NEU DIFFERENTIATION FACTOR (HEREGULIN) ACTIVATES A P53-DEPENDENT PATHWAY IN CANCER-CELLS

Previously we reported that neu differentiation factor (NDF)/heregulin (HRG) elevates tyrosine phosphorylation of its receptors erbB-3, erbB -4, and erbB-2 (through heterodimer formation). We also showed that bo th NDF/HRG and antibodies to erbB-2 can arrest growth and induce diffe rentiation in breast cancer cells. In this study, we report on the mec hanism of NDF/HRG-induced cellular effects. We show that NDF/HRG and a ntibodies to erbB-2 receptors up-regulate expression of p53 by stabili zing the protein. This is accompanied by upregulation of the p53 induc ible gene, p21(CIP1/WAF1), in a variety of cell lines: MCF7 and their derivatives (MCF7/HER2, MN1 and MCF-7-puro), ZR75T and LnCap cells, Th e induction of p21 is further enhanced when cells are treated with bot h NDF/HRG and DNA-damaging chemotherapeutic agents (i.e. doxorubicin). The NDF/HRG mediated induction of p21 is dependent on wildtype p53, a s it fails to occur in cells expressing dominant negative p53 (MDD2). Furthermore, p21 induction is capable of inactivating cdk2 complexes a s measured by Histone H1 phosphorylation assays. Finally, we show that in primary cultures of breast and other cancers, p21 is significantly induced in response to NDF/HRG treatment. Collectively, these observa tions suggest that the mechanism of breast cancer cell growth inhibiti on and differentiation via erbB receptors activation is through a p53- mediated pathway.