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

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 amplific...

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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
Online Access	Get full text
ISSN	0008-5472 1538-7445
DOI	10.1158/0008-5472.CAN-16-1656

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Abstract	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.
AbstractList	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. 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. Simultaneous inhibition of HER2 and EGFR exploits their distinct roles supporting metastatic progression in human prostate cancer, given preclinical evidence of the efficacy of combination treatment.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. Simultaneous inhibition of HER2 and EGFR exploits their distinct roles supporting metastatic progression in human prostate cancer, given preclinical evidence of the efficacy of combination treatment. 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- Kappa B 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. [copy2016 AACR.
Author	Nagrath, Sunitha Paul, Alyssa Chou, Andrew El-Sawy, Layla Ignatoski, Kathleen Woods Morgan, Todd Wilson, Steven James Broses, Luke J. Thomas, Dafydd Keller, Evan Day, Mark L. Day, Kathleen C. Shah, Rajal Daignault-Newton, Stephanie Hall, Christopher Kunja, Lakshmi P. Dawsey, Scott J. Hiles, Guadalupe Lorenzatti Palanisamy, Nallasivam Kozminsky, Molly
AuthorAffiliation	2 Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 5 Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 3 Department of Pathology, University of Michigan, Ann Arbor, Michigan 6 Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 7 European, Egyptian Pharmaceutical Industries, Alexandria, Egypt 1 Department of Urology, University of Michigan, Ann Arbor, Michigan 4 Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan
AuthorAffiliation_xml	– name: 2 Translational Oncology Program, University of Michigan, Ann Arbor, Michigan – name: 5 Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan – name: 4 Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan – name: 1 Department of Urology, University of Michigan, Ann Arbor, Michigan – name: 3 Department of Pathology, University of Michigan, Ann Arbor, Michigan – name: 7 European, Egyptian Pharmaceutical Industries, Alexandria, Egypt – name: 6 Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/27793843$$D View this record in MEDLINE/PubMed
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Snippet	Activation of the EGF receptors EGFR (ErbB1) and HER2 (ErbB2) drives the progression of multiple cancer types through complex mechanisms that are still not... Simultaneous inhibition of HER2 and EGFR exploits their distinct roles supporting metastatic progression in human prostate cancer, given preclinical evidence... Activation of the epidermal growth factor receptors EGFR (ErbB1) and HER2 (ErbB2) drive the progression of multiple cancer types through complex mechanisms...
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SubjectTerms	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
Title	HER2 and EGFR Overexpression Support Metastatic Progression of Prostate Cancer to Bone
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