Date of Award

Spring 2018

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Assoc. Professor Leonie Young

Second Supervisor

Professor Arnold Hill

Keywords

Breast Neoplasms; Diagnostic Techniques, Endocrine; Transcription Factors

Abstract

Tamoxifen has been the gold standard treatment of oestrogen receptor positive breast cancer for over 40 years. While its use has significantly improved the outlook for breast cancer patients, up to 40% of patients relapse while on therapy. Steroid receptor co-activator 1 (SRC-1) is a master regulatory protein which is overexpressed in breast cancer. It is associated with high grade tumours, disease recurrence and is an independent predictor of poor disease-free survival. SRC-1 interacts with nuclear receptors and other transcription factors to initiate transcriptional networks and regulate downstream genes which enable the cell to evade therapy. Here, a top-down approach to map out the transcriptional network, regulated by SRC-1 in endocrine resistant breast cancer was taken. RNA-sequencing was performed to identify the transcriptional targets of SRC-1. Molecular characterization identified E2F7, NFIA, DEK, SMAD2, SMARCA1, ASCL1 and TRPS1 as SRC-1-regulated transcription factors/chromatin remodellers. Rapid immunoprecipitation of mass endogenous proteins was employed to uncover SRC-1 interacting partners. STAT1 was confirmed as an SRC-1-interacting transcription factor in endocrine resistant breast cancer. Extended analysis of the SRC-1 effector target gene network revealed genes important in activating cell cycle, proliferation and pathways in cancer. Concerted activity of the SRC-1-mediated network is responsible for driving the highly migratory and proliferative phenotypes of endocrine resistant breast cancer. Moreover, they play a significant role in regulating the undifferentiated tumour population. Upon clinical investigation, high expression of this SRC-1-regulated network is predictive of poor disease-free survival in a tamoxifen-treated patient population. This study provides important insight into a SRC-1-STAT1 complex initiating a transcriptional cascade and regulating key genes involved in endocrine resistance.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

7.7 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2018.

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