On the role of endothelin-converting enzyme-1 (ECE-1) and neprilysin in human breast cancer.
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.
Smollich
Martin
M
Department of Obstetrics and Gynecology, University Hospital of Münster, Albert-Schweitzer-Str. 33, 48149, Münster, Germany.
Götte
Martin
M
Yip
George W
GW
Yong
Eng-Siang
ES
Kersting
Christian
C
Fischgräbe
Jeanett
J
Radke
Isabel
I
Kiesel
Ludwig
L
Wülfing
Pia
P
D016282:Aspartic Acid Endopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D019332:Endothelin-1 / Q000502:physiology; D000072396:Endothelin-Converting Enzymes; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008666:Metalloendopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D015260:Neprilysin / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis
D019332:Endothelin-1; D012333:RNA, Messenger; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes