HYPERPLASIA AND TUMORS IN LUNG, BREAST AND OTHER TISSUES IN MICE CARRYING A RAR-BETA-4-LIKE TRANSGENE

Transgenic mice were generated which express a truncated nuclear retin oic acid receptor beta (RAR beta), closely resembling the natural isof orm RAR beta 4, under the control of the MMTV promoter. The transgene was expressed in salivary gland, testis, lung and mammary tissue in tw o different lines. At similar to 11-14 months virtually all the transg enic mice showed hyperplasia of the lung alveolar epithelium with an e xcess of type II pneumocytes. Hyperplasia of the mammary alveoli and t erminal ducts was also seen in some females. Salivary glands and some sebaceous glands were hyperplastic in most male transgenic mice, but o nly rarely in females or in non-transgenics. Primary benign and malign ant tumours were more numerous in transgenic mice than in controls, wi th a total of 23 in 43 mice versus two in 33 non-transgenic animals. T reatment with dexamethasone to increase transgene expression resulted in exaggerated versions of the above phenotypes. Over-expression of RA R beta 4 therefore appears to predispose various tissues to hyperplasi a and neoplasia, and this by contrast to the RAR beta 2 isoform, which has tumour suppressor activity. A survey of ratios of RAR beta 4:-RAR beta 2 expression in human lung tumour cell lines showed an increase compared with normal lung tissue, suggesting that RAR beta 4 may play a similar role in human tumorigenesis.