当前位置： SCI文献检索 > BREAST CANCER RESEARCH AND TREATMENT期刊下所有文献 > Selective ETAR antagonist atrasentan inhibits hypoxia-induced breast cancer cell invasion.

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.

journal_name

Breast Cancer Res Treat

journal_title

Breast cancer research and treatment

authors

Smollich M,Götte M,Kersting C,Fischgräbe J,Kiesel L,Wülfing P

doi

10.1007/s10549-007-9589-5

subject

Has Abstract

pub_date

2008-03-01 00:00:00

pages

175-82

issue

eissn

0167-6806

issn

1573-7217

journal_volume

108

pub_type

杂志文章

在线工具

Selective ETAR antagonist atrasentan inhibits hypoxia-induced breast cancer cell invasion.