Activation of the epidermal growth factor receptors EGFR (ErbB1) and HER2 (ErbB2) drive the progression of multiple cancer types through complex mechanisms that are still not fully understood. In this study, we report that HER2 expression is elevated in bone metastases of prostate cancer independently of gene amplification. An examination of HER2 and NF-κB receptor (RANK) coexpression revealed increased levels of both proteins in aggressive prostate tumors and metastatic deposits. Inhibiting HER2 expression in bone tumor xenografts reduced proliferation and RANK expression while maintaining EGFR expression. In examining the role of EGFR in tumor-initiating cells (TIC), we found that EGFR expression was required for primary and secondary sphere formation of prostate cancer cells. EGFR expression was also observed in circulating tumor cells (CTC) during prostate cancer metastasis. Dual inhibition of HER2 and EGFR resulted in significant inhibition of tumor xenograft growth, further supporting the significance of these receptors in prostate cancer progression. Overall, our results indicate that EGFR promotes survival of prostate TIC and CTC that metastasize to bone, whereas HER2 supports the growth of prostate cancer cells once they are established at metastatic sites.
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Cancer research. 2016 Oct 28 [Epub ahead of print]
Kathleen C Day, Guadalupe Lorenzatti Hiles, Molly Kozminsky, Scott J Dawsey, Alyssa Paul, Luke J Broses, Rajal Shah, Lakshmi P Kunju, Christopher Hall, Nallasivam Palanisamy, Stephanie Daignault-Newton, Layla El-Sawy, Steven J Wilson, Andrew Chou, Kathleen M Ignatoski, Evan T Keller, Dafydd G Thomas, Sunitha Nagrath, Todd M Morgan, Mark L Day
Urology, University of Michigan., Chemical Engineering, Biointerfaces Institute, Translational Oncology Program, University of Michigan., Internal Medicine, Case Medical Center., Urologic Pathology, Miraca Life Sciences Research Institute., Pathology, University of Michigan., Chemical Engineering, University of Massachusetts., Urology, Henry Ford Health System., Biostatistics, University of Michigan., None, University of Cincinnati., Surgery, University of Michigan., Urology and Pathology, University of Michigan School of Medicine., Pathology, The University of Michigan., Chemical Engineering, University of Michigan., translational oncology, University of Michigan .