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Title: Post-transcriptional regulation of estrogen receptor-α by miR-17-92 interaction and LMTK3 phosphorylation in breast cancer
Author: Jacob, Jimmy
ISNI:       0000 0005 0732 5307
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Estrogen receptor-α (ERα) is expressed in two-thirds of BCs and is a well-known prognostic and predictive marker. For this reason it is one of the most studied proteins in BC. To understand how ERα positive BC develops, it is crucial to investigate both how this protein is regulated and which genes are modulated by it. MicroRNAs (miRNAs) control gene expression post-transcriptionally by interacting through sequence complementarity to their target transcripts. Through a microarray approach, we identified the subset of miRNAs modulated by ERα, that include up-regulation of miRNAs derived from the processing of two paralogous primary (pri-) transcripts, pri-miR-17-92 and pri-miR-106a-363. Characterisation of the miR-17-92 locus confirmed that the ERα target protein c-MYC binds its promoter in an estrogen-dependent manner. These findings indicated that miRNAs derived from these pri-miRNAs (miR-18a, miR-19b and miR-20b) target and down-regulate ERα, whilst a subset of pri-miRNA-derived mature miRNAs inhibit protein translation of the ERα transcriptional p160 co-activator, AIB1. Therefore, different subsets of the miRNAs identified act as part of a negative autoregulatory feedback loop. We observed that levels of pri-miR-17-92 increase earlier than the mature miRNAs derived from it, implicating precursor cleavage modulation after transcription. Pri-mir-17-92 is immediately cleaved by Drosha to pre-miR-18a, indicating that its regulation occurs during the formation of the mature molecule from the precursors. Furthermore, we wanted to explore the new kinases that regulate the ERα activity. Thereby, we performed kinome screening (by RNAi technologies) to determine kinases that regulate ERα in MCF-7 BC cells and identified a novel kinase, LMTK3, which acts as positive regulator of ERα's transcriptional activity. This could be a new therapeutic target and/or a novel biomarker for BC, although further studies are required to validate this. Together, these studies identify new transcriptional and translational factors that regulate ERα expression in BC.
Supervisor: Stebbing, Justin; Castellano, Leandro Sponsor: Breast Cancer Campaign
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral