Date of Award

Summer 2018

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Darran O'Connor

Second Supervisor

Dr Triona Ni Chonghaile

Funder/Sponsor

Irish Cancer Society

Keywords

Breast Neoplasms, Neuropeptides

Abstract

While survival rates for breast cancer patients in Ireland is on the rise, a significant proportion of women will unfortunately succumb to this malicious disease. Previously, we identified high expression of the neuropeptide CART to indicate worse survival, and worse response to tamoxifen, in a subset of breast cancer patients. While the role of CART in other disease states is better understood, the role of CART in breast cancer remains elusive. To this end, we aimed to further our understanding of the role CART plays in estrogen receptor positive (ER+) breast cancer.

Through transcriptomic profiling, we identified a number of genes, both upregulated and downregulated by CART, to be potential genes controlled by the Estrogen Receptor alpha (ERα). Owing to this finding, we hypothesized that CART may alter the binding partners of ERα, and understanding what complexes are recruited to ERα by CART may not only help us understand the role of CART in ER+ breast cancer better, but also potentially identify actionable future targets. Our results indicated that CART may potentially promote an interaction between ERα and two novel ERα interactors, a zincfinger protein (WIZ) and a poorly understood E3 ligase (HECTD4). Additionally, we identified members of the BAF-chromatin remodelling complex to be significantly enriched interactors in the presence of CART. One identified subunit of this complex, SMARCD1, stood out as a potentially interesting target due to previous research highlighting its importance in nuclear receptor function. Knockdown of SMARCD1 resulted in altered morphology and growth of ER+ breast cancer cells, and caused transcriptional deregulation in a gene-specific manner. While knockdown of SMARCD1 did not further sensitize cells to anti-endocrine therapy, we identified a number of other BAF-complex subunits to be significantly upregulated in cell line models of anti-endocrine resistance.

We suggest that a potential mechanism by which CART indicates worse survival is through altered recruitment of BAF-complex subunits to ERα, and certain members of this complex may be attractive targets worthy of future interrogation.

Creative Commons License

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

File Size

9.43 MB

Comments

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

Available for download on Thursday, May 30, 2019

Share

COinS