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Title: The role of MAF, an androgen regulated transcription factor in prostate cancer
Author: O'Hanlon Brown, Ciara
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Prostate cancer is a common, relatively asymptomatic tumour which predominantly affects an elderly population. The majority of prostate cancers are Androgen Receptor (AR) positive and demonstrate androgen dependent growth. Androgen deprivation therapy is the cornerstone of prostate cancer treatment. Understanding the androgen response in prostate cancer is thus central to understanding the molecular biology of the disease. Microarray analysis of the androgen response in the LNCaP prostate cancer model has previously identified MAF as the highest ranking transcription factor among genes whose expression is significantly upregulated in response to the synthetic androgen R1881. MAF is a member of the Maf family, a group of leucine zipper transcription factors widely expressed in human tissues. Little is known regarding the role MAF plays in the prostate and in prostate cancer. This project seeks to address this question. The results presented here confirm the androgen regulation of MAF at an mRNA and protein level in LNCaP cells. This regulation has been studied further through analysis of AR transactivation of the MAF promoter. Knockdown of MAF expression using siRNA has an inhibitory effect on the growth of LNCaP cells. Knockdown was also seen to inhibit the expression of a subset of androgen regulated genes. Microarray analysis of gene expression in LNCaP cells was performed follwing siRNA knockdown of MAF expression and has identified a set of genes that may be regulated by MAF in LNCaP cells. Immunohistochemical analysis of a prostate cancer tissue microarray was performed and this demonstrated MAF expression in prostate cancer tissue samples and in normal prostate epithelium. Interestingly it appears that the level of MAF expression in prostate cancers is inversely correlated with increasing Gleason grade. MAF expression appears greatly reduced/absent in metastatic prostate cancers. Taken together, this data highlights MAF as an androgen regulated transcription factor. We propose that MAF plays a role in the down stream propogation of androgen signalling in LNCaP cells. Loss of MAF expression with increasing Gleason grade and in metastatic prostate cancer represents dedifferentiation of prostate cancer epithelial cells with disease progression. It may thus delineate a subset of prostate cancers less likely to respond to androgen deprivation therapy.
Supervisor: Buluwela, Laki ; Ali, Simak ; Waxman, Jonathan Sponsor: Joron Charitable Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available