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Differential Signaling by an Anti-p185^HER2 Antibody and Heregulin¹

Departments of Experimental Therapeutics [X-F. L., R. V., A. M., R. K., R. C. B.] and Molecular Oncology [G. B. M.], Division of Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul 135-230, Korea [D. S. B.]

To understand the molecular mechanisms by which anti-p185^HER2 antibody and the ligand heregulin inhibit tumor growth, we have investigated several signaling proteins and pathways. We report here that anti-p185^HER2 monoclonal antibody ID5 induced tyrosine phosphorylation of HER2 in SKBr3 breast cancer cells that overexpress p185^HER2. Heregulin ß1 induced phosphorylation of both HER3 and HER2. ID5 produced a greater association of phospholipase C (PLC)-1 with HER2 than did heregulin. Concordantly, ID5, but not heregulin, increased PLC-1 activity. However, the G₁ cell cycle arrest and induction of p27^Kip1 produced by ID5 were not affected by the inhibition of PLC-. ID5 preferentially induced binding of the M_r 46,000 isoform of SHC to HER2, whereas heregulin preferentially induced binding of the M_r 52,00 isoform of SHC to HER3. Heregulin, but not ID5, induced the p85 subunit of phosphatidylinositol 3'-kinase (PI3-K) to interact with HER3. Heregulin induced sustained activation of PI3-K signaling, whereas ID5 had only a transient effect. Heregulin, but not ID5, activated the c-Jun-NH₂-terminal kinase cascade. Pretreatment of SKBr3 cells with ID5 decreased heregulin-induced association of HER2 with HER3 as well as the activation of c-Jun-NH₂-terminal kinase and PI3-K activities. Inhibition of the mitogen-activated protein kinase pathway in SKBr3 cells did not affect heregulin-induced G₂-M-phase arrest, apoptosis, and differentiation. Heregulin-induced apoptosis could be blocked by inhibition of p70s6k, but not by inhibition of PI3-K. Heregulin-induced differentiation could be eliminated by inhibition of PI3-K. We conclude that ID5 and heregulin signal via different pathways, although both agents can inhibit the clonogenic growth of cells that overexpress HER2.

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