Loss of breast cancer metastasis suppressor 1 protein expression predicts reduced disease-free survival in subsets of breast cancer patients

Abstract

Purpose: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes.

Experimental design: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining.

Results: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P=0.006) or HER2 positive (P=0.039) and <50 years old at diagnosis (P=0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P=0.008) or PR (P=0.029) or HER2 overexpression (P=0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status.

Conclusions: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.

Fig. 1

A, normal breast ductal epithelium and myoepithelial cells showing strong positive (3+) staining for BRMS1 (×200 magnification). In addition, scattered endothelial and inflammatory cells in the adjacent stroma can be seen showing staining, serving as an internal positive control. B, BRMS1-positive breast cancer case showing strong nuclear immunoreactivity within tumor cells as well as staining of adjacent endothelium (×400 magnification). C, BRMS1-negative breast cancer case showing a loss of nuclear staining within tumor cells (×400 magnification).

Fig. 2

Kaplan-Meier curves showing the disease-free survival for subgroups of patients stratified by ER/BRMS1 staining (A), PR/BRMS1 staining (B), and HER2/BRMS1 staining (C). Loss of BRMS1 expression led to a further reduction in disease-free survival in ER-negative (P = 0.008), PR-negative (P = 0.028), and HER2-positive (P = 0.026) subgroups.