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Title: Identification of genes associated with endocrine resistance in breast cancer
Author: Burmi, Rajpal Singh
ISNI:       0000 0004 2749 3028
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2006
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available