Date of Award

2011

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr. L.S. Young

Keywords

Breast Neoplasms

Abstract

SRC-1 is a p160 nuclear receptor co-activator protein that has been implicated as an important mediator of breast cancer metastasis. A small number of direct SRC-1 target genes have been identified to date. The aim of this work was to verify the recently discovered SRC-1 target SlOOB and to adopt a genome wide approach using modern, high throughput technologies to identify new SRC-1 transcriptional targets.

To identify novel SRC-1 target genes luminal B LY2 breast cancer cells were used to perform the first ChlP-sequencing experiment of SRC-1. Affymetrix whole genome expression arrays were used to analyse gene expression in LY2 cells treated with SRC-1 siRNA in comparison with those treated scrambled siRNA to complement the ChlP-seq experiment. SRC-1 peaks within the genome were focused near transcription starts sites and often in close proximity to an estrogen response element. Three new putative SRC-1 target genes were selected for further validation.

ADAM22 is a transmembrane disintegrin protein that has been shown to mediate cell migration but has yet to be implicated in tumourigenesis. Knockout, overexpression and ChlP studies confirm ADAM22 as an SRC-1 target gene. Expression of ADAM22 was identified in 49% of patients with breast cancer and its expression was associated with an almost two fold increase in rate of disease relapse. Two other genes, namely BCAS3 and CUXl were identified and validated as SRC-1 target genes and both of these have a known role in breast tumour progression. Elevated levels of SlOOB were detectable in the blood of 10% of patients with breast cancer. Elevated serum SlOOB at time of diagnosis is an independent predictor of disease progression in breast cancer.

An unbiased, genome wide approach has identified a variety of novel, direct SRC-1 target genes. A series of molecular and translational studies have validated SlOOB as a clinically important and detectable target of SRC-1 while ADAM22, as transmembrane protein may offer the first therapeutic target to disrupt the central role of SRC-1 in mediating breast cancer metastasis.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

13,826 KB

Comments

A thesis submitted to the Royal College of Surgeons in Ireland for the degree of Doctor of Philosophy from the National University of Ireland in 2011.

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