HER2 and EGFR Overexpression Support Metastatic Progression of Prostate Cancer to Bone

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 1; pp. 74 - 85
• Main Authors: Day, Kathleen C., Hiles, Guadalupe Lorenzatti, Kozminsky, Molly, Dawsey, Scott J., Paul, Alyssa, Broses, Luke J., Shah, Rajal, Kunja, Lakshmi P., Hall, Christopher, Palanisamy, Nallasivam, Daignault-Newton, Stephanie, El-Sawy, Layla, Wilson, Steven James, Chou, Andrew, Ignatoski, Kathleen Woods, Keller, Evan, Thomas, Dafydd, Nagrath, Sunitha, Morgan, Todd, Day, Mark L.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 01.01.2017
• Subjects: Animals; Blotting, Western; Bone cancer; Bone Neoplasms - secondary; Bone tumors; Cell Line, Tumor; Disease Progression; Epidermal growth factor receptors; ErbB Receptors - biosynthesis; ErbB-1 protein; ErbB-2 protein; Flow Cytometry; Gene amplification; Heterografts; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Male; Metastases; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness - pathology; Neoplastic Cells, Circulating - pathology; Neoplastic Stem Cells - pathology; NF-κB protein; Prostate cancer; Prostatic Neoplasms - pathology; Receptor, ErbB-2 - biosynthesis; Tissue Array Analysis; Tumor cells; Up-Regulation; Xenografts
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-1656

Activation of the EGF receptors EGFR (ErbB1) and HER2 (ErbB2) drives 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. Cancer Res; 77(1); 74–85. ©2016 AACR.