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01-02-2010

Estrogen-Induced Aurora Kinase-A (AURKA) Gene Expression is Activated by GATA-3 in Estrogen Receptor-Positive Breast Cancer Cells

Authors: Shoulei Jiang, Hiroshi Katayama, Jin Wang, Sara Antonia Li, Yan Hong, Laszlo Radvanyi, Jonathan J. Li, Subrata Sen

Published in: Discover Oncology | Issue 1/2010

Abstract

Aurora-A is a proto-oncogenic mitotic kinase that is frequently overexpressed in human epithelial malignancies including in breast and ovarian cancers. The mechanism of transcriptional upregulation of Aurora-A in human breast cancer is not yet elucidated. We report herein that Aurora-A transcription is positively regulated by GATA-3 in response to estrogen in estrogen receptor α (ERα)-positive cells. Transient expression of aurora-A promoter deletion mutants in luciferase constructs identified a GATA binding sequence motif as a functional regulatory element in ERα-positive breast cancer cells. Electrophoretic mobility shift assay identified the binding of regulatory proteins to the GATA element. Anti-GATA-3 antibody generated a supershifted complex. Recruitment of GATA-3 to the aurora-A promoter was verified by chromatin immunoprecipitation analysis with GATA-3 antibody. Ectopic expression of GATA-3 resulted in elevated expression of Aurora-A in both ERα-positive and negative cells while siRNA-mediated silencing led to downregulation of endogenous Aurora-A in ERα-positive cells. Estrogen treatment of ERα-positive cells induced increased Aurora-A expression with enhanced recruitment of GATA-3 to the aurora-A promoter. Finally, in the ACI rat model of estrogen-induced breast cancer, known to be associated with elevated Aurora-A expression, we observed increased expression of GATA-3 in preinvasive and invasive mammary epithelial cells exposed to prolonged estrogen treatment and in developing breast tumors. These results demonstrate a direct positive role of estrogen in regulating Aurora-A expression through activation of the ERα-GATA-3 signaling cascade and suggest that this pathway may be critical in the origin of estrogen-stimulated sporadic breast cancer.

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Title: Estrogen-Induced Aurora Kinase-A (AURKA) Gene Expression is Activated by GATA-3 in Estrogen Receptor-Positive Breast Cancer Cells
Authors: Shoulei Jiang
Hiroshi Katayama
Jin Wang
Sara Antonia Li
Yan Hong
Laszlo Radvanyi
Jonathan J. Li
Subrata Sen
Publication date: 01-02-2010
Publisher: Springer-Verlag
Published in: Discover Oncology / Issue 1/2010
Print ISSN: 1868-8497
Electronic ISSN: 2730-6011
DOI: https://doi.org/10.1007/s12672-010-0006-x

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