GENES INVOLVED IN PRENEOPLASTIC PROGRESSION

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The aim of this research is to identify and characterize genes that specify susceptibility to tumor promoter-induced neoplastic transformation in mice and humans. Evidence suggesting the involvement of such genes in animal and human systems has come from the observation that animals can be bred for sensitivity to tumor promotion. Two genes that specify sensitivity to promotion of neoplastic transformation by tumor promoters in mouse epidermal JB6 cells have been previously cloned. These putative genes, termed pro-1 and pro-2, have been sequenced and are being characterized with respect to mode of activation and regulation of expression. Unique pro-1-hybridizing transcripts have been identified in mouse cytoplasmic and poly(A)+ RNA. P- cells express lower levels of this transcript than do P+ or cells transformed by the tumor promoter, 12-0-tetradecanoylphorbol- 13-acetate (TPA), suggesting overexpression as a possible mode of activation. Genomic DNA of a Chinese nasopharyngeal carcinoma cell line, CNE2, confers promotion sensitivity (P+) activity on resistant mouse cells. This activity is, at least in part, attributable to activated homologs of mouse pro-1, as shown by screening a CNE2 genomic library with a mouse pro-1 probe and testing the homologs for P+ activity after transfection into resistant mouse cells. Inactive pro-1 homologs isolated from a normal human library and from the CNE2 library are being compared with activated CNE2 pro-1 to ascertain the mode of activation. Heteroduplex analysis is being carried out to pinpoint nonhomologous sequences. Assay of chimeric constructs of sequence from human pro-1 that is P+ active or inactive is expected to elucidate sequences critical to biological activity. Two cDNA libraries, one from initiation-promotion induced skin papillomas and the other from a squamous carcinoma, have yielded clones homologous to pro-2, containing cDNA fragments of 2.1 and 0.9 kb. This finding is significant in that it not only facilitates intron-exon assignment in the genomic clone, but also opens up investigation of the role of pro-2 expression in carcinogenesis in vivo.