The differential effects of mutant p53 alleles on advanced murine lung cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-11, Vol.65 (22), p.10280-10288
• Main Authors: JACKSON, Erica L, OLIVE, Kenneth P, TUVESON, David A, BRONSON, Roderick, CROWLEY, Denise, BROWN, Michael, JACKS, Tyler
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - pathology; Alleles; Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Disease Progression; Experimental respiratory system tumors; Genes, p53 - genetics; Loss of Heterozygosity; Lung Neoplasms - genetics; Lung Neoplasms - pathology; MAP Kinase Signaling System; Medical sciences; Mice; Mutation; Paranasal Sinus Neoplasms - genetics; Paranasal Sinus Neoplasms - pathology; raf Kinases - metabolism; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumors; Up-Regulation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-2193

We report a direct comparison of the differential effects of individual p53 mutations on lung tumor growth and progression, and the creation of a murine model of spontaneous advanced lung adenocarcinoma that closely recapitulates several aspects of advanced human pulmonary adenocarcinoma. We generated compound conditional knock-in mice with mutations in K-ras combined with one of three p53 alleles: a contact mutant, a structural mutant, or a null allele. p53 loss strongly promoted the progression of K-ras-induced lung adenocarcinomas, yielding a mouse model that is strikingly reminiscent of advanced human lung adenocarcinoma. The influence of p53 loss on malignant progression was observed as early as 6 weeks after tumor initiation. Furthermore, we found that the contact mutant p53R270H, but not the structural mutant p53R172H, acted in a partially dominant-negative fashion to promote K-ras-initiated lung adenocarcinomas. However, for both mutants, loss-of-heterozygosity occurred uniformly in advanced tumors, highlighting a residual tumor-suppressive function conferred by the remaining wild-type allele of p53. Finally, a subset of mice also developed sinonasal adenocarcinomas. In contrast to the lung tumors, expression of the point-mutant p53 alleles strongly promoted the development of sinonasal adenocarcinomas compared with simple loss-of-function, suggesting a tissue-specific gain-of-function.