Overexpression of Endothelin-A-receptor in breast cancer: regulation by estradiol and cobalt-chloride induced hypoxia.
Previous studies have demonstrated the potential significance of Endothelin (ET)-1 and its receptors, ETAR and ETBR, in the development and progression of breast cancer. The objective of this study was to assess the expression levels and potential regulation of the "ET axis" in human non-neoplastic and neoplastic breast tissue as well as in various human breast cancer cell lines. Expression of ET-1, ETAR and ETBR was evaluated in 31 neoplastic and 7 non-neoplastic breast tissue samples and in six human breast cancer cell lines using conventional and quantitative real-time RT-PCR, Western blotting and immunohistochemistry. The effects of 17beta-estradiol (E2) and cobalt-chloride (CoCl2) treatment on ET-1, ETAR and ETBR expression were studied in vitro. ETAR mRNA expression levels were found to be statistically significantly higher in breast cancer specimens than in non-neoplastic breast tissue (p<0.001). For ET-1 and ETBR mRNA expression, no significant difference was observed between the two groups. All cell lines exhibited expression of ET-1 and ETAR mRNA, whereas none showed significant ETBR mRNA expression. We observed a strong and reproducible induction of ETAR mRNA and protein expression by E2 and CoCl2 in MDA-MB-468 and BT-474 cells and in MDA-MB-453 and SK-BR-3 cells with a maximum increase after 8 and 16 h of treatment, respectively, while MCF-7 and HBL-100 cells showed a constitutive expression pattern. The present data suggest a novel mechanism in the regulation of ETAR expression in breast cancer. Based on these findings, a combination of ETAR-antagonists with adjuvant endocrine treatment seems to be a reasonable therapeutic strategy.
Wülfing
Pia
P
Department of Obstetrics and Gynecology, Münster University Hospital, D-48129 Münster, Germany. wuelfip@uni-muenster.de
Götte
Martin
M
Sonntag
Barbara
B
Kersting
Christian
C
Schmidt
Hartmut
H
Wülfing
Christian
C
Buerger
Horst
H
Greb
Robert
R
Böcker
Werner
W
Kiesel
Ludwig
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016587:Antimutagenic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D003035:Cobalt / Q000494:pharmacology*; D018450:Disease Progression; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis; D044022:Receptor, Endothelin A / Q000096:biosynthesis*; D044023:Receptor, Endothelin B / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D016587:Antimutagenic Agents; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D003035:Cobalt; D004958:Estradiol; C018021:cobaltous chloride