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.

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

“…Its overexpression in cancer has been correlated with the mechanisms of cell migration and invasiveness, and more recently has been associated with breast cancer progression and bone metastases formation [130]. In our samples, we detected 2 isoforms, one of which with an icrease of 19.7 folds, versus non-tumoral tissues expressing this protein.…”

Application of post-genomic techniques in dog cancer research

“…75 Remarkably, this paper was the first to identify MCP as cancer biomarker. Other studies on different human malignancies [76][77][78][79][80] validated MCP as a cancer biomarker, further supporting the use of dogs as useful models for human cancer. Studies on the serum proteome changes of canine lymphoma have been carried out by combining ion exchange chromatography and surface-enhanced laser desorption ionisation (SELDI) mass spectrometry.…”

A gene expression signature‐based nomogram model in prediction of breast cancer bone metastases

“…Clinical studies concerning on risk factors of BC bone metastases were limited. 26 Our previous study identified that lymph node metastases and ESR status were independent risk factors in predicting BC spine metastases. 27 Besides, Chen et al 28 indicated that axillary lymph node metastases and the concentrations of CA125, CA153, ALP, and hemoglobin were independent risk factors for BCBM.…”

“…Clinical studies concerning on risk factors of BC bone metastases were limited . Our previous study identified that lymph node metastases and ESR status were independent risk factors in predicting BC spine metastases .…”