Aims: To establish the role of miRNAs in the regulation and signaling induced by the new oncogenic kinase LMTK3, and to understand their role in estrogenic signaling and tumorigenesis. Objectives: 1. To identify LMTK3/FOXO3a-regulated miRNAs using the UCSC genome browser, miRNA expression profiling arrays, chromatin immunoprecipitation and luciferase reporter assays. We also wish to establish whether these miRNAs regulate LMTK3 expression post-transcriptionally aiming to reveal an active feedback loop. 2. To study the effects of miRNA-induced regulation on the direct/indirect actions of LMTK3, such as estrogen receptor-alpha (ERa) regulation, cell proliferation/viability and endocrine resistance. 3. To assess the clinical relevance of FOXO3a-regulated and/or LMTK3-targeting miRNAs, by correlating levels of pre- and mature miRNAs with LMTK3 and ERa expression, in well characterised patient cohorts (n=1210) with comprehensive survival data. Methodology: This project uses a range of cell and molecular biology techniques, bioinformatics and tissue handling techniques, which are well established in the host laboratory. Scientific and Medical Opportunities This proposal derives from the interplay of two recent publications from the host laboratory and aims to elucidate a novel mechanism of LMTK3 regulation. Estrogen driven pathways are crucial to breast tumorigenesis and LMTK3 plays an important role here. We wish to study how the interaction between the ERa and LMTK3 is regulated and controlled by microRNAs, which may help us better understand resistance to hormonal therapies. This work which will not occur in isolation (an LMTK3 based drug discovery strategy has also commenced) has broad and far-reaching basic science strengths, and thus its ultimate impact to patients may not be immediately evident. However, the elucidation of a new regulatory system has the potential to produce broad, fundamental insights into new basic science processes.