The purpose of this study is to define the activity of nuclear transcriptio factors involved in regulating the proliferation and transformation of human breast epithelial cells, with the long term goal of identifying new targets for future chemopreventive agents. We are presently studying the transcription factors in normal and malignant breast epithelial cells which are activated by mitogenic peptide hormones, such as the Jun/Fos, STAT, and Myc/Max families of transcription factors. Over the last year, we have demonstrated that multiple growth factors induce activation of the Jun and Fos transcription factors in normal and malignant breast epithelial cells. However, the expression and activity of these transcription factors differ in normal and malignant cells. Normal proliferating breast epithelial cells have higher levels of Jun and Fos expression and activity than do breast cancer cells. In addition, these normal cells fail to increase their AP-1 activity in response to EGF stimulation or overexpression of activated oncogenes. We are now studying the expression of various """"""""downstream"""""""" genes which are regulated by the Jun and Fos in normal and malignant breast epithelial cells to determine if they are differentially expressed in normal and malignant breast epithelial cells. Studies over the last year have shown that STAT and Myc/Max transcription factors are also expressed in normal and malignant human breast cells. A detailed characterization of their expression and activity in human mammary cells will allow us to determine the relative role of each of these transcription factor families in controlling breast cell proliferation and transformation. We are now studying various transcription factor inhibitors that block the activity of AP-1, Myc/Max, and STAT transcription factors. Over the last year, we have shown that an inhibitor of AP-1 can suppress AP-1 activity and proliferation in immortalized mammary epithelial cells and in breast cancer cells. Studies are ongoing to characterize similar inhibitors of the other transcription factor families. By interfering with transcription factor function, we may be able to block signal transduction pathways at a distal point where the signals from multiple growth factors converge and thus prevent proliferation or transformation of breast epithelial cells. Thus, these studies may identify new cellular targets fo future chemopreventive agents.
