The advent of targeted molecular therapies for the treatment of breast cancer has improved patient outcomes. However, for patients with triple negative breast cancer (TNBC), chemotherapy remains an essential part of their treatment regimen, often producing variable response rates and treatment resistance. MicroRNAs (miRNAs) play an important role in modulating the cellular response to stress, by regulating gene expression at the post-transcriptional level. They are attractive therapeutic candidates as they can regulate multiple biochemical pathways through their partial complementarity with hundreds of mRNAs and can be synthesized de novo, bypassing years of drug development. We set out to discover synthetic lethal microRNA-based therapies that may reduce treatment resistance. Synthetic lethal interactions between miRNA mimics and low dose (IC20) chemotherapy (e.g. epirubicin, docetaxel) were observed in a primary screen of 1550 miRNA mimics across four breast cancer cell lines representing different breast cancer subtypes. These responses were most frequently observed in TNBC cell lines. To further investigate the mechanisms controlling this synergy and it’s effect on cell viability in the TNBC subtype, MDA-MB231 cells were transfected with strongly synthetic lethal candidate miRNA mimics and treated with low dose epirubicin. Protein lysates were harvested at various time points following epirubicin exposure and were analysed using the Bio-Plex Multiplex system to determine the potential pathways involved in this synergistic relationship. The data suggests candidate miRNA mimics respectively interact with the DNA damage and mitogen-activated protein kinase (MAPK) pathways to synergise with epirubicin, causing a lethal phenotype. Further research aims to determine the pathway components with the greatest influence in this synthetic lethal interaction. This may provide mechanistic insights into the observed synthetic lethal interactions or reveal potential new targets for synthetic lethal combination therapies for TNBC patients.