Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Identification of genes associated with endocrine resistance in breast cancer

Burmi, Rajpal Singh. 2006. Identification of genes associated with endocrine resistance in breast cancer. PhD Thesis, Cardiff University.

[thumbnail of U584099.pdf] PDF - Accepted Post-Print Version
Download (37MB)

Abstract

Resistance to tamoxifen, Faslodex and oestrogen-deprivation represents a major hurdle in breast cancer management, and determining the underlying factors driving resistant growth may improve treatment and prognosis. Expression microarrays (Atlas Plastic Human 12K Microarrays GeneSifter software) were used to identify genes altered in breast cancer models with acquired resistance to tamoxifen (TamR) or Faslodex (FasR) versus their parental MCF-7 cell line through cluster analysis, t-testing and ontological examination. Selected genes were verified by PCR, Western blotting and immunocytochemistry. Alongside known breast cancer-related genes (PEA3, vitronectin), two novel genes increased in resistance were the securin/cell-cycle regulator Pituitary Tumour-Transforming Gene-1 (PTTG1) (p=0.013 and p=0.013 in TamR and FasR cells respectively), and GDNF receptor-a3 (GFRa3) (p=0.014 in TamR cells) that promotes cell survival signalling via its coreceptor RET. Increased levels of PTTG1, GFRa3, or their family members were observed in further endocrine resistant states, including an additional faslodex-resistant model that has progressed to a highly-aggressive state (FasR-Lt) and cells resistant to oestrogen-deprivation (X-MCF-7). PTTG1 and GFRa3 induction in response to an anti-EGFR agent in the resistant models implicated these genes in limiting its growth inhibitory effect, and GFR<x3 ligand (arternin) was shown to overcome anti-EGFR response (78% growth recovery). mRNA studies in clinical disease revealed a significant association of PTTG1 with lymph node spread (p=0.001), high tumour grade (p=0.001) and proliferation (p<0.001), while GFRa3 was enriched in ER-negative tumours (p=0.01), showing loss of tubular differentiation (p=0.04) and expressing EGFR (p=0.013), profiles implying roles in clinical resistance and aggressive tumour behaviour. Promisingly, PTTG1 or GFRo3 siRNA significantly reduced cell growth (by 72% p=0.003 and 81% p=0.004 respectively), proliferative capacity (by 23% p<0.001 and 32% p<0.001 respectively) and induced apoptosis (by 43% p=0.05 and 103% p=0.05 respectively) in resistant models. Cumulatively, these data indicate PTTG1 and GFRa3 may provide useful biomarkers and perhaps new therapeutic targets for multiple resistant states.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
ISBN: 9781303174575
Funders: Tenovus, Breast Cancer Campaign
Date of First Compliant Deposit: 30 March 2016
Last Modified: 09 Jan 2018 22:28
URI: https://orca.cardiff.ac.uk/id/eprint/55621

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics