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FOXM1 recruits nuclear Aurora kinase A (AURKA) to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells

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Title: FOXM1 recruits nuclear Aurora kinase A (AURKA) to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells
Authors: Lam, EW
Bella, L
Zona, S
Yong, J
Item Type: Journal Article
Abstract: Substantial evidence suggests that breast cancer initiation, recurrence and drug resistance is supported by breast cancer stem cells (BCSCs). Recently, we reported a novel role of Aurora kinase A (AURKA) in BCSCs, as a transactivating co-factor in the induction of the c-Myc oncoprotein. However, the mode of action and transcriptional network of nuclear AURKA in BCSCs remain unknown. Here, we report that nuclear AURKA can be recruited by FOXM1 as a co-factor to transactivate FOXM1-target genes in a kinase-independent manner. In addition, we show that AURKA and FOXM1 participate in a tightly coupled positive feedback loop to enhance BCSC phenotype. Indeed, kinase-dead AURKA can effectively transactivate the FOXM1 promoter through a Forkhead response element (FKHR), while FOXM1 can activate AURKA expression at the transcriptional level in a similar manner. Consistently, breast cancer patient samples portrayed a strong and significant correlation between the expression levels of FOXM1 and AURKA. Moreover, both FOXM1 and AURKA were essential for maintaining the BCSC population. Finally, we demonstrated that the Aurora kinase A inhibitor AKI603 and FOXM1 inhibitor thiostrepton acted synergistically to inhibit cytoplasmic Aurora kinase A activity and disrupt the nuclear AURKA/FOXM1 positive feedback loop respectively, resulting in a more effective inhibition of the tumorigenicity and self-renewal ability of BCSCs. Collectively, our study uncovers a previously unknown tightly coupled positive feedback signalling loop between AURKA and FOXM1, crucial for BCSC self-renewal. Remarkably, our data reveals a novel potential therapeutic strategy for targeting both the cytoplasmic and nuclear AURKA function to effectively eliminate BCSCs, so as to overcome both breast cancer and drug resistance.
Issue Date: 23-Jan-2017
Date of Acceptance: 17-Nov-2016
URI: http://hdl.handle.net/10044/1/42692
DOI: https://dx.doi.org/10.1038/onc.2016.490
ISSN: 1476-5594
Publisher: Nature Publishing Group
Start Page: 3428
End Page: 3440
Journal / Book Title: Oncogene
Volume: 36
Copyright Statement: © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permissionfrom the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Breast Cancer Now
Breast Cancer Now
Funder's Grant Number: C37/A12011
2012NovemberPhD016
2012MayPR070
2014NovPhD326
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
DRUG-RESISTANCE
TRANSCRIPTION FACTOR
EPIRUBICIN TREATMENT
SELECTIVE AURORA
EXPRESSION
INHIBITOR
CARCINOMA
FOXO3A
PROTEINS
LEUKEMIA
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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