title: Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers.
abstract: Targeted therapies against basal-like breast tumors, which are typically 'triple-negative breast cancers (TNBCs)', remain an important unmet clinical need. Somatic TP53 mutations are the most common genetic event in basal-like breast tumors and TNBC. To identify additional drivers and possible drug targets of this subtype, a comparative study between human and murine tumors was performed by utilizing a murine Trp53-null mammary transplant tumor model. We show that two subsets of murine Trp53-null 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 cut-off and a requirement that the gene was deemed essential in at least 5% of human breast cancer cell lines from an RNA-mediated interference screen database. Five potential personalized drug target genes, which were spontaneously amplified loci in both murine and human basal-like tumors, were identified: 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 Trp53-null tumors, thus identifying a potential shared driver with a subset of human basal-like breast cancers. 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Adam D
authors.identifier: 0000-0002-4924-1767
authors.initials: AD
authors.lastname: Pfefferle
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Yash N
authors.initials: YN
authors.lastname: Agrawal
authors.affiliation: The McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO 63108, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.affiliation: The McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO 63108, USA.
authors.forename: Krishna L
authors.initials: KL
authors.lastname: Kanchi
authors.affiliation: Department of Biomedical Sciences, University at Albany, Rensselaer, NY 12144, USA.
authors.forename: Jason I
authors.initials: JI
authors.lastname: Herschkowitz
authors.affiliation: The McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO 63108, USA.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Rosen
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA cperou@med.unc.edu.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D033481:Chromosomes, Mammalian / Q000235:genetics; D000077547:Crizotinib; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D057285:Precision Medicine; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism
chemical_list: D011720:Pyrazoles; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D000077547:Crizotinib
keywords: Basal-like breast cancer; Exome sequencing; Genetically engineered mouse models; Personalized genomics; Whole-genome sequencing; p53