Analysis of BCRP expression in breast cancer patients

Abstract

Breast cancer resistance protein (BCRP, ABCG2) is a xenobiotic half-transporter protein. It is a member of the ATPbinding cassette protein family and functions as an energy-dependent efflux pump. BCRP is involved in multidrug resistance. The study aimed at examining BCRP expression in breast cancers and at defining a relationship between activity of this protein and clinical course of the cancer. Materials and Methods: We analyzed the expression of BCRP in 101 stage II breast cancer patients. All the patients were diagnosed and treated at the Lower Silesia Oncology Centre (LSOC) between January 1993 and June 1994. After the treatment the patients remained under constant control at LSOC. Mean duration of the observation was 14.2 years (ranging between 9.1 and 16.5 years). Data related to relapse of the disease and deaths were obtained from medical documentation stored in LSOC. The immunohistochemical reactions were performed on paraffin sections of primary tumours, using monoclonal antibodies against BCRP. The intensity of immunohistochemical reactions with BCRP antibody was evaluated using the semi-quantitative IRS (ImmunoReactive Score) scale, which took into account the intensity of the colour reaction and percentage of positive cells. Results of the immunohistochemical reactions, pathological and of clinical observations were subjected to statistical analysis. Correlations between these factors and BCRP were analyzed using Spearman and Chi2 tests. In order to estimate the survival rate, we used Kaplan Meier statistics, log-rank tests and Cox proportional hazard regression. Results: In our analysis we observed a positive correlation between the expression of the BCRP protein and grade of tumour advancement (r=0.2 p=0.03). We found also a negative correlation between the expression of BCRP and the estrogen (r=0,24 p=0,02) and progesteron (r=0,28 p=0,02) receptors. In a univariate analysis a significantly shorter disease free survival (DFS) and disease specific survival (DSS) was noted in patients with metastases to the lymph nodes (p=0,003 and p=0,0006), over the age of 50 years old ((p=0,02 and p=0,04) and clearly statistically significant in patients with a high expression of BCRP (p=0,00044 and p=0,00005). Overall survival (OS) was shorter in patients over the age of 50 (p=0,01), with higher stage of the disease – IIB (p=0,025), with metastases to the lymph nodes (p=0,003) and also clearly statistically significant in patients with a high expression of BCRP (p=0.00004). A multivariate analysis allowed to reveal that only higher expression of BCRP and metastases to lymph nodes were typical for cases of DFS (p=0,0028 and p=0,00015), DSS (p=0,00052 and 0,000017) and OS (p=0,0018 and p=0,000007) time. Conclusions: We demonstrated that high BCRP expression level is associated with poor survival in early stage breast cancer patients.