Rescue of HER-2-positive breast carcinoma cells from dormancy by growth factors produced during wound healing

Background

Clinical and experimental data have raised the possibility that surgical removal of the primary tumor promotes the growth of metastatic lesions.

Purpose

This study was undertaken to determine the effect of wound healing drainages and postsurgical sera obtained from breast carcinoma (BC) patients on proliferation of dormant BC cells and to assess the role of HER2 oncoprotein in this proliferation.

Method

Proliferation of dormant BC cells was evaluated in vitro by SRB colorimetric assay. Growth factors were identified by inhibition with specific antibodies and displacement of ¹²⁵I-EGF from its receptor. Cellular damage was measured by creatine phospho-kinase level. The role of HER2 was analyzed by removal of HER2 from the membrane and inhibition by the anti-HER2 monoclonal antibody herceptin.

Results

Healing wound drainages and postsurgical sera from BC patients stimulated the in vitro growth of BC cells. Removal of the HER2 oncoprotein from BC cell membrane led to a dramatic decrease in the induced proliferation. Drainage-induced proliferation was around 50% inhibited by antibodies directed against EGF-like factors, including HB-EGF and TGF-α . Levels of these growth factors in postsurgical sera, as well as the level of drainage-induced proliferation, were directly correlated with the entity of surgery (r = 0.8, P = 0.0007 and r = 0.64, P = 0.009, respectively). Treatment of the tumor cells with herceptin, abolished the patients' drainage-induced proliferation when added to cultures before the growth stimulus.

Conclusion

HER2 overexpression by BC cells plays a major role in the postsurgery rescue of metastatic BC cells from dormancy. Herceptin appears to inhibit this growth induction. A prospective randomized clinical trial of perioperative treatment with herceptin of BC patients is starting.