Towards the prognostic significance and therapeutic potential of HER3 receptor tyrosine kinase in human colon cancer

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translational Relevance As a member of the EGFR receptor tyrosine kinases family, HER3 pseudo-kinase was shown to play a crucial role in regulation of oncogenic processes. Dysregulation of this receptor is associated with the progression of different human cancers including those of the breast and colon cancer. Our studies show that HER3 over-expression represents a putative prognostic marker since it correlates with reduced patient survival. We also show that HER3 is over-expressed in human colon cancer cell lines and that HER3 is functionally associated with cancer-related cell processes. Our findings identify HER3 as a promising target for colon cancer therapy development. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: Abnormal accumulation and dysregulation of the epidermal growth factor receptor family member HER3 is associated with the development of various human cancers including those of the breast,-lung, and ovary. We have previously demonstrated that in melanoma HER3 is frequently overexpressed, and is associated with poor prognosis. However, the importance of HER3 in colon cancer and its putative prognostic significance is still unknown. Experimental Design: HER3 expression was analysed in primary colon tumors from 110 patients by immunohistochemistry and correlated with time of progression. Parallel to this, the influence of HER3 over-expression on cell proliferation,-migration,-invasion, and apoptosis was investigated in four different colon cancer cell lines including DLD-1, LoVo, CaCO2, and T-84. Results: HER3 was detected at high frequency and exclusively at the membrane of the primary tumors. Elevated HER3 expression levels may serve as a putative prognostic marker since it associates with cell proliferation and decreased time to disease progression. High HER3 protein expression as well as phosphorylation levels were detected in tested cells. HER3 down-regulation by RNA interference abrogated cell proliferation, migration, and invasion. In addition, suppression of HER3 resulted in a G2/M cell cycle arrest, induced apoptosis and led to morphological changes in colon cancer cell lines. Furthermore, application of a monoclonal antibody specific to the extracellular portion of the receptor reduced heregulin-ß1-induced migration and invasion, and also induced apoptosis in colon cancer cell lines. Conclusion: We postulate that HER3 is critically involved in colon cancer progression and may serve as a novel target for therapeutic intervention. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.