The purpose of this study is to define the activity of nuclear transcription 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. Such transcription factors include those activated by peptide hormones, such as epidermal growth factor (EGF), insulin-like growth factors (IGFs), and the heregulins, as well as those activated by the steroid hormones, such as estrogen, progesterone, and retinoic acid. We are presently studying the transcription factors in breast epithelial cells which are activated by mitogenic peptide hormones, such as the Jun/Fos, STAT, Myc/Max, and C/EBP families of transcription factors. Over the last year, we have characterized Jun and Fos transcription factor activity in normal human mammary epithelial cells, in non-tumorigenic, immortal human breast epithelial cells, and in breast cancer cells. Multiple growth factors, including those important for controlling the growth of breast epithelial cells, such as EGF and IGF-1, induce activation of the Jun and Fos transcription factors in these cells. In addition, an inhibitor of Jun and Fos blocks this growth factor-induced activation of these transcription factors. We have also studied the expression and activity of the STAT and myc/max transcription factors, and have shown that these transcription factors are expressed in human breast cancer 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 attempting to use specific transcription factor inhibitors to block growth factor-induced proliferation and oncogene- induced transformation of human breast epithelial cells. 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 prevent proliferation or transformation of breast epithelial cells. Thus, these studies may identify new cellular targets for future chemopreventive agents.
