gamma-secretase inhibition promotes cell death, Noxa upregulation and sensitization to BH3 mimetic ABT-737 in human breast cancer cells.

Abstract : ABSTRACT: INTRODUCTION: Inappropriate Notch signalling, downstream of -secretase activity, is understood to have tumor-promoting function and to be associated with poor outcome in cancer, of the breast in particular. The molecular basis of anti-tumoral effects of its inhibitors, remain however poorly characterized. Moreover, the effects of their combination with the pro-apoptototic pharmacological inhibitor of Bcl2/BclxL, ABT-737, have never been evaluated. In this study, we thus specifically addressed the biological consequences of targeting -secretase and Bcl2/BclxL, alone or simultaneously, in breast cancer cell lines as well as in a novel human breast cancer ex vivo assay. METHODS: Using in vitro 2D or 3D cultures of breast cancer cells plus a novel preclinical short term ex vivo assay that correctly maintains human mammary tissue integrity and preserves tumor microenvironment, we tested the effects of the pharmalogical -secretase inhibitor GSIXII used as a single agent or in combination with ABT-737. RESULTS: We show herein that the -secretase inhibitor GSIXII, efficiently induces apoptosis in breast cancer cell lines by a process that relies on the induction of Noxa, a pro-apoptotic Bcl2-homology 3 domain (BH3)-only protein of the Bcl-2 family that functions as an inhibitor of anti-apoptotic Mcl1. GSIXII also targets mammary cancer stem-like cells since it dramatically prevents in vitro mammosphere formation. Moreover, combining GSIXII treatment with ABT-737, a BH3-mimetic inhibitor of additional anti-apoptotic proteins such as Bcl-2 and Bcl-xL leads to both synergistic apoptotic response in breast cancer cells and to an inhibitory effect on mammosphere formation. These effects are also found when a Notch transcriptional inhibitor, SAHM1, is used. Finally, we evaluated individual human tumor responses to -secretase inhibition alone or in combination with ABT-737 in ex vivo assays. Analysis of a series of 30 consecutive tumors indicated that a majority of tumors are sensitive to apoptosis induction by GSIXII and that association of GSIXII with ABT-737 leads to an enhanced induction of apoptosis in tumor cells. CONCLUSIONS: We thus provide evidence that -secretase, and downstream Notch signalling, are relevant targets in breast cancer. GSIXII, used as single agent or in combination with clinically relevant BH3-mimetics, is a promising innovative pro-apoptotic strategy to treat mammary tumors.
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Breast Cancer Research, BioMed Central, 2012, 14 (3), pp.R96. 〈10.1186/bcr3214〉
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Céline Séveno, Delphine Loussouarn, Sophie Bréchet, Mario Campone, Philippe Juin, et al.. gamma-secretase inhibition promotes cell death, Noxa upregulation and sensitization to BH3 mimetic ABT-737 in human breast cancer cells.. Breast Cancer Research, BioMed Central, 2012, 14 (3), pp.R96. 〈10.1186/bcr3214〉. 〈inserm-00713823〉

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