SUPPRESSED TRANSFORMATION AND INDUCED-DIFFERENTIATION OF HER-2 NEU-OVEREXPRESSING BREAST-CANCER CELLS BY EMODIN

The amplification and overexpression of the HER-2/neu proto-oncogene, which encodes the tyrosine kinase receptor p185(neu), have been observ ed frequently in tumors from human breast cancer patients and are corr elated with poor prognosis. To explore the potential of chemotherapy d irected at the tyrosine kinase of p185(neu), we have found that emodin (3-methyl-1,6,8-trihydroxyanthraquinone) a tyrosine kinase inhibitor, suppresses autophosphorylation and transphosphorylation activities of HER-2/neu tyrosine kinase, resulting in tyrosine hypophosphorylation of p185(neu) in HER-2/neu-overexpressing breast cancer cells. Emodin, at a 40-mu M concentration, which repressed tyrosine kinase of p185(ne u), efficiently inhibited both anchorage-dependent and anchorage-indep endent growth of HER-2/neu-overexpressing breast cancer cells. However , the inhibition was much less effective for those cells expressing ba sal levels of p185(neu) under the same conditions. Emodin also induced differentiation of HER-2/neu-overexpressing breast cancer cells by ex hibiting a morphological maturation property of large lacy nuclei surr ounded by sizable flat cytoplasm and by showing a measurable productio n of large lipid droplets, which is a marker of mature breast cells, T herefore, our results indicate that emodin inhibits HER-2/nea tyrosine kinase activity and preferentially suppresses growth and induces diff erentiation of HER-2/neu-overexpressing cancer cells. These results ma y have chemotherapeutic implications for using emodin to target HER-2/ neu-overexpressing cancer cells.