Breast Cancer Research and Treatment

, Volume 140, Issue 3, pp 505–517

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

  • Daniele Fanale
  • Viviana Bazan
  • Lidia Rita Corsini
  • Stefano Caruso
  • Lavinia Insalaco
  • Marta Castiglia
  • Giuseppe Cicero
  • Giuseppe Bronte
  • Antonio Russo
Preclinical Study

DOI: 10.1007/s10549-013-2649-0

Cite this article as:
Fanale, D., Bazan, V., Corsini, L.R. et al. Breast Cancer Res Treat (2013) 140: 505. doi:10.1007/s10549-013-2649-0

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.

Keywords

AURKA Breast cancer Cell cycle HIF-1α Hypoxia 

Supplementary material

10549_2013_2649_MOESM1_ESM.xls (83 kb)
Table S1Pattern of common differentially expressed genes in breast cancer cell lines in response to hypoxia (XLS 83 kb)
10549_2013_2649_MOESM2_ESM.xls (28 kb)
Table S2DEGs involved in cell cycle regulation pathway (XLS 28 kb)
10549_2013_2649_MOESM3_ESM.xls (24 kb)
Table S3DEGs involved in HIF-1a network (XLS 24 kb)
10549_2013_2649_MOESM4_ESM.xls (23 kb)
Table S4DEGs involved in AURKA signaling pathway (XLS 23 kb)

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Daniele Fanale
    • 1
  • Viviana Bazan
    • 1
  • Lidia Rita Corsini
    • 1
  • Stefano Caruso
    • 1
  • Lavinia Insalaco
    • 1
  • Marta Castiglia
    • 1
  • Giuseppe Cicero
    • 1
  • Giuseppe Bronte
    • 1
  • Antonio Russo
    • 1
  1. 1.Section of Medical Oncology, Department of Surgical, Oncological and Stomatological SciencesUniversity of PalermoPalermoItaly

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