The rasH2 transgenic mouse: nature of the model and mechanistic studies on tumorigenesis

The rasH2 mouse is a hemizygous transgenic mouse carrying the c-Ha-ras oncogene and that gene's promotor/enhancer within the genetic background of a BALB/cByJ x C57BL/6J F1 mouse. Approximately 3 copies of the transgene are integrated in a tandem array into chromosome number 15. The transgene is transmitted stably without point mutation in hot spots and is expressed in all tissues over 20 backcross generations. The homozygous c-Ha-ras genotype is lethal. Hemizygotes are selected by polymerase chain reaction (PCR) analysis of tail tips after birth. Spontaneous tumors in hemizygous transgenic mice are rare until 6 months of age. The observed rasH2 tumor spectrum, including lung adenoma/adenocarcinoma, forestomach and skin papillomas, Harderian gland adenoma, liver proliferative lesions, splenic hemangioma/sarcoma, and lymphoma is consistent with the BALB/c and C57BL/6 background. In the rasH2 mouse, point mutations of the transgene induced by genotoxins are reported frequently but not in all tumors. Elevated levels of transgene expression were detected in all genotoxin-induced tumors in the rasH2. Increased transgene expression was independent of the mutation rate in transgenic and endogenous ras genes. These observations suggest that the overexpression of transgenic c-Ha-ras is responsible for accelerated tumor development.