dc.contributor.authorWang, Guangxue
dc.contributor.authorGormley, Michael
dc.contributor.authorQiao, Jing
dc.contributor.authorZhao, Qian
dc.contributor.authorWang, Min
dc.contributor.authorDi Sante, Gabriele
dc.contributor.authorDeng, Shengqiong
dc.contributor.authorDong, Lin
dc.contributor.authorPestell, Tim
dc.contributor.authorJu, Xiaoming
dc.contributor.authorCasimiro, Mathew C.
dc.contributor.authorAddya, Sankar
dc.contributor.authorErtel, Adam
dc.contributor.authorTozeren, Ayden
dc.contributor.authorLi, Qinchuan
dc.contributor.authorYu, Zuoren
dc.contributor.authorPestell, Richard George
dc.identifier.citationWang, G., Gormley, M., Qiao, J., Zhao, Q., Wang, M., Di Sante, G., et al. (2018). Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome. Theranostics, 8(8), 2251-2263.en_US
dc.description.abstractBackground: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood. Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes. Results: Hierarchical clustering of human breast cancers defined four distinct miRNA clusters (G1-G4) associated with distinguishable relapse-free survival by Kaplan-Meier analysis. The cyclin D1-regulated miRNA signature included several oncomirs, was conserved in multiple breast cancer cell lines, was associated with the G2 tumor miRNA cluster, ERα+ status, better outcome and activation of the Wnt pathway. The coding and non-coding genome were discordant within breast cancer subtypes. Seed elements for cyclin D1-regulated miRNA were identified in 63 genes of the Wnt signaling pathway including DKK. Cyclin D1 restrained DKK1 via the 3'UTR. In vivo studies using inducible transgenics confirmed cyclin D1 induces Wnt-dependent gene expression. Conclusion: The non-coding genome defines breast cancer subtypes that are discordant with their coding genome subtype suggesting distinct evolutionary drivers within the tumors. Cyclin D1 orchestrates expression of a miRNA signature that induces Wnt/β-catenin signaling, therefore cyclin D1 serves both upstream and downstream of Wnt/β-catenin signaling.en_US
dc.format.extent13 p.en_US
dc.rights© 2018 Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.en_US
dc.subjectCyclin D1en_US
dc.titleCyclin D1-mediated microRNA expression signature predicts breast cancer outcomeen_US
dc.typeJournal Article
dc.contributor.schoolLee Kong Chian School of Medicineen_US
dc.description.versionPublished versionen_US

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