine kinases
ERBB2 overexpressing cancers are generally ER ____?
negative
Are they more aggressive than ER+ cancers?
yes
How does ERBB2 signalling cause cancer?
under normal conditions, when EGF binds the ERBB2, you get dimerization and tyrosine kianse activity leading to cell signaling pathways which promote G1 to S phase progression
with the mutation, the dimerization domain is constitutively open so that you always have tyrosine kinase activity and uncontrolled proliferation
What are the two drugs against the ERBB2 receptor?
Trastuzumab (Hercephin)
Lapatinib
How do these drugs work differently from each other?
Transtuzumab is against the receptor
Lapatinib blocks the kinase active site of the EGFR-ERBB2 herheterodimer
