Investigating the role of iASPP in normal prostate development and prostate tumourigenesis

Thesis

Loss of TP63 expression in the prostate epithelium is a hallmark of invasive prostate cancer. An inability of prostate epithelial cells to undergo apoptosis, a process regulated by both TP63 and TP53, is a feature of their malignant transformation. p53 mutations in prostate cancer are uncommon, being mainly associated with advanced metastatic disease. Therefore it is likely that the inability of wild-type p53 to initiate and execute apoptosis is due to molecular alterations elsewhere in the apoptotic pathway. iASPP is an inhibitory member of the ASPP family of proteins and is known to inhibit p53-mediated apoptosis and regulate p63 function.

In this work we have investigated how iASPP can affect normal prostate development and prostate tumourigenesis. By utilising an iASPP-deficient mouse model, we show that iASPP plays a key role in normal prostate development and homeostasis by maintaining the TP63-positive basal cell lineage of the prostate epithelium. The loss of iASPP is associated with alterations in differentiation, proliferation and apoptosis, resulting in a smaller organ size. Furthermore, by using both benign and malignant human prostate tissue we show that changes in iASPP expression have prognostic value. Nuclear and cytoplasmic iASPP expression are significantly increased in prostate cancer and associate with poor clinical outcome. Increased nuclear iASPP associates with cells that express high levels of TP53, suggesting that iASPP cooperates with mutant p53 to enhance its gain-of-function activity. Analysis of iASPP expression in both the mouse and human prostate epithelium led to the identification of iASPP as a novel junctional protein. In vitro studies suggest that membranous iASPP functions to add strength and stability to cell-to-cell contacts, and its' reduction increases cellular invasion and motility. Finally, iASPP significantly reduces chemosensitivity of prostate cancer cells, given the evident dual functionality of iASPP as both an oncoprotein and a tumour suppressor, depending on cellular localisation, targeting this protein to improve therapy efficacy may be challenging.

Authors: Morris, E; Emma victoria Morris

• Publication date: 2013
• DOI: 10.5287/ora-002wqxbk7
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: p53; p63; prostate; iASPP
• Subjects: Medical Sciences