Abstract
Chromosomal instability (CIN), a feature of most adult neoplasms from their early stages onward, is a driver of tumorigenesis. However, several malignancy subtypes, including some triple-negative breast cancers, display a paucity of genomic aberrations, thus suggesting that tumor development may occur in the absence of CIN. Here we show that the differentiation status of normal human mammary epithelial cells dictates cell behavior after an oncogenic event and predetermines the genetic routes toward malignancy. Whereas oncogene induction in differentiated cells induces massive DNA damage, mammary stem cells are resistant, owing to a preemptive program driven by the transcription factor ZEB1 and the methionine sulfoxide reductase MSRB3. The prevention of oncogene-induced DNA damage precludes induction of the oncosuppressive p53-dependent DNA-damage response, thereby increasing stem cells' intrinsic susceptibility to malignant transformation. In accord with this model, a subclass of breast neoplasms exhibit unique pathological features, including high ZEB1 expression, a low frequency of TP53 mutations and low CIN.
MeSH terms
-
Adolescent
-
Adult
-
Aged
-
Aged, 80 and over
-
Animals
-
Breast Neoplasms / genetics*
-
Breast Neoplasms / metabolism
-
Carcinoma / genetics*
-
Carcinoma / metabolism
-
Cell Differentiation / genetics*
-
Cell Line, Tumor
-
Cell Transformation, Neoplastic / genetics
-
Chromatin Immunoprecipitation
-
DNA Damage
-
Epithelial Cells / cytology
-
Epithelial Cells / metabolism*
-
Female
-
Flow Cytometry
-
Fluorescent Antibody Technique
-
Gene Expression Profiling
-
Gene Expression Regulation, Neoplastic*
-
Genomic Instability / genetics*
-
Humans
-
Immunoblotting
-
Mammary Glands, Human / cytology
-
Methionine Sulfoxide Reductases / genetics*
-
Methionine Sulfoxide Reductases / metabolism
-
Mice, Inbred NOD
-
Middle Aged
-
Reactive Oxygen Species
-
Real-Time Polymerase Chain Reaction
-
Sequence Analysis, DNA
-
Stem Cells / cytology
-
Stem Cells / metabolism*
-
Tissue Array Analysis
-
Tumor Suppressor Protein p53 / genetics
-
Tumor Suppressor Protein p53 / metabolism
-
Young Adult
-
Zinc Finger E-box-Binding Homeobox 1 / genetics*
-
Zinc Finger E-box-Binding Homeobox 1 / metabolism
Substances
-
Reactive Oxygen Species
-
TP53 protein, human
-
Tumor Suppressor Protein p53
-
ZEB1 protein, human
-
Zinc Finger E-box-Binding Homeobox 1
-
Methionine Sulfoxide Reductases
-
MSRB3 protein, human