Department of Chemical Engineering and Applied Chemistry, University of Toronto, Ontario, Canada.
Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
Breast Cancer (Dove Med Press). 2012 Jun 21;4:83-90. doi: 10.2147/BCTT.S26437.
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.
γ-分泌酶复合物是多亚基蛋白酶复合物，可对包括 Notch 受体在内的 60 多种Ⅰ型跨膜蛋白进行膜内切割。由于 Notch 信号的失调与乳腺癌的发生和进展有关，因此小分子 γ-分泌酶抑制剂（GSIs）正在多项临床试验中被测试用于乳腺癌的治疗潜力。在这里，简要回顾了 γ-分泌酶复合物的结构和 GSI 的发展，讨论了 Notch 和其他几种 γ-分泌酶底物在乳腺癌中的作用，以及 γ-分泌酶抑制和 Notch 抑制之间的区别，以及与 GSI 相关的副作用。更好地了解影响乳腺癌对 GSI 反应性的分子机制可能有助于制定策略来增强抗肿瘤活性，同时减轻 GSI 的副作用。
