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Title: Role of Claudin-5 in the progression of human breast cancer
Author: Escudero-Esparza, Astrid
ISNI:       0000 0004 2750 6896
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2010
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A key step in metastasis is the interaction and penetration of the vascular endothelium by cancer cells. Tight Junctions (TJ) are located between the cancer epithelial cells themselves functioning in an adhesive manner, and between the endothelial cells. They represent a critical barrier which the cancer cells must overcome in order to penetrate and initiate metastasis. The Claudin family are TJ proteins expressed in both endothelial and epithelial cells. They participate in the formation of tissue barriers between different tissue compartments by regulating the efflux of molecules through TJ complexes. This thesis examined the level of expression and distribution of Claudin-5 in human breast cancer tissues and analysed them against clinical parameters. The effect of knockdown and forced expression of Claudin-5 in the MDA-MB-231 aggressive breast cancer cell line and in the HECV human endothelial cell line was also examined. Results revealed that Claudin-5 is aberrantly expressed in human breast cancer and has a link to the clinical outcome of the patient. Patients who died from breast cancer had higher levels of Claudin-5 compared with patients who remained disease-free. Furthermore, patients whose tumours expressed high levels of Claudin-5 had shorter survival than those with low levels. Investigating in vitro the effect of altering levels of expression of Claudin-5 in MDA-MB-231and HECV cells revealed that the role of Claudin-5 was not primarily in keeping the cell barrier tight suggesting little function in the TJ of these cells, in fact a link was identified between Claudin-5 and cell motility. Furthermore, a possible link between Claudin-5 and N-WASP, and Claudin-5 and ROCK was demonstrated when interactions between these proteins were seen in both cell lines. Moreover, cell motility was assessed following treatment with N-WASP inhibitor, Arp2/3 inhibitor and ROCK inhibitor. Results show that the knockdown of Claudin-5 in HECV cells masked their response to N-WASP inhibitor, Arp2/3 inhibitor and ROCK inhibitor. A parallel response was observed in the knockdown of Claudin-5 in MDA-MB-231 after treatment with N-WASP inhibitor and Arp2/3 inhibitor however treatment with ROCK inhibitor did not reveal any differences in motility in this particular cell line. This study portrays a very new and interesting role for Claudin-5 in cell motility involving the N-WASP and ROCK signalling cascade indicating a possible role for Claudin-5 in the metastasis and progression of human breast cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available