HER2 and EGFR Overexpression Support Metastatic Progression of Prostate Cancer to Bone.
Day KC, Lorenzatti Hiles G, Kozminsky M, Dawsey SJ, Paul A, Broses LJ, Shah R, Kunju LP, Hall C, Palanisamy N, Daignault-Newton S, El-Sawy L, Wilson SJ, Chou A, Ignatoski KM, Keller ET, Thomas DG, Nagrath S, Morgan TM, and Day ML. HER2 and EGFR overexpression support metastatic progression of prostate cancer to bone. Cancer Res 2017; 77(1):74-85.
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.
Medical Subject Headings
Animals; Blotting, Western; Bone Neoplasms; Cell Line, Tumor; Disease Progression; ErbB Receptors; Flow Cytometry; Heterografts; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Invasiveness; Neoplastic Cells, Circulating; Neoplastic Stem Cells; Prostatic Neoplasms; Receptor, ErbB-2; Tissue Array Analysis; Up-Regulation