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
