Related Experiment Video
Updated: Mar 27, 2026
Models of Bone Metastasis
Published on: September 4, 2012
CAPG and GIPC1: Breast Cancer Biomarkers for Bone Metastasis Development and Treatment
Jules A Westbrook1, David A Cairns1, Jianhe Peng1
1Affiliations 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*).
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.
