On the role of endothelin-converting enzyme-1 (ECE-1) and neprilysin in human breast cancer

Abstract

Endothelin-1 (ET-1) and its receptors, ET(A)R and ET(B)R, are overexpressed in breast carcinomas. However, little is known about the relevance of endothelin-converting enzyme-1 (ECE-1) and ET-1 degrading neprilysin (NEP). In this study, expression of ECE-1 and NEP was determined in 600 breast cancer tissue samples by immunohistochemistry; staining results were correlated with clinicopathological parameters. For ECE-1 expression, we found a significant correlation with VEGF (P < 0.001) and ET(A)R expression (P = 0.048). While patients with ECE-1 overexpressing tumours had more frequent disease recurrence (P = 0.03), NEP overexpression correlated with improved disease-free survival (DFS) (P = 0.023) and less frequent metastasis (P = 0.046). Also, a decrease of NEP expression with malignant progression (G1-G3) was found. ECE-1 inhibition using the selective ECE-1 inhibitor RO 67-7447 in MCF-7 breast cancer cells led to a significantly decreased ET-1 expression and reduced cell invasiveness (54.3% of controls, P = 0.014). Our results indicate that overexpression of ECE-1 is associated with unfavourable outcome, whereas NEP positively influences survival. Thus, expression of ECE-1 and NEP may have prognostic relevance. Due to the anti-invasive effect of the selective ECE-1 inhibitor, targeting ECE-1 may represent an innovative option in future breast cancer therapy.

Isoforms of endothelin-converting enzyme-1 (ECE-1) have opposing effects on prostate cancer cell invasion

“…Elevated ECE-1 levels are increasingly being correlated with tumour progression in PC and other types of malignancies (Egidy et al, 2000b;Arun et al, 2001;Dawson et al, 2004Dawson et al, , 2006Awano et al, 2005;Smollich et al, 2007). We have previously recognised the ability of ECE-1 to promote PC cell invasion in vitro (Dawson et al, 2004).…”

“…Although ECE-1 has been reported in a number of cancers (Ahmed et al, 2000;Egidy et al, 2000aEgidy et al, , 2000bArun et al, 2001;Usmani et al, 2002;Dawson et al, 2004Dawson et al, , 2006Awano et al, 2005;Smollich et al, 2007), specific isoforms present have yet to be identified. To our knowledge, ECE-1a expression has not been reported in any cancer cells either in vitro or in vivo, and only ECE-1c is abundant in prostate and lung cancer (Ahmed et al, 2000;Dawson et al, 2006).…”

“…Endothelin-1 is generated from its inactive precursor big ET-1 by endothelin-converting enzyme 1 (ECE-1). We and others have shown that ECE-1 expression is significantly elevated in tumours (Ahmed et al, 2000;Eberl et al, 2000;Egidy et al, 2000b;Arun et al, 2001;Usmani et al, 2002;Dawson et al, 2004Dawson et al, , 2006Awano et al, 2005;Smollich et al, 2007). We have previously demonstrated that ECE-1 is present in PC cell lines and primary tissues, and is expressed at the cell surface and intracellularly (Dawson et al, 2004(Dawson et al, , 2006, with levels of ECE-1 elevated in primary malignant stromal cells as compared with benign (Dawson et al, 2004).…”

Neprilysins: An Evolutionarily Conserved Family of Metalloproteases That Play Important Roles in Reproduction in Drosophila

“…In mammals, seven members of this family have been identified, of which neprilysin (NEP) and endothelin converting enzyme (ECE) are the best studied. These proteins have been implicated in various diseases including cardiovascular disease (Segura and Ruilope 2011;Wick et al 2011), Alzheimer's disease (Mulder et al 2012;Klein et al 2013), inflammation and inflammatory disorders (Wong et al 2011), and cancer (Smollich et al 2007;Maguer-Satta et al 2011).…”

ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole

“…Consequently, the ET system was proposed as a potential target for anticancer therapy [2,3]. Selective ET A R antagonism inhibits hypoxia-induced breast cancer cell invasion [7], and ECE-1 inhibition decreases ET-1 secretion and invasion of breast cancer cells [8].…”