Overexpression of pl85(c-erbB-2) (HER2) is observed in up to 30 percent of breast and ovarian cancers and is often associated with a poor prognosis. Antibodies reactive with the extracellular domain of HER2 can inhibit growth of cancer cells that overexpress HER2 and can potentiate the activity of cytotoxic drugs including cisplatin, paclitaxel and doxorubicin. Despite FDA approval of the anti-HER2 antibody trastuzumab (Herceptin) for clinical use, mechanisms by which anti-HER2 antibodies inhibit tumor cell growth and potentiate chemotherapy are not well understood. In our previous studies, treatment of cancer cells that overexpress HER2 with antiHER2 antibodies have induced cell cycle arrest in G1/S and inhibited anchorage independent growth. Binding of anti-HER2 antibody upregulated p27K1P1, downregulated cyclin E and CDK2, and increased association of p27K1P1 with CDK2. Anti-HER2 antibody inhibited the interaction of HER2 with HER3, downregulated constitutive activity of phosphinositol-3-kinase (P13 kinase) and blocked heregulin induced signaling through P13 kinase to AKT and P70S6 kinases.
The aims of the current proposal include: 1) to define the mechanisms by which specific unconjugated anti-HER2 antibodies inhibit growth of tumor cells that overexpress HER2; 2) to determine the mechanisms by which anti-p 185 HER2 antibodies potentiate the activity of paclitaxel; and 3) to define the interaction of HER2/HER3 driven activation of P13 kinase with endogenous abnormalities of the P13 kinase pathway. We will test the hypothesis that cell cycle arrest, inhibition of clonogenic growth, inhibition of angiogenesis and potentiation of chemotherapy relate to inhibition of signaling through the P13 kinase pathway. As a fraction of ovarian and breast cancers exhibit amplification of P13 kinase subunits, amplification of AKT and mutation of the PTEN lipid phosphatase that dephosphorylates phosphatidylinositol 3,4,5 P3, we also predict that the impact of anti-HER2 antibodies will depend upon the particular alterations in P13 kinase signaling within individual cancers.
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