LRH-1 as a target for the development of new breast cancer therapies
File(s)
Author(s)
Kyle, Fiona
Type
Thesis
Abstract
Estrogen drives the growth and development of estrogen receptor alpha (ERα) positive breast cancer and ERα is the target for hormonal therapies that inhibit its activity. A substantial proportion of patients become resistant to these therapies, demonstrating a need for new therapies.
Gene expression microarray studies have been performed with a view to identifying potential novel therapeutic targets, biomarkers or forming the basis of identifying a molecular signature for endocrine resistance. These studies have identified candidate genes whose expression is altered in models of endocrine resistance. Investigation of the molecular pathways particularly highlights cell survival and regulation of apoptosis and indicates that these pathways play a key role in the development of resistance.
Microarray analysis also identified the liver receptor homolog 1 (LRH-1, NR5A2), a member of the nuclear receptor superfamily of transcription factors, as an estrogen regulated gene in MCF7 cells. Functional analysis showed that LRH-1 regulates breast cancer cell growth, acting in part by regulating ERα expression. Gene expression profiling of MCF-7 cells following RNAi for LRH-1 identified LRH-1 regulated genes. LRH-1 is known to regulate expression of CYP19A1 (aromatase), responsible for estrogen biosynthesis through the aromatisation of aromatase. Together, our findings identify LRH-1 as a potential therapeutic target for breast cancer treatment. Results of screening for small molecule inhibitors of LRH-1 will be presented, together with analysis of gene expression profiling for LRH-1 regulated genes.
Gene expression microarray studies have been performed with a view to identifying potential novel therapeutic targets, biomarkers or forming the basis of identifying a molecular signature for endocrine resistance. These studies have identified candidate genes whose expression is altered in models of endocrine resistance. Investigation of the molecular pathways particularly highlights cell survival and regulation of apoptosis and indicates that these pathways play a key role in the development of resistance.
Microarray analysis also identified the liver receptor homolog 1 (LRH-1, NR5A2), a member of the nuclear receptor superfamily of transcription factors, as an estrogen regulated gene in MCF7 cells. Functional analysis showed that LRH-1 regulates breast cancer cell growth, acting in part by regulating ERα expression. Gene expression profiling of MCF-7 cells following RNAi for LRH-1 identified LRH-1 regulated genes. LRH-1 is known to regulate expression of CYP19A1 (aromatase), responsible for estrogen biosynthesis through the aromatisation of aromatase. Together, our findings identify LRH-1 as a potential therapeutic target for breast cancer treatment. Results of screening for small molecule inhibitors of LRH-1 will be presented, together with analysis of gene expression profiling for LRH-1 regulated genes.
Version
Open Access
Date Issued
2014-09
Date Awarded
2015-12
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Ali, Simak
Buluwela, Laki
Coombes, Charles
Sponsor
Cancer Research UK
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)