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Title: Nicastrin and the gamma-secretase complex in breast cancer
Author: Rashied, Sabeena Rasul
ISNI:       0000 0004 2702 562X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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γ‐secretase is a membrane‐bound proteolytic complex, formed by nicastrin, APH1, presenilin and pen‐2, which cleaves over sixty known substrates, including Notch and Ecadherin, thus regulating cellular processes such as proliferation and adhesion. High levels of nicastrin have been demonstrated in 47.3 % (n=1050) high tumour grade breast tissues, whereas it is absent in 100% normal human breast (n=40). Although the mechanism for nicastrin up‐regulation in breast cancer is unknown, preliminary data suggests posttranscriptional regulation. Therefore, γ‐secretase is an important therapeutic target in breast cancer. GSI1, a commercial γ‐secretase inhibitor is cytotoxic exclusively for breast cancer cell lines, whereas non‐tumourigenic breast cells are not affected. GSI1 triggers G2/M arrest, culminating in apoptosis through down‐regulation of XIAP, Bcl‐2, Bax and Bcl‐XL in breast cancer cells. In addition, similar cytotoxicity has been found in a panel of cell lines derived from several types of cancer. We discuss whether the cytotoxic effect of GSI1 in breast cancer cell lines is mediated through inhibition of γ‐secretase or the proteasome. RNA interference of individual γ‐secretase components indicates that NCSTN knock‐down elicits 55% cell growth reduction, whereas knock‐down of the other complex components does not inhibit cell growth to the same extent. In addition, NCSTN siRNA reduces invasion in breast cancer cells. Disseminated and circulating tumour cells (CTCs) are clinically used as indicators of metastasis. Nicastrin has been found to be expressed by a rare population of cells in bone marrow aspirates and in CTCs from breast cancer patients with high risk of relapse. Thus, from the pharmacological point of view, nicastrin represents a novel therapeutic target. In addition, it is a novel biomarker for breast cancer with potential diagnostic applications.
Supervisor: Yague, Ernesto ; Buluwela, Laki ; Slade, Martin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral