Thomas, Hilary; (1997) A feasibility study of oncogene transgenic mice as therapeutic models in cytokine research. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Transgenic mice carrying the activated rat c-neu oncogene under transcriptional control of the MMTV promoter were backcrossed to BALB/c mice, with the aim of developing a model for cancer therapy. A total of 86 of 268 transgene positive mice in the first five generations developed 93 histologically diverse tumours (median age of onset 18 months). The cumulative incidence of breast tumours at 24 months was 18%, and overall tumour incidence 31%. As well as expected c-neu expressing breast cancers, lymphomas and Harderian gland carcinomas developed. All of the mammary carcinomas, Harderian gland carcinomas and lymphomas expressed c-erb B2. Virgin mice had fewer mammary tumours than those with two litters (p= 0.006), further litters did not affect tumour incidence. Breast carcinomas metastasised to the lungs, and lymphomas were widely disseminated. The tumours showed a range of architectural patterns which resembled human breast cancers or lymphomas. This diversity was reflected in S-phase fraction and aneuploidy. Mammary tumours transplanted to nude mice showed variable responses to IFN-α and -γ. A tumour transplanted to BALB/c mice responded to IL- 12. Groups of mice treated prophylactically with IFN-α and -γ, and IL-2 and IL-7 from the third and fourth generations respectively were studied for tumour development. No statistically significant differences were noted between the groups except an increased incidence of B-cell lymphomas in the IL-7 treated group. There was a significant decline in transgene positivity with successive generations (X2 test for trend p<0.001) but transmission of transgene, litter number and offspring viablity was not changed in homozygotes. The diversity, histologic and biologic resemblance to human cancer suggests the model has potential for evaluating novel therapies. Genetic and environmental manipulations are underway to increase tumour incidence and decrease age of onset.

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