AN ACTIVATED ALLELE OF THE C-ERBB-2 ONCOGENE IMPAIRS KIDNEY AND LUNG-FUNCTION AND CAUSES EARLY DEATH OF TRANSGENIC MICE

The pathogenicity of the human c-erbB-2 oncogene was evaluated in tran sgenic mice. A DNA sequence comprising the promoter-enhancer region of the MMTV LTR and a constitutively activated allele of the human c-erb B-2 growth factor receptor gene was introduced into the germ line of m ice. Expression of the transgene was observed in kidney, lung, mammary gland, salivary gland, Harderian gland, and in epithelial cells of th e male reproductive tract. All transgenic mice expressing the c-erbB-2 receptor died within four months of birth. Histopathological analysis suggests that preneoplastic lesions in kidney and lung most likely ca used organ failure and the early death of the transgenic mice. Focal d ilatation and atypical proliferation of the tubular epithelial cells w as found in the kidney. These hyperplastic lesions were found adjacent to normal tubules. Immunohistochemistry showed that normal renal stru ctures were completely negative for c-erbB-2 protein expression. Atypi cal pseudopapillary proliferation of bronchial and bronchiolar epithel ial cells narrowed the bronchial lumen in lung. Alveoli appeared norma l. The expression of c-erbB-2 protein was strictly limited to the prol iferating epithelial cells and not detected in normal tissue. The mamm ary glands of two parous mice were underdeveloped, lacking lobular-alv eolar structures and were lactation deficient. Only a few ducts were i nterspersed in the fat pad. A virgin mouse developed a focal adenocarc inoma infiltrating the mammary fat pad. Expression of the c-erbB-2 pro tein was enhanced in the proliferating epithelial cells. Transgenic ma les were sterile. Epithelial hyperplasia and hypertrophy in the epidid ymis, vas deferens and seminal vesicles was found. The transgene is no t uniformly expressed in the tissues where the MMTV LTR is transcripti onally active. The scattered transgene expression invariably coincides with epithelial hyperplasia.