This proposal is a resubmission of a competitive renewal submitted first on November 1, 1988, revised on July 1, 1989, and now reflecting reviewers criticisms on last review. The broad, long term objectives of this revision are to examine genetic alterations which are selected at an early stage of human mammary carcinogenesis. Alterations in the erbB family, containing the receptor for epidermal growth factor (EGF-R) and the receptor-like erbB-2 and erbB-3 proteins, have been selected for closer scrutiny based on published information and preliminary data presented here which suggests their early appearance and maintenance in human breast cancer initiation and progression. Intraductal carcinoma has been selected for study because it represents the earliest lesion recognized clinically as breast malignancy. The hypothesis of this grant is: alterations leading to increased catalytic activity of erbB proto-oncogenes result in noninvasive breast malignancy, are maintained during progression, and second steps are required for invasion to occur. In the specific aims of this grant we will confirm a high frequency of erbB-2 overexpression in noninvasive breast cancer, evaluate the expression of the other members of the erbB family, and examine the mechanism of high level overexpression in noninvasive breast cancer. Other mechanisms which lead to increased catalytic activity of these receptors will be examined, including the presence and source of specific ligands in the microscopic environment of intraductal carcinoma. By proliferating normal and intraductal carcinoma cells in vitro, we will investigate other genes highly expressed in the malignancy when compared to normal cells. This will be done by constructing cDNA libraries from intraductal carcinoma cells which will be hybridized to cDNA probes from normal and malignant cells. Finally, normal mammary epithelial cells will be stably transfected with erbB-2 and the phenotype of transfectants compared to normal mammary cells, intraductal cells, and invasive cancers.