The present work reports the first evidence on PC-PLC accumulation and association with HER2 on the plasma membrane of HER2-overexpressing breast cancer cells and on the effects of PC-PLC inhibition on HER2 internalization, degradation, and recycling and on cell proliferation after transient or continuous cell exposure to anti-HER2 monoclonal Abs, including trastuzumab. The gene discussed is HSPG2; the disease is breast cancer.