Targeting the Endothelin-A-Receptor Inhibits Breast Carcinoma Growth in Vivo

Abstract

Previously we found Endothelin-A-receptor (ETAR) to be overexpressed in breast carcinomas and demonstrated its potential significance as a target for breast cancer treatment. In the present study, we investigated the antitumoral effects of the selective ETAR antagonist atrasentan (ABT-627; 10mg/kg/d i.p.) in a MCF-7 xenografted nude mouse breast cancer model (animals: n=40). Treatment was initiated 10 days after tumor cell implantation and atrasentan effects were compared to those of paclitaxel (20mg/kg i.p. q4d) either alone or in combination with atrasentan. Atrasentan showed significant tumor growth inhibition as compared to controls (P=0.002). At the initial evaluation of tumor size, of all three treatment groups atrasentan was the most potent therapy with a 40% reduction in tumor growth as compared to controls. Throughout the first three weeks of therapy, atrasentan effects further on were superior to all other treatments. However, in the last week of treatment (d22) the tumor size in one animal of the atrasentan group began to rise excessively. Analysis of this non-responder demonstrated a down-regulation of ETAR expression on the mRNA and protein level. To test the suggested chemopreventative efficacy of atrasentan we performed a second study in MCF-7 xenografts receiving either atrasentan or vehicle only starting the treatment on the day of tumor cell inoculation. One week after tumor cell inoculation, in all controls but only in four of eight atrasentan-treated mice a tumor was detectable (P=0.021). Over the complete course of treatment (30dd) atrasentan treatment resulted into a significantly decreased tumor growth when compared with controls (mean tumor volume: 16.6 vs. 37.3mm3; P<0.001). These results support a potential therapeutic benefit of selective ETAR-antagonism in the treatment of ETAR-positive breast cancer. In particular, our data provide evidence for ETAR as a potential target for breast cancer chemoprevention.