There has been increasing awareness of the significance of interactions between stromal cells and epithelial cells in development, homeostasis, and wound healing in a variety of tissues. Stromal-epithelial interactions are likely to be of importance in modulating proliferation, motility, differentiation, morphogenesis, and other functions in normal breast tissues and it is probable that these interactions continue to have a central role during the development and progression of breast carcinoma. We have demonstrated that the growth factor-receptor systems for hepatocyte growth factor (KGF) and keratinocyte growth factor (KGF) are present in normal breast cells and tissues, as well as breast carcinomas. HGF and KGF are unique because they have been shown to be key modulators in paracrine stromal-epithelial interactions that occur in many organ systems. Breast stromal cells, but not normal epithelial cells, produce messenger RNAs coding for HGF and KGF. Conversely, breast cancer and normal epithelial cells express HGF receptor and KGF receptor. We have demonstrated that normal breast epithelial cells proliferate in response to HGF or KGF in the absence of epidermal growth factor. We have also detected messenger RNAs that are likely to code for alternative HGF and KGF receptors expressed in breast epithelial cells. Each of these alternative receptors could regulate the responses of cancer cells and normal breast epithelial cells to HGF and KGF. Alterations in the KGF and HGF growth factor-receptor systems could be important in the development of breast cancer. Our objectives are to (I) characterize the functions of alternative HGF rec tor- and KGF receptor-coding sequences, (2) localize KGF and HGF growth factor- receptor mRNAs and proteins in neoplastic and normal breast tissue, (3) determine the effects of HGF and KGF on the proliferation, migration, and differentiation of breast carcinoma cells and normal breast cells, and (4) determine the role of anomalous expression of HGF receptor and KGF receptor genes in disease recurrence and overall survival in breast cancer patients. The proposed studies should lead to a better understanding of the roles of these interactions in normal breast and breast cancer tissues. They could also lead to novel therapies to intervene in the development of breast cancer and control its progression.