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 cells. Introduction of the neu oncogene, a transforming homologue of the human proto-oncogene c-erbB-2, produced a variety of abnormal patterns of epithelial growth, many of which resembled lesions found in human breasts. In four of 43 oncogene-bearing glands, areas of ductal carcinoma in situ were found, an abnormality previously observed in transgenic neu-bearing mice. Six glands developed localized areas of dense stroma containing excess ductal structures comprised of mildly hyperplastic epithelium. These areas resembled the human breast lesion termed sclerosing adenosis. Other glands developed hyperplastic epithelium, sometimes with multilayering of the cells and/or atypical changes such as abnormally large nuclei. In human breasts such lesions would be termed mild or atypical hyperplasia. In all the abnormal areas examined, levels of neu protein above background level were detected by immunohistochemistry. 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 oncogene suggests that the matching lesions in the human breast may be stages on one pathway to tumour development.