Development of Herceptin resistance in breast cancer cells
Herceptin resistance in breast cancer cells is not caused by downregulation of HER-2 surface expression or AKT protein levels, but is associated with loss of nuclear p27 and enhanced AKT phosphorylation, while a mouse isotype 4D5 antibody retains growth‑inhibitory activity.
In a study of breast cancer cell lines, Herceptin (trastuzumab) inhibited proliferation and induced G1 arrest in BT‑474 cells through HER‑2 binding and cell‑cycle inhibition, but these effects were lost in Herceptin‑resistant derivatives. Resistance was not due to loss of surface HER‑2 expression or reduced AKT protein, although phosphorylated AKT was increased, and there was a loss of nuclear p27 expression. A mouse IgG1 isotype (4D5) retained growth inhibition in the resistant clones.
Understanding the mechanisms of Herceptin resistance can inform the development of alternative therapeutics or combination strategies that overcome resistance and improve outcomes for HER‑2 positive breast cancer patients.
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