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 ETBR. In this study, we evaluated the expression of ET-I and ET receptors in breast carcinomas and determined its clinical and prognostic significance. Experimental Design: We analyzed expression of ET-1, ETAR, and ETBR in 176 breast carcinomas using a semiquantitative 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 ETBR 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 ETAR and ETBR expression with positive estrogen receptor status. Elevated expression of ET-1, ETAR, and ETBR 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 ETAR 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 ETAR expression may improve the prediction of relapse and death and facilitate an individually based risk-directed adjuvant therapy in breast cancer patients.