title: Selective ETAR antagonist atrasentan inhibits hypoxia-induced breast cancer cell invasion.
abstract: Tumour hypoxia, being widespread in solid tumours, is related to an increased risk of invasion and metastasis as well as to resistance to chemotherapy and radiotherapy. Hypoxia-inducible factor-1alpha (HIF-1alpha) has emerged as the key regulator of the cellular response to hypoxia. In primary breast cancers, HIF-1alpha is overexpressed, and high levels of HIF-1alpha predict for early relapse and increased metastasis. The endothelin (ET) axis, comprising the peptides ET-1, -2, -3 and their receptors A (ETAR) and B (ETBR), is another regulatory system of major relevance in human breast cancer. However, little is known about the interaction of HIF-1alpha and the ET axis in breast carcinomas. Therefore, we analysed expression of HIF-1alpha and the ET axis in 600 breast cancer tissue samples by immunohistochemistry, observing a significant correlation between expression of HIF-1alpha and ET-1 (P<0.001). In vitro, hypoxia was found to double ET-1 secretion of MCF-7 breast cancer cells (203.5% of controls; P<0.001), thereby promoting an invasive phenotype. Of note, real-time PCR analysis revealed that the increase of ET-1 was not due to enhanced transcription of the ET-1 gene. In invasion assays, breast cancer cell invasiveness was strongly increased by hypoxia (150.0% of controls; P=0.007). Most important, this increase was completely inhibited by the selective ETAR antagonist atrasentan. In conclusion, we provide evidence for a relevant interaction between hypoxia and the ET axis in breast cancer cells. Our data suggest that tumour hypoxia induces breast carcinoma invasiveness by releasing intracellularly stored ET-1. However, induction of invasiveness may be inhibited by selective ETAR antagonism, thus emphasising the promising status of the ET axis as a therapeutic target in breast cancer.
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital of Münster, Albert-Schweitzer-Str. 33, 48149, Münster, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Smollich
authors.forename: M
authors.initials: M
authors.lastname: Götte
authors.forename: C
authors.initials: C
authors.lastname: Kersting
authors.forename: J
authors.initials: J
authors.lastname: Fischgräbe
authors.forename: L
authors.initials: L
authors.lastname: Kiesel
authors.forename: P
authors.initials: P
authors.lastname: Wülfing
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D000077868:Atrasentan; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003035:Cobalt / Q000494:pharmacology; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D044022:Receptor, Endothelin A / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D003035:Cobalt; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C018021:cobaltous chloride; D000077868:Atrasentan