The aberrant action of growth factors and their receptors is one of major determinants in the uncontrolled proliferation and evolution of normal breast epithelium to cancer cells. Many clinical, cellular, and molecular biology studies have indicated that abnormal expression of epidermal growth factor (EGF), transforming growth factor alpha (TGFalpha), and their shared receptor (EGFR or the related receptors erbB2/neu and erbB3) is frequently associated with malignant transformation of breast cells. Dr. Fu and others have recently demonstrated that EGF can induce rapid tyrosine phosphorylation and nuclear translocation of transcription factor p9l (p9l, or STAT1alpha). Through its SH2 domain, p9l directly interacts with EGFR and is activated in a ligand-dependent manner. Activated p9l translocates to the nucleus and stimulates specific transcription of the oncogene c-fos in vitro and in vivo. These studies suggest that EGF can use a direct signaling pathway to control nuclear transcriptional events (Fu and Zhang, 1993). Recently, studies from other laboratories have demonstrated that EGF, PDGF, CSF-l, IL-3, IL-5, IL-6, and IL-1O all use the similar direct pathway in controlling nuclear transcriptional events (reviewed by Darnell et al., 1994). A fundamental question in breast cancer research is whether and how this direct signaling pathway is involved in abnormal cell growth and transformation of breast cells. My recent results have shown that p9l seems to be very important in signaling oncogene expression in breast cancer cells, especially those cells which over-express EGFR. A deeper understanding of the role of these signaling events may eventually suggest a basis for the treatment of breast cancer. This fellowship will allow me to further investigate the role of this direct signaling pathway in breast cancer cells, especially, in response to an autocrine- and/or paracrine- acting growth factor such as EGF.
