Wiskott Aldrich Syndrome protein and it's role in breast cancer

Pereira, Gordon Anthony 2014. Wiskott Aldrich Syndrome protein and it's role in breast cancer. MD Thesis, Cardiff University. Item availability restricted.

Preview	PDF - Accepted Post-Print Version Download (6MB) | Preview
	PDF - Supplemental Material Restricted to Repository staff only Download (1MB)

Abstract

Breast Cancer continues to be the most common form of cancer in women. The ability of tumour cells to spread from primary and metastatic tumours is the primary cause of death in patients with cancer. Thus, it rightly follows that significant research is dedicated to the pathways and mechanisms controlling metastases in order to guide therapeutic approaches. Wiskott Aldrich Syndrome [WAS] is an X-linked recessive condition with immunodeficiency as the clinical manifestation. It is caused by mutations of the Wiskott Aldrich Syndrome [WAS] gene, which codes for a cytoplasmic protein with multiple functions. Two major complexes that are linked to the NWASP family, namely the ERM family and Rho GTPases are aberrantly expressed in human breast cancer. Additionally, X chromosome inactivation which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been shown to occur more frequently in breast and ovarian cancer patients. Individuals with WAS are known to have skewed X inactivation. In addition, they are more susceptible to certain forms of malignancy, primarily haematological. This formed the basis of the present study, which sought to elucidate the role of WAS protein in human breast cancer, and to determine if it plays a role as a tumour suppressor. We also attempted to determine its biological role and association with clinical outcome in patients with breast cancer. We examined the correlation of NWASP with human breast cancer in vitro, in vivo and in human breast cancer tissue. Immunohistochemistry studies of frozen sectioned human breast cancer tissues revealed that breast cells stained positively for NWASP and that cancer cells in tumour tissues stained very weakly. Quantitative RT-PCR revealed that breast cancer tissues had significantly lower levels of NWASP compared to normal background breast tissue. Although no significant correlation was found with tumour grade and TNM staging, lower levels of transcript were seen to correlate with clinical outcome following a 10 year follow up. The invasive human breast cancer cell line, MDA-MB-231 was used to over-express NWASP, with over-expression resulting in cells with reduced motility and invasion, increased adhesion to the basement membrane and more significantly, reduced tumour growth in vivo. This has important implications in understanding the mechanism whereby cancer cells become more motile and presents an interesting tool in analysing the progression of human breast cancer. 12

Item Type:	Thesis (MD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Date of First Compliant Deposit:	30 March 2016
Last Modified:	23 Oct 2023 15:23
URI:	https://orca.cardiff.ac.uk/id/eprint/61762

Actions (repository staff only)

Edit Item