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Targeting γ-secretase in breast cancer

Authors Han J, Shen

Received 16 March 2012

Accepted for publication 17 April 2012

Published 21 June 2012 Volume 2012:4 Pages 83—90

DOI https://doi.org/10.2147/BCTT.S26437

Review by Single-blind

Peer reviewer comments 3

Jianxun Han,1 Qiang Shen2

1Department of Chemical Engineering and Applied Chemistry, University of Toronto, 2Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada

Abstract: γ-secretase complexes are multisubunit protease complexes that perform the intramembrane cleavage of more than 60 type-I transmembrane proteins, including Notch receptors. Since dysregulated Notch signaling has been implicated in the tumorigenesis and progression of breast cancer, small molecule γ-secretase inhibitors (GSIs) are being tested for their therapeutic potential in breast cancer treatment in several clinical trials. Here, the structure of γ-secretase complex and the development of GSIs are briefly reviewed, the roles of Notch and several other γ-secretase substrates in breast cancer are discussed, and the difference between γ-secretase inhibition and Notch inhibition, as well as the side effects associated with GSIs, are described. A better understanding of molecular mechanisms that affect the responsiveness of breast cancer to GSI might help to develop strategies to enhance the antitumor activity and, at the same time, alleviate the side effects of GSI.

Keywords: γ-secretase, GSI, Notch, breast cancer

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