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Published, Version of Record (VoR)CC BY-NC V4.0, Open
Journal article
Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome
Theranostics, v 8(8), pp 2251-2263
01 Jan 2018
PMID: 29721077
Featured in Collection : UN Sustainable Development Goals @ Drexel
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, ERa+ 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/beta-catenin signaling, therefore cyclin D1 serves both upstream and downstream of Wnt/beta-catenin signaling.
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Details
- Title
- Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome
- Creators
- Guangxue Wang - Tongji UniversityMichael Gormley - Thomas Jefferson UniversityJing Qiao - Tongji UniversityQian Zhao - Tongji UniversityMin Wang - Baruch S. Blumberg InstituteGabriele Di Sante - Baruch S. Blumberg InstituteShengqiong Deng - Tongji UniversityLin Dong - Tongji UniversityTim Pestell - Thomas Jefferson Univ, Dept Canc Biol, 233 South 10th St, Philadelphia, PA 19104 USAXiaoming Ju - Thomas Jefferson UniversityMathew C. Casimiro - Baruch S. Blumberg InstituteSankar Addya - Thomas Jefferson UniversityPaolo Fortina - Thomas Jefferson Univ, Dept Canc Biol, 233 South 10th St, Philadelphia, PA 19104 USAAyden Tozeren - Drexel UniversityQinchuan Li - Tongji UniversityZuoren Yu - Baruch S. Blumberg InstituteRichard G. Pestell - Nanyang Technological University
- Publication Details
- Theranostics, v 8(8), pp 2251-2263
- Publisher
- Ivyspring Int Publ
- Number of pages
- 13
- Grant note
- 81370175; 81572593; 81372299 / Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) Breast Cancer Research foundation Dr. Ralph and Marian C. Falk Medical Research Trust Pennsylvania Department of Health R01CA070896; R01CA086072 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 2016YFA0101202 / National Key Research and Development Program of China Stem Cell and Translational Research R01CA086072 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Decision Sciences (and Management Information Systems); [Retired Faculty]
- Web of Science ID
- WOS:000427107300017
- Scopus ID
- 2-s2.0-85044358873
- Other Identifier
- 991019167716504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Medicine, Research & Experimental