Trp53 haploinsufficiency modifies EGFR-driven peripheral nerve sheath tumorigenesis.
Malignant peripheral nerve sheath tumors (MPNSTs) are genetically diverse, aggressive sarcomas that occur sporadically or in association with neurofibromatosis type 1 syndrome. Reduced TP53 gene expression and amplification/overexpression of the epidermal growth factor receptor (EGFR) gene occur in MPNST formation. We focused on determining the cooperativity between reduced TP53 expression and EGFR overexpression for Schwann cell transformation in vitro (immortalized human Schwann cells) and MPNST formation in vivo (transgenic mice). Human gene copy number alteration data, microarray expression data, and TMA analysis indicate that TP53 haploinsufficiency and increased EGFR expression co-occur in human MPNST samples. Concurrent modulation of EGFR and TP53 expression in HSC1λ cells significantly increased proliferation and anchorage-independent growth in vitro. Transgenic mice heterozygous for a Trp53-null allele and overexpressing EGFR in Schwann cells had a significant increase in neurofibroma and grade 3 PNST (MPNST) formation compared with single transgenic controls. Histological analysis of tumors identified a significant increase in pAkt expression in grade 3 PNSTs compared with neurofibromas. Array comparative genome hybridization analysis of grade 3 PNSTs identified recurrent focal regions of chromosomal gains with significant enrichment in genes involved in extracellular signal-regulated kinase 5 signaling. Collectively, altered p53 expression cooperates with overexpression of EGFR in Schwann cells to enhance in vitro oncogenic properties and tumorigenesis and progression in vivo.
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota; Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota. Electronic address: eric.rahrmann@stjude.org.
Eric P
EP
Rahrmann
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota; Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota.
Branden S
BS
Moriarity
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
George M
GM
Otto
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota; Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota.
Adrienne L
AL
Watson
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Kwangmin
K
Choi
Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Margaret H
MH
Collins
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida.
Margaret
M
Wallace
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota.
Beau R
BR
Webber
Department of Lab Medicine and Pathology, BioNet, University of Minnesota, Minneapolis, Minnesota.
Colleen L
CL
Forster
Department of Pathology, University of Washington, Seattle, Washington.
Anthony E
AE
Rizzardi
Department of Pathology, University of Washington, Seattle, Washington.
Stephen C
SC
Schmechel
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Nancy
N
Ratner
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota; Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota; Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota; Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
David A
DA
Largaespada
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D057895:Haploinsufficiency; D006801:Humans; D008822:Mice, Transgenic; D018317:Nerve Sheath Neoplasms / Q000235:genetics* / Q000473:pathology; D012509:Sarcoma / Q000235:genetics / Q000473:pathology; D012583:Schwann Cells / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors