MDA468 GROWTH-INHIBITION BY EGF IS ASSOCIATED WITH THE INDUCTION OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P21(WAF1)

Epidermal growth factor (EGF) usually stimulates the proliferation of a variety of normal and malignant cells. In contrast, MDA468, a human breast cancer cell line with a very high number of EGF receptors, is g rowth inhibited in response to concentrations of EGF that stimulate mo st other cells. The purpose of this study was to elucidate the cellula r mechanisms involved in EGF-induced growth inhibition. EGF treatment stimulated the sustained expression of the cyclin-dependent kinase (CD K) inhibitor p21(WAF1). The p21(WAF1) induction in EGF-treated MDA468 cells is propably p53-independent since these cells contain no active p53. The promoter for p21(WAF1) gene contains binding sites for signal transducer and activator of transcription (STAT) and EGF is known to activate members of this family of transcription factors. Using electr ophoretic mobility shift assays (EMSA), we found that EGF activates ST AT1 and STAT3 in the MDA468 cells. These activated STATs specifically recognized the three conserved STAT-responsive elements in the p21(WAF 1) gene promoter, suggesting that STATs may be responsible for the p21 (WAF1) induction by EGF in MDA468 cells. The sustained rise in p21(WAF 1) in response to EGF is proposed to be a means of growth inhibition i n these cells.