Mechanisms and relevance of alternative processing of miRNAs and 5'isomiRs in breast cancer

• Applicant: Dr. Cindy Körner
• Subject Area: Gynaecology and Obstetrics ; Bioinformatics and Theoretical Biology ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437616695

Breast cancer (BRCA) is the most frequently diagnosed cancer in women in Germany and worldwide. Notably, carcinomas arising from mammary tissue are heterogeneous between patients. Therapeutic options and prognosis are determined by the expression of key receptors and consequently by the resulting gene expression alterations. Yet, patients suffering from any subtype of BRCA are at risk of relapse or metastasis making it highly important to better understand disease mechanisms and consequently potential therapeutic targets. BRCA development and progression is associated with fundamental alterations in the expression of coding genes, but also of non-coding players such as miRNAs. These small RNA molecules exert their regulatory functions by binding to target mRNAs based on their seed sequence, nucleotides 2-8 of the miRNA molecule, to reduce expression of the target proteins. 5’isomiRs are naturally occurring derivatives of cellular miRNAs arising from alternative processing of the primary miRNA transcript. Importantly, they exhibit a shifted seed sequence as compared to their canonical counterpart. Consequently, this shift by one or two nucleotides can largely alter their target spectrum and thereby also their impact on cellular phenotypes both in BRCA and other contexts. Despite their proven relevance to cancer-related phenotypes and despite reports on aberrant processing of individual miRNAs in cancer, it has not yet been studied comprehensively, if processing and maturation is altered in cancer in general and how this might be explained on a molecular level. Therefore, we aim here to systematically characterize the miRNA processing landscape in BRCA and investigate the molecular mechanisms underlying the generation of 5’isomiRs. Along this line, we aim to gain insights into the molecular mechanisms and the biological relevance of aberrant regulation of 5’isomiR processing in cancer and characterize the phenotypic consequences. For that purpose, we will strategically combine computational analyses of patient data sets to generate solid hypotheses with comprehensive in vitro and eventually in vivo validation of these hypotheses. Based on the preliminary results that we have obtained in the first funding phase, we hypothesize that there is a complex interplay between cell cycle, splicing and miRNA maturation which is coherently perturbed in carcinogenesis and cancer progression. Hence, it is of crucial importance to determine if these alterations in the RNA processing machinery also contribute to phenotypic advantages for the cancer cells as this might open new perspectives for risk assessment, patient stratification and potentially also personalized therapy based on the individual RNA processing pattern.

• DFG Programme: Research Grants