A model of pulmonary adenocarcinomas was produced in transgenic mice harboring a chimeric gene comprising the SV40 large T antigen under the control of a transcriptional region derived from the human surfactant protein C (SP-C) gene. Transgenic mice succumbed with pulmonary tumors within 4-5 months of age. By histology, the tumors were adenocarcinomas with lepidic, papillary, and solid growth patterns that were indistinguishable from adenocarcinomas occurring in humans. Immunocytochemistry demonstrated the lack of staining for neuroendocrine markers, consistent with the identification of the tumors as non-small cell rather than small cell carcinomas. The presence of SV40 large T mRNA in the lung and tumors was detected by in situ hybridization and Northern blot analysis. Exogenous SV40 large T mRNA and endogenous CC10 (a nonciliated respiratory epithelial cell marker) and SP-C (a Type II alveolar cell marker) mRNAs were expressed at variable levels in the lung tumors. SV40 large T mRNA and CC10 mRNA were detected in the majority of tumors, while SP-C mRNA was detected less frequently. The heterogeneity of bronchiolar and alveolar cell markers in the tumors from the transgenic mice supports the concept that tumorigenesis was initiated in distinct subsets of epithelial cells that produce characteristic adenocarcinomas of the lung.