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Identification of Molecular Mediators of Endocrine Resistant and Brain Metastatic Breast Cancer Through Analysis of Omics Data.

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thesis
posted on 11.03.2022, 10:15 authored by Nicola Cosgrove

Breast cancer metastases is one of the leading causes of cancer related death in women worldwide. Our fundamental understanding of treatment resistance, disease progression and metastasis in cancer has greatly improved with the advent of -omic technologies. However, a deeper understanding of the molecular complexity, in particular, in the context of brain metastasis is still lacking. In this thesis, through interrogation of high through-put transcriptomic, genomic and other data, clinically relevant molecular mediators of endocrine resistant and brain metastatic breast cancer are identified.


Estrogen receptor positive (ER+) cancer accounts for ≈70% of all breast cancer cases, with endocrine resistance a major clinical problem. In results Chapter 2, elucidation of the role p160 proteins, SRC-1 and AIB1, play in endocrine resistance is given. Specifically, a previously under appreciated novel role for Nucleosome Remodeling and Deacetylase (NuRD) complex mediated gene repression is demonstrated, along with identification of PARP1 as common to p160 interactomes in endocrine resistant cells. Moreover, data here, underscores the necessity to better understand the role of epigenetic aberrations in breast cancer metastases, in particular in the context of treatment resistance and clinically relevant receptor discordance.


In Chapter 3 and 4, along with intrinsic molecular subtype switching observed in brain metastases, most prominent in ER+ patients; an unprecedented subtype specific analysis of molecular alterations in brain metastatic breast cancer is provided, where collectively, this study will serve as a critical reference for future transcriptomic studies of brain metastases. Lastly, in Chapter 4, DNA repair deficiency is found to be enriched in brain metastatic disease. Compelling pre-clinical data indicates homologous recombination deficiency (HRD) specifically may be a key therapeutic vulnerability to exploit for treatment of breast cancer brain metastases, and should inform future clinical studies.


In conclusion, work presented here comprehensively characterises novel molecular mediators of endocrine resistant and brain metastatic breast cancer with potential therapeutic implications for treatment.

Funding

Breast Cancer Ireland

History

First Supervisor

Prof. Leonie Young

Second Supervisor

Dr. Simon Furney

Comments

Submitted for the Award of Doctor of Philosophy to the Royal College of Surgeons in Ireland, 2021.

Published Citation

Cosgrove N. Identification of molecular mediators of endocrine resistant and brain metastatic breast cancer through analysis of omics data. [PhD Thesis] Dublin: Royal College of Surgeons in Ireland; 2021

Degree Name

Doctor of Philosophy (PhD)

Date of award

31/05/2021

Programme

  • Doctor of Philosophy (PhD)

Research Area

  • Cancer