Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome

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.

A Novel Long Non-Coding RNA-01488 Suppressed Metastasis and Tumorigenesis by Inducing miRNAs That Reduce Vimentin Expression and Ubiquitination of Cyclin E

“…Thus, a novel cyclin D1/miR-17-5p/miR-20 forms a regulatory feedback loop in breast cancer. Recently, differentially expressed miRNAs in a breast cancer cell line were determined using high-throughput screening [ 35 ]. These findings suggest that cyclin D1 acts as a regulator of miRNA.…”

Recent advances with cyclin-dependent kinase inhibitors: therapeutic agents for breast cancer and their role in immuno-oncology

“…A cyclin D1-regulated miRNA signature, was identified in breast cancer cells that included several onco-mirs including miR-193b. When assessed in a superset of 459 breast cancer samples, the cyclin D1-regulated miRNA signature was associated with the Gormley 2 (G2) breast cancer miRNA subset, ERα + status and activation of the Wnt pathway [6]. Seed elements for cyclin D1-regulated miRNA were identified in 63 genes of the Wnt signaling pathway including DKK [6].…”

“…When assessed in a superset of 459 breast cancer samples, the cyclin D1-regulated miRNA signature was associated with the Gormley 2 (G2) breast cancer miRNA subset, ERα + status and activation of the Wnt pathway [6]. Seed elements for cyclin D1-regulated miRNA were identified in 63 genes of the Wnt signaling pathway including DKK [6]. These findings were consistent with studies conducted profiling a large number of different types of cancer cells that identified a distinct class of miRNAs (miR-193b, miR-193a-3p, miR-195-5p, miR-214-5p, miR-890) that target nearly all cyclins/CDKs.…”

“…Using this approach genetic subtypes of breast cancer have been described in which specific patterns of expression were identified for the coding genome [3]. Growing evidence suggests both the coding and non-coding genome govern the onset and progression of tumorigenesis [4,5] and more recently subtypes of breast cancer have been also demonstrated using patterns of expression for the non-coding genome [6–8].…”

“…Breast cancer may be characterized based on either the coding [3] or non-coding (Gormley classification, G1-4) [6]. The CCND1 gene, which encodes cyclin D1, has been identified as amplified in 29–58% of breast cancers (Cancer Genome Atlas Network, 2012).…”