PhD defence K. (Katharina) Uhr

Non-coding RNAs are a potential source of novel biomarkers. This thesis explores the clinical and biological significance of various types of non-coding RNAs. Biomarkers are urgently needed since resistance to therapy and predicting outcome are still major problems in breast cancer management. Although useful biomarkers are available for certain treatments, for the large majority of biologically active drugs there are none. Studying breast cancer cell lines as model for breast cancer enables large drug screenings and assessment of genomic characteristics. Associating drug screening data of 34 drugs on 36 breast cancer cell lines with the expression of 411 microRNAs (miRNAs), a family of non-coding RNA species, led to the discovery of eleven miRNAs linked to response of eight of the studied drugs. Other genomics features (i.e. mutations, methylation and copy number aberrations) associated with drug response of the cell lines as well, e.g. defects in the RB1 signaling pathway predicted resistance to the drug 17-AAG. Turning to primary breast tumors, and exploring another and fairly novel family of non-coding RNAs, circular RNAs (circRNAs), we noted that circRNAs are generated from many genes. Performing clinical association with these different non-coding RNA species in advanced breast cancer, we noted that the miRNA hsa-miR-7 was predictive for poor response to first line tamoxifen treatment while circRNA circCNOT2 was linked to poor progression-free survival on aromatase inhibitor treatment. In conclusion, in this thesis it was discovered that circRNAs are an abundant species and that specific non-coding RNAs were related to treatment resistance.

The public defence will take place at the Prof. Andries Queridoroom, 3rd floor Education Center, Erasmus MC. The ceremony will begin exactly at 11.30 hrs. In light of the solemn nature of the ceremony, we recommend that you do not take children under the age of 6 to the first part of the ceremony.