title: FOXM1 recruits nuclear Aurora kinase A to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells.
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 Forkhead box subclass M1 (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, whereas 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 AURKA inhibitor AKI603 and FOXM1 inhibitor thiostrepton acted synergistically to inhibit cytoplasmic AURKA 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 reveal 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.
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.|Department of Laboratory Medicine, Guangzhou First People's Hospital, Guangzhou Medical College, Guangzhou, China.
authors.forename: N
authors.initials: N
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Zona
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: S-X
authors.initials: SX
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: M
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Medical Oncology, The Eastern Hospital of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: F-M
authors.initials: FM
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: S-S
authors.initials: SS
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, Guangzhou First People's Hospital, Guangzhou Medical College, Guangzhou, China.
authors.forename: B
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Bella
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: J-S
authors.initials: JS
authors.lastname: Yong
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: E W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University, Guangzhou, China.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D025461:Feedback, Physiological; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C576917:AURKA protein, human; D064096:Aurora Kinase A