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Expression of Endothelin-1, Endothelin-A, and Endothelin-B Receptor in Human Breast Cancer and Correlation with Long-Term Follow-Up¹

Department of Obstetrics and Gynecology [P. W., A. R., R. R. G., L. K.], Gerhard-Domagk-Institute of Pathology [R. D., C. K., C. P., W. B.]; Department of Urology [C. W.], Westfälische Wilhelms-University, 48129 Münster, Germany; Institute of Pathology, Heinrich-Heine-University, 40225 Düsseldorf, Germany [R. D., C. P.]

Purpose: Endothelin-1 (ET-1) is overexpressed in breast carcinomas and stimulates tumor cell growth in an autocrine and paracrine fashion via its receptors, ET_AR 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 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 ET_AR 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 ET_AR 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.

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