Loss of p53 expression correlates with metastatic phenotype and transcriptional profile in a new mouse model of head and neck cancer.
Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most frequent cancer worldwide. Because HNSCC is largely acquired by environmental carcinogen exposure rather than through germ line mutations, there are no known familial forms of the disease in humans nor are there inbred rodent strains prone to spontaneous head and neck tumors. Transgenic animals with inactivation of tumor suppressor genes commonly mutated in human cases of HNSCC provide attractive models for studying the pathogenesis of head and neck cancer. p53 is the most frequently inactivated tumor suppressor gene in HNSCC. We used a chemical induction protocol in mice heterozygous for the p53 gene to evaluate how p53 inactivation contributed to head and neck carcinogenesis the mouse model. Metastatic squamous cell carcinomas developed in 100% of animals. Histopathologically, the tumors ranged from well to poorly differentiated and showed many molecular features of human HNSCC. Mice carrying only one p53 allele developed tumors with significantly reduced latency compared with wild-type controls (average, 18 versus 22 weeks). Metastatic cancer cells showed complete loss of p53 expression when compared with primary tumors. Transcriptional profiling showed not only distinct genetic differences between primary and metastatic tumors, but also when cancers from heterozygous null and wild-type animals were compared. Our results provide novel insights into the molecular genetics of tumor progression in head and neck cancer.
Ku
Tony K S
TK
Center for Craniofacial Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Nguyen
Dan C
DC
Karaman
Mazen
M
Gill
Parkash
P
Hacia
Joseph G
JG
Crowe
David L
DL
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53