title: 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.
authors.affiliation: 1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Merino
authors.affiliation: 1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: S A
authors.initials: SA
authors.lastname: Best
authors.affiliation: 1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: M-L
authors.initials: ML
authors.lastname: Asselin-Labat
authors.affiliation: 1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Vaillant
authors.affiliation: 1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Pal
authors.affiliation: 1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: R A
authors.initials: RA
authors.lastname: Dickins
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: R L
authors.initials: RL
authors.lastname: Anderson
authors.affiliation: 1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.affiliation: 1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Bouillet
authors.affiliation: 1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia [3] Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Lindeman
authors.affiliation: 1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Visvader
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins