Association of microRNA-7 and its binding partner CDR1-AS with the prognosis and prediction of 1st-line tamoxifen therapy in breast cancer

K Uhr,J A Foekens,A M Sieuwerts,D Hammerl,M Smid,J W M Martens,V De Weerd

doi:10.1038/s41598-018-27987-w

K Uhr, J A Foekens + Show 5 more

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https://doi.org/10.1038/s41598-018-27987-w

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Journal: Scientific Reports	Publication Date: Jun 25, 2018
Citations: 32	License type: open-access

Affiliation: Erasmus MC Cancer Institute

Abstract

The large number of non-coding RNAs (ncRNAs) and their breadth of functionalities has fuelled many studies on their roles in cancer. We previously linked four microRNAs to breast cancer prognosis. One of these microRNAs, hsa-miR-7, was found to be regulated by another type of ncRNA, the circular non-coding RNA (circRNA) CDR1-AS, which contains multiple hsa-miR-7 binding sites. Based on this finding, we studied the potential clinical value of this circRNA on breast cancer prognosis in a cohort based on a cohort that was previously analysed for hsa-miR-7 and in an adjuvant hormone-naïve cohort for 1st-line tamoxifen treatment outcomes, in which we also analysed hsa-miR-7. A negative correlation was observed between hsa-miR-7 and CDR1-AS in both cohorts. Despite associations with various clinical metrics (e.g., tumour grade, tumour size, and relapse location), CDR1-AS was neither prognostic nor predictive of relevant outcomes in our cohorts. However, we did observe stromal CDR1-AS expression, suggesting a possible cell-type specific interaction. Next to the known association of hsa-miR-7 expression with poor prognosis in primary breast cancer, we found that high hsa-miR-7 expression was predictive of an adverse response to tamoxifen therapy and poor progression-free and post-relapse overall survival in patients with recurrent disease.

Highlights

Non-coding RNAs[1] are defined as genes that are transcribed into RNAs, but not translated into proteins, and are not structural RNAs like tRNA or rRNA2
CDR1-AS is generated from a linear transcript, following the general observation that circular RNA (circRNA) are spliced from longer transcripts and it shares a promoter with the long non-coding RNAs (lncRNAs) LINC00632, which is about 50x less abundant than the circRNA8
Considering the fact that CDR1-AS is recognised to be an hsa-miR-7 sponge[7], we addressed whether CDR1-AS expression was related to hsa-miR-7 expression and, if so, whether its expression was associated with breast cancer prognosis

Summary

Introduction

Non-coding RNAs (ncRNAs)[1] are defined as genes that are transcribed into RNAs, but not translated into proteins, and are not structural RNAs like tRNA or rRNA2. MicroRNAs, which regulate mRNA translation[3], are likely the best studied subgroup of ncRNAs; apart from this family is the recently recognised large group of long non-coding RNAs (lncRNAs)[4] These lncRNAs are over 200 nt long[5] and have a multitude of mechanisms that affect cellular activity, e.g., (1) by influencing the accessibility of genes to the transcriptional machinery by interacting with chromatin modifiers[6]; (2) by supporting DNA looping, promoter binding and activator/transcription factor recruitment, which can increase gene expression[4,6]; (3) by influencing mRNA splicing and mRNA stability and increasing translation[6]; and (4) by influencing protein phosphorylation, methylation and stability[6]. A less common mechanism involves RNA-binding proteins that are located further away from the circRNA, which can be classified as trans-acting factors[13]

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