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  • Original Article
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Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2

Abstract

Evasion of cell death is fundamental to the development of cancer and its metastasis. The role of the BCL-2-mediated (intrinsic) apoptotic program in these processes remains poorly understood. Here we have investigated the relevance of the pro-apoptotic protein BIM to breast cancer progression using the MMTV-Polyoma middle-T (PyMT) transgenic model. BIM deficiency in PyMT females did not affect primary tumor growth, but substantially increased the survival of metastatic cells within the lung. These data reveal a role for BIM in the suppression of breast cancer metastasis. Intriguingly, we observed a striking correlation between the expression of BIM and the epithelial to mesenchymal transition transcription factor SNAI2 at the proliferative edge of the tumors. Overexpression and knockdown studies confirmed that these two genes were coordinately expressed, and chromatin immunoprecipitation analysis further revealed that Bim is a target of SNAI2. Taken together, our findings suggest that SNAI2-driven BIM–induced apoptosis may temper metastasis by governing the survival of disseminating breast tumor cells.

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Acknowledgements

We are grateful to K Rogers, L Whitehead, C Nowell for help with imaging, K Birchall, L Reid and G Siciliano for animal husbandry; B Helbert and C Young for mouse genotyping; K Breslin, M Robati and K Liu for technical assistance. We thank D Metcalf and JM Adams for useful discussion and advice, LA O’Reilly for antibodies and D Huang for knockout MEF cell lines. This work was supported by the National Health and Medical Research Council, Australia (NHMRC, 461221 and 1016701); NHMRC IRIISS; the Victorian State Government through Victorian Cancer Agency funding of the Victorian Breast Cancer Research Consortium and Operational Infrastructure Support; the Australian Cancer Research Foundation; and The National Breast Cancer Foundation. DM was supported by a NBCF Early Career Fellowship, RLA by a senior NBCF Fellowship, and SAB by a NHMRC Postgraduate Scholarship #1017256. JEV and GJL were supported by an NHMRC Australia Fellowship and Research Fellowship (637307), respectively.

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Correspondence to G J Lindeman or J E Visvader.

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Merino, D., Best, S., Asselin-Labat, ML. et al. Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2. Oncogene 34, 3926–3934 (2015). https://doi.org/10.1038/onc.2014.313

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