Suppressed Transformation and Induced Differentiation of HER-2/neu-overexpressing Breast Cancer Cells by Emodin¹ Free

The amplification and overexpression of the HER-2/neu proto-oncogene, which encodes the tyrosine kinase receptor p185^neu, have been observed frequently in tumors from human breast cancer patients and are correlated with poor prognosis. To explore the potential of chemotherapy directed 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-µm concentration, which repressed tyrosine kinase of p185^neu, efficiently inhibited both anchorage-dependent and anchorage-independent growth of HER-2/neu-overexpressing breast cancer cells. However, the inhibition was much less effective for those cells expressing basal levels of p185^neu under the same conditions. Emodin also induced differentiation of HER-2/neu-overexpressing breast cancer cells by exhibiting a morphological maturation property of large lacy nuclei surrounded by sizable flat cytoplasm and by showing a measurable production of large lipid drop-lets, which is a marker of mature breast cells. Therefore, our results indicate that emodin inhibits HER-2/neu tyrosine kinase activity and preferentially suppresses growth and induces differentiation of HER-2/neu-overexpressing cancer cells. These results may have chemotherapeutic implications for using emodin to target HER-2/neu-overexpressing cancer cells.