TY - JOUR
T1 - HER2 and EGFR overexpression support metastatic progression of prostate cancer to bone
AU - Day, Kathleen C.
AU - Hiles, Guadalupe Lorenzatti
AU - Kozminsky, Molly
AU - Dawsey, Scott J.
AU - Paul, Alyssa
AU - Broses, Luke J.
AU - Shah, Rajal
AU - Kunja, Lakshmi P.
AU - Hall, Christopher
AU - Palanisamy, Nallasivam
AU - Daignault-Newton, Stephanie
AU - El-Sawy, Layla
AU - Wilson, Steven James
AU - Chou, Andrew
AU - Ignatoski, Kathleen Woods
AU - Keller, Evan
AU - Thomas, Dafydd
AU - Nagrath, Sunitha
AU - Morgan, Todd
AU - Day, Mark L.
N1 - Publisher Copyright:
©2016 AACR.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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-kB 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.
AB - 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-kB 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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U2 - 10.1158/0008-5472.CAN-16-1656
DO - 10.1158/0008-5472.CAN-16-1656
M3 - Article
C2 - 27793843
AN - SCOPUS:85009247291
SN - 0008-5472
VL - 77
SP - 74
EP - 85
JO - Cancer research
JF - Cancer research
IS - 1
ER -