GRB7 and HER2 protein overexpression and breast cancer outcome

Abstract

11102 Background: The growth factor receptor-bound protein-7 gene (GRB7) encodes a multi-domain signal transduction molecule and is located in close proximity to human epidermal growth factor receptor 2 (HER2) on chromosome 17q11–12. This study examines the roles of GRB7 protein in human breast cancer. Methods: We performed western blotting analysis of protein extracts from 563 annotated frozen breast tumors, collected from 1988 - 1998. GRB7 and HER2 bands were assigned low or high values compared to specific protein controls, and tubulin bands. Chi-square tests were used to test the hypothesis that there was no association between expression status of GRB7 or HER2 with clinical covariates and outcomes. Univariate Cox regression was performed to identify risk factors and Cox proportional hazards backward step model for variable selection to identify independent predictors of progression free survival. All P values were two sided. P values less than 0.05 were considered statistically significant. HER 2 gene amplification status was determined by fluorescence in situ hybridization (FISH). Results: GRB7 protein over-expression was associated with negative estrogen (< 5 fmole/mg protein) and progesterone receptor (< 10fmole/mg protein) status, higher grade (1, 2, or 3), larger primary tumor size (< 2.0 vs. > 2.0 cm), (more) axillary lymph node involvement (continuous), higher clinical stage (1, 2, 3, or 4) and shortened progression free survival (months). We found a discrepancy in HER2 and GRB7 protein over-expression. Isolated GRB7 protein over-expression correlated with inferior progression free survival, while HER2 protein over-expression without GRB7 protein over-expression did not. Multivariate analysis revealed that GRB7 over-expression was an independent predictor of progression free survival (hazard ratio 1.69: 95% confidence interval, 1.073 - 2.672; P = 0.0236). All 18 tumors submitted to FISH analysis that over-expressed both HER2 and GRB7 proteins and no tumors (0 / 10) with HER2 but no GRB7 protein over-expression demonstrated HER2 gene amplification. Conclusions: GRB7 protein over-expression is an independent adverse prognostic factor in breast cancer. No significant financial relationships to disclose.