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Title: Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome
Authors: Ertel, Adam
Wang, Guangxue
Gormley, Michael
Qiao, Jing
Zhao, Qian
Wang, Min
Di Sante, Gabriele
Deng, Shengqiong
Dong, Lin
Pestell, Tim
Ju, Xiaoming
Casimiro, Mathew C.
Addya, Sankar
Tozeren, Ayden
Li, Qinchuan
Yu, Zuoren
Pestell, Richard George
Keywords: Cyclin D1
Issue Date: 2018
Source: Wang, 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.
Series/Report no.: Theranostics
Abstract: Background: 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.
DOI: 10.7150/thno.23877
Rights: © 2018 Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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