Expression of endothelin-1, endothelin-A, and endothelin-B receptor in human breast cancer and correlation with long-term follow-up

Purpose: Endothelin-1 (ET-1) is overexpressed in breast carcinomas and stimulates tumor cell growth in an autocrine and paracrine fashion via its receptors, ETAR and ET_BR. In this study, we evaluated the expression of ET-1 and ET receptors in breast carcinomas and determined its clinical and prognostic significance. Experimental Design: We analyzed expression of ET-1, ET_AR, and ET_BR in 176 breast carcinomas using a semi-quantitative immunohistochemical approach. Statistical analysis of clinicopathological variables such as pT stage, pN stage, hormone receptor status, Her-2/neu amplification, histological grade, and long-term follow-up data were performed. Results: We observed a moderate to strong cytoplasmic staining for ET-1 in 69 (43.1%), for ETAR in 74 (46.5%), and for ET _BR in 86 (53.4%) cases of primary breast cancer. A correlation was found between increased ET-1 expression and its receptors with several clinicopathological parameters that characterize aggressive types of breast cancer, with the exception of increased ET_AR and ET_BR expression with positive estrogen receptor status. Elevated expression of ET-1, ET_AR, and ET_BR was more common in breast carcinomas of patients with lower disease-free survival time and overall survival. In addition, a statistically significant correlation was observed between ETAR expression and reduced disease-free survival time (P = 0.041). Interestingly, the prognostic impact of ET_AR expression was shown to be more pronounced in the subgroup of patients with a putative favorable prognosis according to classic prognostic factors. Conclusions: Therefore, analysis of ET_AR expression may improve the prediction of relapse and death and facilitate an individually based risk-directed adjuvant therapy in breast cancer patients.