Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-ovorexpresessed tamoxifen-resistant breast cancer cells

HER2/neu (erbB-2) overexpression has been causally associated with tamoxife n resistance in human breast cancer cells. Forced expression of HER2 in MCF -7 breast cancer cells resulted in mitogen-activated protein kinase (MAPK) hyperactivity and tamoxifen resistance. Inhibition of HER2 and MAPKs with A G1478 and U0126, respectively, as well as dominant-negative MEK-1/2 constru cts restored the inhibitory effect of tamoxifen on estrogen receptor (ER)-m ediated transcription and cell proliferation, Both AG1478 and U0126 also re stored the tamoxifen-mediated association of ER with nuclear receptor corep ressor (N-CoR) in the antiestrogen-resistant MCF-7 cells. Treatment with a combination of tamoxifen and a HER2 kinase inhibitor reduced tumor MAPK act ivity and markedly prevented growth of HER2-overexpressing MCF-7 xenografts in athymic mice, Thus, blockade of HER2 and MAPK signaling may enhance tam oxifen action and abrogate antiestrogen resistance in human breast cancer.