This project is based on our demonstration that the cytotoxic activities of chemotherapeutic agents are modulated alterations in the activities of cellular signal transduction pathways, including those associated with HER-2, EGF, IGF1, and FGF, PDGF, and estrogen. We are exploring these phenomena and asking about the efficacy of simultaneously blocking two steps in signal transduction, EGFR and rats. In addition, we are examining the activation of the transcriptional activators NF-kappaB, and Sp-1 in wild-type and drug resistant breast (and ovarian) cancer cells by chemotherapy and EGFR antibodies. In addition to documenting the anti- growth properties of agents that modulate tyrosine kinase receptors, we have found a pleotrophic role for bFGF in breast cancer, with a strong synergism with mAb 225, which causes elevation in p27/KIP1, resulting in inhibition of CDK2 activity and cell cycle arrest. Combination treatment with anti-EGF receptor Mab 225 and a farnesyltransferase inhibitor (FT1) restores the sensitivity of MCF10A-ras cells to EGFR blockade and leads to greater growth suppression of human breast cancer cells than either reagent alone. We plan further studies of the interactions between EGFR and HER2 when stimulated to EGF or heregulin and when blocked by mAb 225 against the EGF receptor and/or mAb 4D5 against HER2, expecting that dual mAb therapy may further enhance drug cytotoxicity. We will explore whether signaling induced by bFGF or IGF can reverse changes in receptor tyrosine kinase activity, PI/3 kinase activity, Ras-GTP, apoptosis, or MAP kinase activity that results from exposure of breast cancer cells to mAb 225 or mAb 4D5. We plan further studies of FT1 treatment combined with EGF receptor blockade. Since FTIs are entering clinical trials this year and mAb 225 is in trials, a positive result can be translated into the clinic rapidly. Having shown that NF-kappaB and SP-1 induction occurs in cDDP, paclitaxel, and melphalan treated cells, and that this activation can be prevented by herbimycin A or flavopiridol, we plan to study these drug effects and the effect of EGFR receptor modulation on NF-kappaB binding activity in breast cancer cells and its effect on cytotoxicity following chemotherapy.
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