Endothelin-1-, endothelin-A-, and endothelin-B-receptor expression is correlated with vascular endothelial growth factor expression and angiogenesis in breast cancer.
OBJECTIVE
Endothelin-1 (ET-1) and its receptors (ET(A)R and ET(B)R), referred to as the endothelin (ET) axis, are overexpressed in breast carcinomas, and influence tumorigenesis and tumor progression by various mechanisms, including angiogenesis. The objective of the study was to clarify if expression of the ET axis participates in angiogenesis of breast carcinoma


METHODS
We analyzed expression of ET-1, ET(A)R, ET(B)R, and vascular endothelial growth factor (VEGF) immunohistochemically in 600 tissue array specimens from 200 paraffin-embedded breast carcinomas performing tissue microarray technology. Microvessel density (MVD) was determined by counting microvessels (identified by factor VIII) in each core specimen.


RESULTS
Moderate or strong immunostaining was observed for ET-1 in 25.4%, for ET(A)R in 43.7%, and for ET(B)R in 22.2% of breast carcinomas. Of all cases, 44.7% showed significant expression of VEGF. MVD varied between different tumor specimens (range, 0-80; median, 17). We observed a statistically significant correlation between MVD and ET expression status with higher MVD in ET-positive tumors. Moreover, expression of VEGF was found more frequently in tumors with overexpression of the ET axis (each P < 0.001). Staining of VEGF was correlated positively with MVD CONCLUSIONS: These results indicate that increased ET-1, ET(A)R, and ET(B)R expression is associated with increased VEGF expression and higher vascularity of breast carcinomas and, thus, could be involved in the regulation of angiogenesis in breast cancer. Our findings provide evidence that the expression pattern of the ET-axis and in particular of ET(A)R may have clinical relevance in future antiangiogenic targeted therapies for breast cancer.
Wülfing
Pia
P
Department of Obstetrics and Gynecology, University of Münster, Muenster, Germany. wuelfip@uni-muenster.de
Kersting
Christian
C
Tio
Joke
J
Fischer
Rudolph-Josef
RJ
Wülfing
Christian
C
Poremba
Christopher
C
Diallo
Raihanatou
R
Böcker
Werner
W
Kiesel
Ludwig
L
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D019332:Endothelin-1 / Q000096:biosynthesis*; D005169:Factor VIII / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D008833:Microcirculation; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D044022:Receptor, Endothelin A / Q000096:biosynthesis*; D044023:Receptor, Endothelin B / Q000096:biosynthesis*; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D019332:Endothelin-1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D042461:Vascular Endothelial Growth Factor A; D005169:Factor VIII