 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Jul 08, 2016 |
| Title |
Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers |
| Organism |
Mus musculus |
| Experiment type |
Genome variation profiling by genome tiling array
|
| Summary |
Breast cancer is the second leading cause of cancer related death in American women. Patient care is complicated by inherent tumor heterogeneity that can be classified into at least six intrinsic subtypes. While targeted treatments are standard of care for most subtypes, there remains a clinical need for targeted therapies against basal-like tumors that are typically ‘triple negative breast cancers’. As such, the molecular mechanisms underlying basal-like tumors are under intense investigation to identify genetic drivers and possible drug targets of this subtype. Somatic p53 mutations are one of the most common genetic events in basal-like breast tumors. This genetic foundation primes cells to accumulate secondary genetic aberrations, a subset of which is predicted to promote tumorigenesis. To identify additional drivers of basal-like tumors, a comparative study between human and murine tumors was performed utilizing a p53null mammary transplant murine model. The p53null mammary transplant murine model produced a genomically diverse set of tumors, a subset of which we show resemble the human basal-like subtype. Microarray and sequencing technologies were used to interrogate the secondary genetic aberrations of these murine tumors which were then compared to human basal-like tumors to highlight conserved features. Of the ‘omic’ datasets analyzed, DNA copy number variation produced the largest number of conserved candidate driver genes. These candidate gene lists were further filtered using a DNA-RNA Pearson correlation cutoff of 0.5 and a requirement that the gene was deemed essential in at least one human basal-like cell line from a genome-wide RNA-mediated interference screen database. These steps highlighted seven potential driver genes that are at amplified loci in both murine and human basal-like tumors: Atp11a, Col4a2, Cul4a, Lamp1, Met, Pnpla6, and Tubgcp3. Inhibition of Met using Crizotinib caused Met amplified tumors to regress, confirming that this genetic event is a driver in a subset of p53null transplant mammary tumors. This study identifies MET as a driver of basal-like murine tumors, thus identifying a shared potential driver of human basal-like breast cancer. Our results also highlight the importance of comparative genomic studies for discovering drug targets and for providing models to study whether patient populations are likely to respond to selective targeted treatments.
|
| |
|
| Overall design |
Agilent CGH microarrays were performed comparing DNA from BALB/c p53null mammary transplant tumors to DNA from FVB wild-type mice
|
| |
|
| Contributor(s) |
Pfefferle AD, Agrawal YN, Herschkowitz JI, Koboldt DC, Kanchi KL, Mardis ER, Rosen JM, Perou CM |
| Citation(s) |
27149990 |
| |
| Submission date |
Jul 18, 2015 |
| Last update date |
Jul 08, 2016 |
| Contact name |
Charles M. Perou |
| E-mail(s) |
[email protected]
|
| Organization name |
University of North Carolina at Chapel Hill
|
| Department |
Professor of Genetics, and Pathology & Laboratory Medicine; Lineberger Comprehensive Cancer Center
|
| Street address |
12-044 Lineberger Comprehensive Cancer Center CB# 7295
|
| City |
Chapel Hill |
| State/province |
NC |
| ZIP/Postal code |
27599-7264 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL4092 |
Agilent-014695 Mouse Genome CGH Microarray 244A (G4415A) (Feature Number version) |
|
| Samples (5)
|
|
| Relations |
| BioProject |
PRJNA290272 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE71071_RAW.tar |
220.8 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
|
|
|
|
 |
Less...
More...