Alterations in protooncogenes can result in their inappropriate activation and many of these alterations are believed to play a role in the pathogenesis of some human malignancies. Screening studies looking for alterations in protooncogenes in human breast cancers reveal that amplification and/or overexpression of the HER-2/neu gene occurs in some 25%-30% of these malignancies. The alterations has been shown to correlate with a poor prognosis in those patients whose tumors contain it. This has led to studies from our laboratory indicating that it may play a role in the pathogenesis of the disease for some patients. Given that the HER-2/neu gene encodes a growth factor receptor found on the membrane of tumor cells and given its potential role in the pathogenesis of some human breast cancers, it is a logical target for the development of new therapeutic approaches directed at this alteration. Studies with monoclonal anti-bodies directed against the extracellular domain of the receptor indicate that many may have significant growth inhibitory properties. Some of these antibodies are currently in clinical testing. Recently, ligands have been identified that interact either directly or indirectly with the human HER-2/neu receptor; however, little is known about the biologic effects of these molecules, There is some controversy as to whether the ligands mediate growth stimulatory or growth inhibitory effects or both. The studies proposed in this application are designed to mimic this alteration in a series of human breast cancer cell lines as well as nonmalignant breast epithelial lines to gain some insights into the potential role of this alteration in the development and/or maintenance of the disease. A greater understanding about the biologic effects of HER-2/neu overexpression as well as the impact of agonists and antagonists to the receptor will be required to fully therapeutically exploit this gene alteration in human breast cancer. Finally, little is known about the biologic effects of other molecular alterations that may occur in combination with HER-2/neu expression.