Role of HER2 in wound-induced breast carcinoma proliferation

Objective: Clinical and experimental data have suggested that surgical removal of primary tumours promotes the growth of metastatic lesions. We assessed the effect of surgery on proliferation of breast carcinomas, in particular those overexpressing HER2 oncoprotein. Methods: Proliferation of breast carcinoma cells was assessed by MIB-1 immunohistochemistry in sections of primary breast carcinomas and in residual tumour found in re-excision specimens, and in in-vitro cell lines by colorimetric assay. Epidermal growth factor (EGF)-like growth factors were measured by displacement of radiolabelled EGF from its receptor. Cellular damage was measured in terms of creatine phosphokinase level. Downmodulation of HER2 was investigated by cytoplasmic expression of anti-HER2 antibody and by inhibition with anti-HER2 antibody trastuzumab. Findings: Residual breast carcinomas that had been surgically removed within 48 days after first surgery showed a significant increase in proliferation if they were HER2-positive. Wound drainage fluid and postsurgical serum samples from patients stimulated in-vitro growth of HER2-overexpressing breast carcinoma cells. Removal of HER2 from the cell membrane led to a striking reduction of the induced proliferation. The amount of EGF-like growth factors in post-surgical serum samples, as well as the extent of drainage-fluid-induced proliferation, directly correlated with the amount of surgical damage assessed by creatine phosphokinase levels (r=0.77, p=0.002 and r=0.69, p=0.009, respectively). Treatment of HER2-positive tumour cells with trastuzumab before adding the growth stimulus abolished drainage-fluid-induced proliferation. Interpretation: HER2 overexpression by breast carcinoma cells has a role in postsurgery stimulation of growth of breast carcinoma cells.