Basal-like breast cancers (BLBC) are an aggressive sub-type of breast cancer which associates with high rates of proliferation and metastasis. However, the molecular mechanisms underlying these tumours are still largely unknown as most BLBC are also triple-receptor negative, which is defined by the lack of expression of oestrogen (ER) and progesterone (PR) receptors, with normal HER2 status. Consequently, there are currently no targeted therapies available for these tumours, which display the worst prognosis of all breast cancer subtypes. TP53 mutations occur within 20% of all breast tumours, however, this rate is observed to increase dramatically to approximately 85% within the basal-like subtype. Moreover, TP53 missense mutations can lead to the production of mutant proteins which possess novel oncogenic capabilities, known as Gain-of-Function (GOF) p53 mutants. These GOF mutants may display wild-type protein conformation (contact mutants) or exhibit conformational alterations to the tertiary protein structure (structural mutants). We have shown that siRNA-mediated knockdown of endogenous mutant p53, particularly contact GOF mutants significantly reduces survival of BLBC cells. We also demonstrate that contact, but not structural, p53 mutant proteins can directly bind to the transcription factor Etsl, and are also involved in upregulation of its expression. We show that mutant p53 interaction with Etsl is a critical event for both survival of these cells and co-regulation of downstream target genes. We have identified several novel mutant p53-specific transcriptional targets, some of which play important roles in the proliferation and survival of BLBC cells. Additionally, we have putatively detected an alternatively-spliced p53 protein isoform following over-expression of a structural GOF p53 mutant in non-tumourigenic and tumour-derived cell lines.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:680241 |
| Date | January 2014 |
| Creators | Oram, L. |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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