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Myoepithelial cell perturbations in BRCA mutation carriers and in DCIS (ductal carcinoma in situ)

ABSTRACT: We describe the gene expression profiles and enhancer landscape of normal myoepithelial cells and perturbations of these in BRCA1 and BRCA2 mutation carriers and in DCIS. We identified a myoepithelial transcription regulatory network orchestrated by p63 and TCF7 and defined the genomic targets of these transcription factors by ChIP-seq. While the majority of myoepithelial cells co-express p63 and TCF7 in normal breast of healthy women, the frequency of these cells is significantly lower in BRCA1 mutation carriers and in DCIS. Downregulation of p63 in MCF10DCIS cells leads to loss of myoepithelial cells and invasive tumors, whereas overexpression of TCF7 enhances tumor growth. Our findings suggest that loss of normal myoepithelial cell function facilitates in situ to invasive carcinoma transition and it may also enhance tumor initiation in BRCA mutation carriers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113909 | GEO | 2019/08/20

REPOSITORIES: GEO

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Project description:Approximately 5% of all breast cancers can be attributed to an inherited mutation in one of two cancer susceptibility genes, BRCA1 and BRCA2. We searched for genes that have the potential to distinguish healthy BRCA1 and BRCA2 mutation carriers from non-carriers based on differences in expression profiling. Using expression microarrays we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control non-carriers. We identified 137 probe sets in BRCA1 carriers and 1345 in BRCA2 carriers with differential gene expression. Gene Ontology analysis revealed that most of these genes relate to regulation pathways of DNA repair processes, cell cycle regulation and apoptosis. Real-time PCR was performed on the 36 genes which were most prominently differentially expressed in the microarray assay; 21 genes were shown to be significantly differentially expressed in BRCA1 or BRCA2 mutation carriers as compared to controls (p<0.05). Based on a validation study with 40 mutation carriers and 17 non-carriers, a multiplex model that included six or more coincidental genes of 18 selected genes was constructed in order to predict the risk of carrying a mutation. The results using this model showed sensitivity 95% and specificity 88%. In summary, our study provides insight into the biological effect of heterozygous mutations in BRCA1 and BRCA2 genes in response to ionizing irradiation induced DNA damage. We also suggest a set of 18 genes that can be used as a prediction and screening tool for BRCA1 or BRCA2 mutational carriers by using easily obtained lymphocytes. Using expression microarrays we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control non-carriers Fresh blood samples were obtained from 9 BRCA1 and 8 BRCA2 mutation carriers and 9 mutation-negative women. Lymphocytes were collected from fresh blood samples, and RNA was extracted one hour after γ-irradiation

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Myoepithelial cell perturbations in BRCA mutation carriers and in DCIS (ductal carcinoma in situ)

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