Inducible transgenics. New lessons on events governing the induction and commitment in mammary tumorigenesis

The advent of spatially and temporally regulated transgenics has allowed a careful dissection of the independent roles of oncogenes and tumor suppressors to the series of events governing initiation, progression and maintenance of tumorigenesis [1]. A surprising theme from these types of studies has been the finding that a single oncogene may drive tumor development, often with an invasive phenotype, but that withdrawal of the initiating oncogene may lead to complete tumor regression. The recent findings from the laboratory of Lewis Chodosh reveal that mammary-targeted expression of the c-Myc oncoprotein is sufficient for the induction of mammary tumorigenesis, and that withdrawal of the oncogenic stimulus results in tumor regression [2]. Previous studies with antisense oligonucleotides directed against c-myc mRNA (and other oncogenes) caused tumor regression, consistent with the model in which maintenance of tumorigenesis can be sustained through expression of a single oncogene. The rapid regression of invasive mammary tumors on withdrawal of mammary-targeted transgenic c-Myc expression [2] is consistent with a growing body of evidence that oncogene expression may be sufficient for the induction of but not the maintenance of tumorigenesis [3,4,5,6].Oncogenic H-RasVal 12 → Gly under control of the reverse tetracycline transactivator targeted by the tyrosinase gene promoter in the p16INK4+/- background induces melanomas [4]. Tumors regressed on withdrawal of H-RasVal 12 → Gly, although approximately one-third developed recurrence of phenotypically distinct neoplasms [4]. Targeting tamoxifen-inducible c-Myc expression to the suprabasal epidermis under control of the Involucrin promoter induced papillomatosis with angiogenesis that was reversible on withdrawal of c-Myc expression [6]. Higher levels of c-Myc expression correlated with more rapid development of the phenotype, and vascular endothelial growth factor production induced by c-Myc was postulated to contribute