INDUCTION OF EPITHELIAL ABNORMALITIES THAT RESEMBLE HUMAN BREAST-LESIONS BY THE EXPRESSION OF THE NEU ERBB-2 ONCOGENE IN RECONSTITUTED MOUSE MAMMARY-GLAND/

We have developed a transplantation system that allows us to introduce oncogenes into mouse mammary epithelial cells in culture and then to reconstitute an epithelial tree in vivo from the genetically altered c ells. Introduction of the neu oncogene, a transforming homologue of th e human proto-oncogene c-erbB-2, produced a variety of abnormal patter ns of epithelial growth, many of which resembled lesions found in huma n breasts. In four of 43 oncogene-bearing glands, areas of ductal carc inoma in situ were found, an abnormality previously observed in transg enic neu-bearing mice. Six glands developed localized areas of dense s troma containing excess ductal structures comprised of mildly hyperpla stic epithelium. These areas resembled the human breast lesion termed sclerosing adenosis. Other glands developed hyperplastic epithelium, s ometimes with multilayering of the cells and/or atypical changes such as abnormally large nuclei. In human breasts such lesions would be ter med mild or atypical hyperplasia. In all the abnormal areas examined, levels of neu protein above background level were detected by immunohi stochemistry. Some staining was localized to membranes (as observed in ductal carcinoma in situ in humans) but cytoplasmic staining was also common in the lesions induced in mice by the neu oncogene. The range of abnormalities seen in the reconstituted glands carrying the neu onc ogene suggests that the matching lesions in the human breast may be st ages on one pathway to tumour development.