Downregulation of wild-type p53 protein by HER-2eu mediated PI3K pathway activation in human breast cancer cells: its effect on cell proliferation and implication for therapy

摘要

Overexpression and activation of HER-2eu (also known as c-erbB-2), a proto-oncogene, was found in about 30% of human breast cancers, promoting cancer growth and making cancer cells resistant to chemo- and radio-therapy Wild-type p53 is ctucial in regulating cell growth and apoptosis and is found to be mutated or deleted in 60-70% of human cancers. And some cancers with a wild-type p53 do not have normal p53 function, suggesting that it is implicated in a complex process regulated by many factors. In the present study, we showed that the overexpression of HER-2eu could decrease the amount of wild-type p53 protein via activating PI3K pathway, as well as inducing MDM2 nuclear tianslocation in MCF7 human breast cancer cells. Blockage of PI.3K pathway with its specific inhibitor LY294002 caused G1-S phase arrest, decreased cell growth rate and increased chemo- and radio-therapeutic sensitivity in MCF7 cells expressing wild-type p53. However, it did not increase the sensitivity to adriamycin in MDA-MB-453 breast cancel cells containing mutant p53. Our study indicates that blocking PI3K pathway activation mediated by HER-2eu overexpression may be useful in the treatment of breast tumors with HER-2eu overexpression and wild-type p53