Shed HER2 extracellular domain in HER2‐mediated tumor growth and in trastuzumab susceptibility
- 15 July 2010
- journal article
- Published by Wiley in Journal of Cellular Physiology
- Vol. 225 (1), 256-265
- https://doi.org/10.1002/jcp.22257
Abstract
The question of the serum HER2 extracellular domain (HER2/ECD) measurement for prediction of response to the anti‐HER2 antibody Trastuzumab is still an open and current matter of clinical debate. To elucidate the involvement of shed HER2/ECD in HER2‐driven tumor progression and in guiding therapy of individual patients, we examined biological effects exerted by elevated HER2/ECD in cancer growth and in response to Trastuzumab. To this purpose SKOV3 tumor cells were stably transfected to release a recombinant HER2/ECD molecule (rECD). Transfectants releasing high levels of 110‐kDa rECD, identical in size to native HER2/ECD (nECD), grew significantly slower than did controls, which constitutively released only basal levels of nECD. While transmembrane HER2 and HER1 were expressed at equal levels by both controls and transfected cells, activation of these molecules and of downstream ERK2 and Akt was significantly reduced only in rECD transfectants. Surface plasmon resonance analysis revealed heterodimerization of the rECD with HER1, ‐2, and ‐3. In cell growth bioassays in vitro, shed HER2 significantly blocked HER2‐driven tumor cell proliferation. In mice, high levels of circulating rECD significantly impaired HER2‐driven SKOV3 tumor growth but not that of HER2‐negative tumor cells. In vitro and in mice, Trastuzumab significantly inhibited tumor growth due to the rECD‐facilitated accumulation of the antibody on tumor cells. Globally our findings sustain the biological relevance of elevated HER2/ECD levels in the outcome of HER2‐disease and in the susceptibility to Trastuzumab‐based therapy. J. Cell. Physiol. 225: 256–265, 2010.Keywords
This publication has 40 references indexed in Scilit:
- A Naturally Occurring HER2 Carboxy-Terminal Fragment Promotes Mammary Tumor Growth and MetastasisMolecular and Cellular Biology, 2009
- Utility of Serum HER2 Extracellular Domain Assessment in Clinical Decision Making: Pooled Analysis of Four Trials of Trastuzumab in Metastatic Breast CancerJournal of Clinical Oncology, 2009
- Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunologic responses in indolent B-cell lymphoma patients with relapsed and measurable disease: a pilot studyBlood, 2009
- Serum HER‐2/neu and relative resistance to trastuzumab‐based therapy in patients with metastatic breast cancerCancer, 2008
- Structural basis for EGFR ligand sequestration by ArgosNature, 2008
- Regulation of Breast Cancer Response to Chemotherapy by Fibulin-1Cancer Research, 2007
- Expression of p95HER2, a Truncated Form of the HER2 Receptor, and Response to Anti-HER2 Therapies in Breast CancerJNCI Journal of the National Cancer Institute, 2007
- EGF–ERBB signalling: towards the systems levelNature Reviews Molecular Cell Biology, 2006
- Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translationThe EMBO Journal, 2006
- Immunological and pathobiological roles of fibulin-1 in breast cancerOncogene, 2003