Scott Breast Cancer Flashcards
What are the two epithelial layers of the breast?
Luminal and myoepithelium
What epithelial layer in the breast has progenitor cells?
Luminal
What epithelial layer in the breast is ER alpha negative?
Myoepithelial layer
What epithelium in the breast is ER alpha positive?
Luminal layer
What epithelial layer in the breast contains stem cells?
Myoepithelial cells
What is the inheritance pattern of BRCA mutations?
Autosomal dominant
Why does inactivation of BRCA1 or BRCA2 result in breast cancer susceptibility?
BRCA1/2 are essential components of homologous recombination arm of DNA repair machinery
What does homologous recombination repair in the DNA?
Ds DNA breaks
A repair defect in BRCA1/2 mutant cells results in what?
Genomic instability
Genomic instability creates the opportunity for what?
accumulation of somatic cancer causing mutations
In the absence of BRCA1, what cells accumulate?
Progenitor cells
What other genes in the DNA damage repair pathway contribute to familial breast cancers?
PALB2, CHECK2, ATM
What is microevolution?
Random somatic mutations that result in dysregulated proliferation and inappropriate survival are selected for
What type of genetic change is the driving force in development of both familial and sporadic cancers?
Somatic genetic changes
Estrogen binding to ER alpha promotes transcription of what in normal breast tissue?
Amphiregulin, a secreted growth factor
What causes the transcription of amphiregulin?
ER binding ER alpha
What is the effect of amphiregulin?
Acts on nearby cells to promote proliferation
In the breast, there are cells that express ER and cells that don’t… which cells proliferate?
The cells without ER
In tumor cells expressing ER, what effect does estrogen have when binding?
Estrogen promotes transcription of cell cycle regulators like cyclin D1; the cells expressing ER undergo proliferation
How are tumor cells different than normal breast epithelial cells?
Tumor cells have increased expression of ER and change what genes are regulated (ie increase Cyclin D1 vs amphiregulin)
Breast tumor cells and normal cells are similar in what way?
No mutations or amplifications of genes encoding estrogen or ER
How does ER promote transcription of a different set of genes in breast cancer?
Overexpression of the pioneer transcription factor FOXA1
What is FOXA1?
Binds closed chromatin and increases cyclin D1 transcription
Cyclin D1 is a key regulator in the what transition of the cell cycle?
G1/S transition
What is the MOA of tamoxifen?
Estrogen analog that bind ER; tamoxifen-ER complex bind DNA and INHIBIT transcription (favors interaction with co-repressors not co-activators)
ERBB2 is part of what receptor family?
EGF - tyrosine kinase
Why is overexpression of ERBB2 oncogenic?
Does not require ligand binding for activation
What drug blocks activity of ERBB2 homodimers?
Trastuzumab
What durg blocks EGFR-ERBB2 heterodimers?
Lapatinib - binds and blocks kinase at active site
