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Anti-HER2 Antibody and Heregulin Suppress Growth of HER2-Overexpressing Human Breast Cancer Cells through Different Mechanisms¹

Departments of Clinical Investigation [X-F. L., A. M., R. C. B.], Molecular Oncology [J. W., G. B. M.], and Bioimmunotherapy [J-Y. W.], Division of Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Previous reports have shown that certain anti-HER2 antibodies and heregulin can inhibit clonogenic growth of breast and ovarian cancers that overexpress HER2. Anti-HER2 antibodies bind to HER2 directly, whereas heregulin does not bind to HER2 alone, but rather interacts with HER2 through the formation of heterodimers with HER3 or HER4. The purpose of the present study was to elucidate the mechanisms by which anti-HER2 antibody and heregulin inhibit tumor growth. The anti-HER2 monoclonal antibody (mAb) ID5 was found to block G₁-S progression of the cell cycle, whereas heregulin inhibited passage through G₂-M. Compatible with the effects on the cell cycle, treatment with mAb ID5 decreased levels of cyclin-dependent kinase (CDK) 2, cyclin E, and CDK6 proteins and reduced cyclin E-CDK2-associated kinase activity; mAb ID5-treated cells had increased p27^Kip1 expression and an increased association of p27^Kip1 with CDK2. In contrast, treatment with heregulin increased protein levels of CDK2, CDK6, CDC2, and cyclin B1. More Retinoblastoma protein was found in the hypophosphorylated state in the cells treated with mAb ID5, whereas more retinoblastoma protein was in the hyperphosphorylated state in heregulin-treated cells. Heregulin was able to induce cell differentiation as assessed by Oil Red O staining and apoptosis as assessed by sub-G₁ peak on flow cytometry and the presence of DNA fragmentation in ApopTag histochemistry staining. Neither differentiation nor apoptosis was observed in the cells treated with mAb ID5. We conclude that anti-HER-2 mAb ID5 and heregulin exert growth inhibition through different mechanisms. In mammary cells overexpressing HER2, anti-HER2 mAb ID5 induces G₁ arrest, whereas heregulin induces G₂-M arrest, cell differentiation, and apoptosis.

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