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14050 Background: We evaluated whether combination of lapatinib, a dual tyrosine kinase inhibitor against EGFR and HER2, and fulvestrant, a full estrogen receptor antagonist, is superior in EGFR and HER2 overexpressing and non-overexpressing breast cancer cell lines regarding cell growth inhibition and effects on the protein expression level on special proteins such as PDK1 and ERK1/2. Methods: MTT assay and western blot analysis were performed in the different breast cancer cell lines BT474, T47D, MCF-7 and Adriamycin resistant MCF7 cells. Incubation time was 72h. Concentration of both agents in western blot: 1x10exp-7M, in MTT assay 10exp-11M to 10exp-5M. Results: MTT assay showed a significant stronger proliferation inhibition by lapatinib and fulvestrant in BT474 cells and non- overexpressing T47D cells at a concentration of 10E-7M compared to single agent treatment. By western blot analysis, we found a synergistic downregulation of PDK1 in the combination treatment both in BT474 and AR MCF7 cells, whereas not in T47D cells. In MCF7 cells a downregulation of p-PDK1 was observed after treatment with fulvestrant alone as well as lapatinib plus fulvestrant. Regarding ERK1/2, a synergistic downregulation could be observed in AR MCF7 cells. A downregulation of a p-ERK was detected in MCF-7 cells after treatment with lapatinib, fulvestrant or both. Conclusion: A synergistic action of lapatinib and fulvestrant was observed in all 4 cell lines despite their different receptor status regarding EGFR, HER2 and ER alpha. Shadeo et al. (2005) showed different copy number profiles in these breast cancer cell lines regarding the examined pathways. We could show by western blot analysis that the combination treatment had inhibitory effect on these cell lines according to their individual up-regulated pathways. Altogether, this suggests that the combination is a promising treatment not only in EGFR and HER2 over-expressing breast cancer and that treatment effect is also dependent on up-regulated pathways more likely than receptor status. No significant financial relationships to disclose.