title: CAPG and GIPC1: Breast Cancer Biomarkers for Bone Metastasis Development and Treatment.
abstract: BACKGROUND
  Bone is the predominant site of metastasis from breast cancer, and recent trials have demonstrated that adjuvant bisphosphonate therapy can reduce bone metastasis development and improve survival. There is an unmet need for prognostic and predictive biomarkers so that therapy can be appropriately targeted.
  
  
  METHODS
  Potential biomarkers for bone metastasis were identified using proteomic comparison of bone-metastatic, lung-metastatic, and nonmetastatic variants of human breast cancer MDA-MB-231 cells. Clinical validation was performed using immunohistochemical staining of tumor tissue microarrays from patients in a large randomized trial of adjuvant zoledronic acid (zoledronate) (AZURE-ISRCTN79831382). We used Cox proportional hazards regression, the Kaplan-Meier estimate of the survival function, and the log-rank test to investigate associations between protein expression, clinical variables, and time to distant recurrence events. All statistical tests were two-sided.
  
  
  RESULTS
  Two novel biomarker candidates, macrophage-capping protein (CAPG) and PDZ domain-containing protein GIPC1 (GIPC1), were identified for clinical validation. Cox regression analysis of AZURE training and validation sets showed that control patients (no zoledronate) were more likely to develop first distant recurrence in bone (hazard ratio [HR] = 4.5, 95% confidence interval [CI] = 2.1 to 9.8, P < .001) and die (HR for overall survival = 1.8, 95% CI = 1.01 to 3.24, P = .045) if both proteins were highly expressed in the primary tumor. In patients with high expression of both proteins, zoledronate had a substantial effect, leading to 10-fold hazard ratio reduction (compared with control) for first distant recurrence in bone (P = .008).
  
  
  CONCLUSIONS
  The composite biomarker, CAPG and GIPC1 in primary breast tumors, predicted disease outcomes and benefit from zoledronate and may facilitate patient selection for adjuvant bisphosphonate treatment.
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Jules A
authors.initials: JA
authors.lastname: Westbrook
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: David A
authors.initials: DA
authors.lastname: Cairns
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Jianhe
authors.initials: J
authors.lastname: Peng
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hanby
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Ingunn
authors.initials: I
authors.lastname: Holen
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wood
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Penelope D
authors.initials: PD
authors.lastname: Ottewell
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Helen
authors.initials: H
authors.lastname: Marshall
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Rosamonde E
authors.initials: RE
authors.lastname: Banks
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Selby
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Robert E
authors.initials: RE
authors.lastname: Coleman
authors.affiliation: Affiliations of authors:Academic Unit of Clinical Oncology, University of Sheffield , Sheffield , UK (JAW*, IH, PDO, REC, JEB*); Cancer Research UK Leeds Centre (JAW, DAC, JP, SLW, REB, PJS, JEB), Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research (DAC*, HM), and Clinical and Biomedical Proteomics Group (JAW, DAC, JP, SLW, REB, PJS, JEB) and Pathology and Tumor Biology (VS, AMH), Leeds Institute of Cancer and Pathology, University of Leeds , UK ; Department of Oncology and Metabolism, University of Sheffield, Sheffield , UK (SLW*).
authors.forename: Janet E
authors.initials: JE
authors.lastname: Brown
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000556:secondary; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000737:chemistry* / Q000556:secondary; D008840:Microfilament Proteins / Q000032:analysis*; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000032:analysis*; D016017:Odds Ratio; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D000077211:Zoledronic Acid
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C492009:GIPC1 protein, human; D007093:Imidazoles; D008840:Microfilament Proteins; D009687:Nuclear Proteins; C066575:CAPG protein, human; D000077211:Zoledronic Acid