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Title: The role of the oestrogen receptor interacting proteins, FKBPL and RBCK1, in breast cancer signalling
Author: Donley , Christopher Blair
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2013
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The aim of this thesis was to further characterise the role of FKBPL and RBCKl in the ERa: signalling pathway. Both RBCKl and FKBPL were found to interact with Hsp90 and ER and this interaction was enhanced by E2. Both RBCKl and FKBPL appear [0 be regulated by the oestrogen. However, both FKBPL and RBCKl bind along with ER« to the promoter of pS2, suggesting a potential role for FKBPL and RBCKl in ERa: trans-activation. RBCKl was shown [0 be the ubiquitin ligase for FKBPL. RBCKl was shown to facilitate the attachment of linear chains of ubiquitin to FKBPL. SiRNA knockdown of RBCKl resulted in increased levels of FKBPL in the T47D cell line, but inversely down-regulation of RBCKl in the MCF-7 cell line resulted in a reduction in FKBPL protein levels, suggesting that there is differential regulation of FKBPL by RBCKl depending on the cell line. FKBPL also appears to have a potential role in regulating the self-ubiquitination of RBCK1. RBCKl was also shown to regulate p21 transcription in a mechanism that was independent of p53. RBCKl siRNA knockdown resulted in increased p21 levels but overexpression of RBCKl in the MCF-7 cell line also increased p21 protein levels, suggesting that RBCKl regulates p21 levels through some post-translation modification, possibly through Akt. High levels of FKBPL and RBCKl were independently shown to correlate with increased patient survival in microarray data sets, and a combination of both high RBCKl and FKBPL was the most favourable phenotype. Finally the levels of RBCKl were shown to reduce the efficacy of tamoxifen in the MCF-7 and T47D cell lines, high RBCKl correlated with decreased tamoxifen efficacy. This effect was mirrored in a • micro-array data set, showing high RBCKl predicted worse response for tamoxifen therapy. Therefore RBCKl and FKBPL have potential as novel biomarkers for endocrine therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available