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01.08.2013 | Preclinical Study | Ausgabe 3/2013

Breast Cancer Research and Treatment 3/2013

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Zeitschrift:
Breast Cancer Research and Treatment > Ausgabe 3/2013
Autoren:
Daniele Fanale, Viviana Bazan, Lidia Rita Corsini, Stefano Caruso, Lavinia Insalaco, Marta Castiglia, Giuseppe Cicero, Giuseppe Bronte, Antonio Russo
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s10549-013-2649-0) contains supplementary material, which is available to authorized users.
Daniele Fanale and Viviana Bazan have contributed equally to this work.

Abstract

Numerous microarray-based gene expression studies performed on several types of solid tumors revealed significant changes in key genes involved in progression and regulation of the cell cycle, including AURKA that is known to be overexpressed in many types of human malignancies. Tumor hypoxia is associated with poor prognosis in several cancer types, including breast cancer (BC). Since hypoxia is a condition that influences the expression of many genes involved in tumorigenesis, proliferation, and cell cycle regulation, we performed a microarray-based gene expression analysis in order to identify differentially expressed genes in BC cell lines exposed to hypoxia. This analysis showed that hypoxia induces a down-regulation of AURKA expression. Although hypoxia is a tumor feature, the molecular mechanisms that regulate AURKA expression in response to hypoxia in BC are still unknown. For the first time, we demonstrated that HIF-1 activation downstream of hypoxia could drive AURKA down-regulation in BC cells. In fact, we found that siRNA-mediated knockdown of HIF-1α significantly reduces the AURKA down-regulation in BC cells under hypoxia. The aim of our study was to obtain new insights into AURKA transcriptional regulation in hypoxic conditions. Luciferase reporter assays showed a reduction of AURKA promoter activity in hypoxia. Unlike the previous findings, we hypothesize a new possible mechanism where HIF-1, rather than inducing transcriptional activation, could promote the AURKA down-regulation via its binding to hypoxia-responsive elements into the proximal region of the AURKA promoter. The present study shows that hypoxia directly links HIF-1 with AURKA expression, suggesting a possible pathophysiological role of this new pathway in BC and confirming HIF-1 as an important player linking an environmental signal to the AURKA promoter. Since AURKA down-regulation overrides the estrogen-mediated growth and chemoresistance in BC cells, these findings could be important for the development of new possible therapies against BC.

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Zusatzmaterial
Table S1 Pattern of common differentially expressed genes in breast cancer cell lines in response to hypoxia (XLS 83 kb)
10549_2013_2649_MOESM1_ESM.xls
Table S2 DEGs involved in cell cycle regulation pathway (XLS 28 kb)
10549_2013_2649_MOESM2_ESM.xls
Table S3 DEGs involved in HIF-1a network (XLS 24 kb)
10549_2013_2649_MOESM3_ESM.xls
Table S4 DEGs involved in AURKA signaling pathway (XLS 23 kb)
10549_2013_2649_MOESM4_ESM.xls
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