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Bcl-2 Determines Susceptibility to Induction of Lung Cancer by Oncogenic CRaf^{1 ,,2}

Institut für Medizinische Strahlenkunde und Zellforschung, Bayerische Julius-Maximilians-Universität, D-97078 Würzburg, Germany [L. M. F., O. Y. T., R. G., U. R. R.]; Pathologisches Institut Histologisches Labor, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany [T. P.]; and Instituto de Investigaciones Biomédicas Alberto Sols, Madrid 28029, Spain [G. C.]

The efficiency of tumor induction by oncogenes is influenced by modifier genes that determine individual susceptibility. We have used a transgenic mouse model to examine the role of a candidate susceptibility gene, bcl-2, for development of Raf oncogene-induced lung adenomas. Loss of bcl-2 greatly retarded tumor development without affecting tumor phenotype. Tumor tissues from bcl-2 positive and negative mice were compared for the fraction of S phase cells by staining for proliferating cell nuclear antigen and for the fraction of apoptotic cells by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. The data indicate that the increased tumor latency in the absence of bcl-2 results primarily from an increased apoptotic rate but also involves a decrease in tumor cell proliferation. Both effects can be rescued by breeding with H2K-bcl-2 transgenic mice demonstrating that loss of bcl-2 was the major genetic factor determining tumor resistance. These findings suggest that bcl-2 is a major susceptibility gene for development of lung cancer in mice and perhaps in humans.

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