title: HER2 and EGFR Overexpression Support Metastatic Progression of Prostate Cancer to Bone.
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.
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Kathleen C
authors: KC
authors: Day
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Guadalupe
authors: G
authors: Lorenzatti Hiles
authors: Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan.|Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
authors: Molly
authors: M
authors: Kozminsky
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Scott J
authors: SJ
authors: Dawsey
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Alyssa
authors: A
authors: Paul
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Luke J
authors: LJ
authors: Broses
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors: Rajal
authors: R
authors: Shah
authors: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors: Lakshmi P
authors: LP
authors: Kunja
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Christopher
authors: C
authors: Hall
authors: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors: Nallasivam
authors: N
authors: Palanisamy
authors: Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Stephanie
authors: S
authors: Daignault-Newton
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|European Egyptian Pharmaceutical Industries, Alexandria, Egypt.
authors: Layla
authors: L
authors: El-Sawy
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Steven James
authors: SJ
authors: Wilson
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Andrew
authors: A
authors: Chou
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Kathleen Woods
authors: KW
authors: Ignatoski
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Evan
authors: E
authors: Keller
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors: Dafydd
authors: D
authors: Thomas
authors: Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan.|Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan.
authors: Sunitha
authors: S
authors: Nagrath
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Todd
authors: T
authors: Morgan
authors: Department of Urology, University of Michigan, Ann Arbor, Michigan. mday@umich.edu.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Mark L
authors: ML
authors: Day
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000556:secondary; D045744:Cell Line, Tumor; D018450:Disease Progression; D066246:ErbB Receptors / Q000096:biosynthesis*; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D046888:Tissue Array Analysis; D015854:Up-Regulation
chemical_list: D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human