In:
Disease Models & Mechanisms, The Company of Biologists, ( 2016-01-01)
Abstract:
Targeted therapies against basal-like breast tumors, which are typically ‘triple negative breast cancers (TNBC)’, remain an important unmet clinical need. Somatic TP53 mutations are the most common genetic event in basal-like and TNBC breast tumors. To identify additional drivers and possible drug targets of this subtype, a comparative study between human and murine tumors was performed utilizing a murine Trp53null mammary transplant tumor model. We show that two subsets of murine Trp53null mammary transplant tumors resemble aspects of the human basal-like subtype. DNA microarray, whole genome, and exome-based sequencing approaches were used to interrogate the secondary genetic aberrations of these tumors, which were then compared to human basal-like tumors to identify conserved somatic genetic features. DNA copy number variation produced the largest number of conserved candidate personalized drug targets. These candidates were filtered using a DNA-RNA Pearson correlation cutoff and a requirement that the gene was deemed essential in at least 5% of human breast cancer cell lines from a RNA-mediated interference screen database. Five potential personalized drug target genes were identified which were spontaneously amplified loci in both murine and human basal-like tumors: Cul4a, Lamp1, Met, Pnpla6, and Tubgcp3. As a proof of concept, inhibition of Met using Crizotinib caused Met amplified murine tumors to initially undergo complete regression. This study identifies Met as a promising drug target in a subset of murine Trp53null tumors, thus identifying a potential shared driver with a subset of human basal-like breast cancer. Our results also highlight the importance of comparative genomic studies for discovering personalized drug targets and for providing a preclinical model for further investigations of key tumor signaling pathways.
Type of Medium:
Online Resource
ISSN:
1754-8411
,
1754-8403
Language:
English
Publisher:
The Company of Biologists
Publication Date:
2016
detail.hit.zdb_id:
2451104-3
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