Negative Selection and Chromosome Instability Induced by Mad2 Overexpression Delay Breast Cancer but Facilitate Oncogene-Independent Outgrowth
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2016 Jun 21;15(12):2679-91.
doi: 10.1016/j.celrep.2016.05.048.
Epub 2016 Jun 9.
Konstantina Rowald  1 ,
Martina Mantovan  1 ,
Joana Passos  1 ,
Christopher Buccitelli  2 ,
Balca R Mardin  2 ,
Jan O Korbel  2 ,
Martin Jechlinger  1 ,
Rocio Sotillo  3
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Affiliations
1 Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy.
2 Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
3 Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy; Division of Molecular Thoracic Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: r.sotillo@dkfz-heidelberg.de.
PMID: 27292643
PMCID: PMC4920917
DOI: 10.1016/j.celrep.2016.05.048
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Konstantina Rowald  et al.
Cell Rep .
2016 .
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2016 Jun 21;15(12):2679-91.
doi: 10.1016/j.celrep.2016.05.048.
Epub 2016 Jun 9.
Authors
Konstantina Rowald  1 ,
Martina Mantovan  1 ,
Joana Passos  1 ,
Christopher Buccitelli  2 ,
Balca R Mardin  2 ,
Jan O Korbel  2 ,
Martin Jechlinger  1 ,
Rocio Sotillo  3
Affiliations
1 Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy.
2 Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
3 Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy; Division of Molecular Thoracic Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: r.sotillo@dkfz-heidelberg.de.
PMID: 27292643
PMCID: PMC4920917
DOI: 10.1016/j.celrep.2016.05.048
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Abstract
Chromosome instability (CIN) is associated with poor survival and therapeutic outcome in a number of malignancies. Despite this correlation, CIN can also lead to growth disadvantages. Here, we show that simultaneous overexpression of the mitotic checkpoint protein Mad2 with Kras(G12D) or Her2 in mammary glands of adult mice results in mitotic checkpoint overactivation and a delay in tumor onset. Time-lapse imaging of organotypic cultures and pathologic analysis prior to tumor establishment reveals error-prone mitosis, mitotic arrest, and cell death. Nonetheless, Mad2 expression persists and increases karyotype complexity in Kras tumors. Faced with the selective pressure of oncogene withdrawal, Mad2-positive tumors have a higher frequency of developing persistent subclones that avoid remission and continue to grow.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Figures
Graphical abstract
Graphical abstract
Figure 1
Mad2 Overexpression Delays Kras -Driven…
Figure 1
Mad2 Overexpression Delays Kras -Driven Tumor Initiation and Leads to Phenotypic Variance (A)…
Figure 2
Mad2 Overexpression Increases Epithelial Cell…
Figure 2
Mad2 Overexpression Increases Epithelial Cell Turnover after 4 Days of Transgene Induction In…
Figure 3
3D Cultures Recapitulate Increased Proliferation…
Figure 3
3D Cultures Recapitulate Increased Proliferation and Apoptosis following Mad2 Induction (A) Representative immunofluorescence…
Figure 4
Time-Lapse Imaging of Organotypic Cultures…
Figure 4
Time-Lapse Imaging of Organotypic Cultures Reveals Error-Prone Mitosis because of Elevated Mad2 Levels…
Figure 5
Mad2 Overexpression Boosts Aneuploidy and…
Figure 5
Mad2 Overexpression Boosts Aneuploidy and Facilitates Tumor Persistence after Oncogene Withdrawal (A) SCNAs…
Figure 6
Elevated Levels of Mad2 Delay…
Figure 6
Elevated Levels of Mad2 Delay Her2 -Driven Breast Tumorigenesis without Affecting Aneuploidy (A)…
See this image and copyright information in PMC
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References
Boveri T. ANTON DOHBN. Science. 1912;36:453–468. - PubMed
Carter S.L., Eklund A.C., Kohane I.S., Harris L.N., Szallasi Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat. Genet. 2006;38:1043–1048. - PubMed
Cerami E., Gao J., Dogrusoz U., Gross B.E., Sumer S.O., Aksoy B.A., Jacobsen A., Byrne C.J., Heuer M.L., Larsson E. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–404. - PMC - PubMed
Chen G., Rubinstein B., Li R. Whole chromosome aneuploidy: big mutations drive adaptation by phenotypic leap. BioEssays. 2012;34:893–900. - PMC - PubMed
Chen G., Mulla W.A., Kucharavy A., Tsai H.-J., Rubinstein B., Conkright J., McCroskey S., Bradford W.D., Weems L., Haug J.S. Targeting the adaptability of heterogeneous aneuploids. Cell. 2015;160:771–784. - PMC - PubMed
MeSH terms
Aneuploidy Actions Search in PubMed Search in MeSH Add to Search
Animals Actions Search in PubMed Search in MeSH Add to Search
Apoptosis Actions Search in PubMed Search in MeSH Add to Search
Breast Neoplasms / metabolism Actions Search in PubMed Search in MeSH Add to Search
Breast Neoplasms / pathology Actions Search in PubMed Search in MeSH Add to Search
Carcinogenesis / metabolism Actions Search in PubMed Search in MeSH Add to Search
Carcinogenesis / pathology Actions Search in PubMed Search in MeSH Add to Search
Cell Cycle Checkpoints Actions Search in PubMed Search in MeSH Add to Search
Cell Proliferation Actions Search in PubMed Search in MeSH Add to Search
Cells, Cultured Actions Search in PubMed Search in MeSH Add to Search
Chromosomal Instability* Actions Search in PubMed Search in MeSH Add to Search
Chromosome Segregation / genetics Actions Search in PubMed Search in MeSH Add to Search
Epithelial Cells / metabolism Actions Search in PubMed Search in MeSH Add to Search
Epithelial Cells / pathology Actions Search in PubMed Search in MeSH Add to Search
Female Actions Search in PubMed Search in MeSH Add to Search
Humans Actions Search in PubMed Search in MeSH Add to Search
Mad2 Proteins / metabolism* Actions Search in PubMed Search in MeSH Add to Search
Mammary Neoplasms, Experimental / genetics* Actions Search in PubMed Search in MeSH Add to Search
Mammary Neoplasms, Experimental / pathology* Actions Search in PubMed Search in MeSH Add to Search
Mice Actions Search in PubMed Search in MeSH Add to Search
Mitosis Actions Search in PubMed Search in MeSH Add to Search
Oncogenes* Actions Search in PubMed Search in MeSH Add to Search
Phenotype Actions Search in PubMed Search in MeSH Add to Search
Proto-Oncogene Proteins p21(ras) / metabolism Actions Search in PubMed Search in MeSH Add to Search
Receptor, ErbB-2 Actions Search in PubMed Search in MeSH Add to Search
Spindle Apparatus / metabolism Actions Search in PubMed Search in MeSH Add to Search
Time-Lapse Imaging Actions Search in PubMed Search in MeSH Add to Search
Transgenes Actions Search in PubMed Search in MeSH Add to Search
Substances
Mad2 Proteins Actions Search in PubMed Search in MeSH Add to Search
ERBB2 protein, human Actions Search in PubMed Search in MeSH Add to Search
Receptor, ErbB-2 Actions Search in PubMed Search in MeSH Add to Search
Hras protein, mouse Actions Search in PubMed Search in MeSH Add to Search
Proto-Oncogene Proteins p21(ras) Actions Search in PubMed Search in MeSH Add to Search
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GEO Profiles
Gene
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Nucleotide (RefSeq)
Nucleotide (Weighted)
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Taxonomy via GenBank
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336045/ERC_/European Research Council/International
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Search in PubMed. Search in NLM Catalog. Add to Search. . 2016 Jun 21;15(12):2679-91. doi: 10.1016/j.celrep.2016.05.048. Epub 2016 Jun 9. Konstantina Rowald  1 , Martina Mantovan  1 , Joana Passos  1 , Christopher Buccitelli  2 , Balca R Mardin  2 , Jan O Korbel  2 , Martin Jechlinger  1 , Rocio Sotillo  3. Expand. Affiliations. 1 Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy. 2 Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. 3 Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy; Division of Molecular Thoracic Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: r.sotillo@dkfz-heidelberg.de. PMID: 27292643. PMCID: PMC4920917. DOI: 10.1016/j.celrep.2016.05.048. Free PMC article. Konstantina Rowald  et al. Cell Rep . 2016 . Free PMC article. Show details. Display options. Format. Search in PubMed. Search in NLM Catalog. Add to Search. . 2016 Jun 21;15(12):2679-91. doi: 10.1016/j.celrep.2016.05.048. Epub 2016 Jun 9. Authors. Konstantina Rowald  1 , Martina Mantovan  1 , Joana Passos  1 , Christopher Buccitelli  2 , Balca R Mardin  2 , Jan O Korbel  2 , Martin Jechlinger  1 , Rocio Sotillo  3. Affiliations. 1 Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy. 2 Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. 3 Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy; Division of Molecular Thoracic Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: r.sotillo@dkfz-heidelberg.de. PMID: 27292643. PMCID: PMC4920917. DOI: 10.1016/j.celrep.2016.05.048. Cite. Display options. Format. Abstract. Chromosome instability (CIN) is associated with poor survival and therapeutic outcome in a number of malignancies. Despite this correlation, CIN can also lead to growth disadvantages. Here, we show that simultaneous overexpression of the mitotic checkpoint protein Mad2 with Kras(G12D) or Her2 in mammary glands of adult mice results in mitotic checkpoint overactivation and a delay in tumor onset. Time-lapse imaging of organotypic cultures and pathologic analysis prior to tumor establishment reveals error-prone mitosis, mitotic arrest, and cell death. Nonetheless, Mad2 expression persists and increases karyotype complexity in Kras tumors. Faced with the selective pressure of oncogene withdrawal, Mad2-positive tumors have a higher frequency of developing persistent subclones that avoid remission and continue to grow. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved. Figures. Graphical abstract. Graphical abstract. Figure 1. Mad2 Overexpression Delays Kras -Driven… Figure 1. Mad2 Overexpression Delays Kras -Driven Tumor Initiation and Leads to Phenotypic Variance (A)… Figure 2. Mad2 Overexpression Increases Epithelial Cell… Figure 2. Mad2 Overexpression Increases Epithelial Cell Turnover after 4 Days of Transgene Induction In… Figure 3. 3D Cultures Recapitulate Increased Proliferation… Figure 3. 3D Cultures Recapitulate Increased Proliferation and Apoptosis following Mad2 Induction (A) Representative immunofluorescence… Figure 4. Time-Lapse Imaging of Organotypic Cultures… Figure 4. Time-Lapse Imaging of Organotypic Cultures Reveals Error-Prone Mitosis because of Elevated Mad2 Levels… Figure 5. Mad2 Overexpression Boosts Aneuploidy and… Figure 5. Mad2 Overexpression Boosts Aneuploidy and Facilitates Tumor Persistence after Oncogene Withdrawal (A) SCNAs… Figure 6. Elevated Levels of Mad2 Delay… Figure 6. Elevated Levels of Mad2 Delay Her2 -Driven Breast Tumorigenesis without Affecting Aneuploidy (A)… See this image and copyright information in PMC. Similar articles. Simultaneous reduction of MAD2 and BUBR1 expression induces mitotic spindle alterations associated with p53 dependent cell cycle arrest and death. Lentini L, Piscitello D, Veneziano L, Di Leonardo A. Lentini L, et al. Cell Biol Int. 2014 Aug;38(8):933-41. doi: 10.1002/cbin.10277. Epub 2014 Apr 10. Cell Biol Int. 2014. PMID: 24687487. The Mad1-Mad2 balancing act--a damaged spindle checkpoint in chromosome instability and cancer. Schuyler SC, Wu YF, Kuan VJ. Schuyler SC, et al. J Cell Sci. 2012 Sep 15;125(Pt 18):4197-206. doi: 10.1242/jcs.107037. Epub 2012 Oct 23. J Cell Sci. 2012. PMID: 23093575 Review. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Sotillo R, Schvartzman JM, Socci ND, Benezra R. Sotillo R, et al. Nature. 2010 Mar 18;464(7287):436-40. doi: 10.1038/nature08803. Epub 2010 Feb 21. Nature. 2010. PMID: 20173739 Free PMC article. Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. Silk AD, Zasadil LM, Holland AJ, Vitre B, Cleveland DW, Weaver BA. Silk AD, et al. Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):E4134-41. doi: 10.1073/pnas.1317042110. Epub 2013 Oct 16. Proc Natl Acad Sci U S A. 2013. PMID: 24133140 Free PMC article. Mitotic kinases: the key to duplication, segregation, and cytokinesis errors, chromosomal instability, and oncogenesis. Li JJ, Li SA. Li JJ, et al. Pharmacol Ther. 2006 Sep;111(3):974-84. doi: 10.1016/j.pharmthera.2006.02.006. Epub 2006 Apr 17. Pharmacol Ther. 2006. PMID: 16603252 Review. See all similar articles. Cited by. HPV16 E6 induces chromosomal instability due to polar chromosomes caused by E6AP-dependent degradation of the mitotic kinesin CENP-E. Cosper PF, Hrycyniak LCF, Paracha M, Lee DL, Wan J, Jones K, Bice SA, Nickel K, Mallick S, Taylor AM, Kimple RJ, Lambert PF, Weaver BA. Cosper PF, et al. Proc Natl Acad Sci U S A. 2023 Apr 4;120(14):e2216700120. doi: 10.1073/pnas.2216700120. Epub 2023 Mar 29. Proc Natl Acad Sci U S A. 2023. PMID: 36989302. Chromosomal Instability as Enabling Feature and Central Hallmark of Breast Cancer. Castellanos G, Valbuena DS, Perez E, Villegas VE, Rondon-Lagos M. Castellanos G, et al. Breast Cancer (Dove Med Press). 2023 Mar 9;15:189-211. doi: 10.2147/BCTT.S383759. eCollection 2023. Breast Cancer (Dove Med Press). 2023. PMID: 36923397 Free PMC article. Review. The Adaptability of Chromosomal Instability in Cancer Therapy and Resistance. Carloni V, Morganti E, Galli A, Mazzocca A. Carloni V, et al. Int J Mol Sci. 2022 Dec 23;24(1):245. doi: 10.3390/ijms24010245. Int J Mol Sci. 2022. PMID: 36613695 Free PMC article. Review. Polar Chromosomes-Challenges of a Risky Path. Vukusic K, Tolic IM. Vukusic K, et al. Cells. 2022 May 3;11(9):1531. doi: 10.3390/cells11091531. Cells. 2022. PMID: 35563837 Free PMC article. Review. Modification of Single Cells Within Mouse Mammary Gland Derived Acini via Viral Transduction. Del Valle LG, Montero MG, Jechlinger M. Del Valle LG, et al. Methods Mol Biol. 2022;2471:185-194. doi: 10.1007/978-1-0716-2193-6_9. Methods Mol Biol. 2022. PMID: 35175597. See all "Cited by" articles. References. Boveri T. ANTON DOHBN. Science. 1912;36:453–468. - PubMed. Carter S.L., Eklund A.C., Kohane I.S., Harris L.N., Szallasi Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat. Genet. 2006;38:1043–1048. - PubMed. Cerami E., Gao J., Dogrusoz U., Gross B.E., Sumer S.O., Aksoy B.A., Jacobsen A., Byrne C.J., Heuer M.L., Larsson E. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–404. - PMC - PubMed. Chen G., Rubinstein B., Li R. Whole chromosome aneuploidy: big mutations drive adaptation by phenotypic leap. BioEssays. 2012;34:893–900. - PMC - PubMed. Chen G., Mulla W.A., Kucharavy A., Tsai H.-J., Rubinstein B., Conkright J., McCroskey S., Bradford W.D., Weems L., Haug J.S. Targeting the adaptability of heterogeneous aneuploids. Cell. 2015;160:771–784. - PMC - PubMed. MeSH terms. Aneuploidy Actions Search in PubMed Search in MeSH Add to Search. Animals Actions Search in PubMed Search in MeSH Add to Search. Apoptosis Actions Search in PubMed Search in MeSH Add to Search. Breast Neoplasms / metabolism Actions Search in PubMed Search in MeSH Add to Search. Breast Neoplasms / pathology Actions Search in PubMed Search in MeSH Add to Search. Carcinogenesis / metabolism Actions Search in PubMed Search in MeSH Add to Search. Carcinogenesis / pathology Actions Search in PubMed Search in MeSH Add to Search. Cell Cycle Checkpoints Actions Search in PubMed Search in MeSH Add to Search. Cell Proliferation Actions Search in PubMed Search in MeSH Add to Search. Cells, Cultured Actions Search in PubMed Search in MeSH Add to Search. Chromosomal Instability* Actions Search in PubMed Search in MeSH Add to Search. Chromosome Segregation / genetics Actions Search in PubMed Search in MeSH Add to Search. Epithelial Cells / metabolism Actions Search in PubMed Search in MeSH Add to Search. Epithelial Cells / pathology Actions Search in PubMed Search in MeSH Add to Search. Female Actions Search in PubMed Search in MeSH Add to Search. Humans Actions Search in PubMed Search in MeSH Add to Search. Mad2 Proteins / metabolism* Actions Search in PubMed Search in MeSH Add to Search. Mammary Neoplasms, Experimental / genetics* Actions Search in PubMed Search in MeSH Add to Search. Mammary Neoplasms, Experimental / pathology* Actions Search in PubMed Search in MeSH Add to Search. Mice Actions Search in PubMed Search in MeSH Add to Search. Mitosis Actions Search in PubMed Search in MeSH Add to Search. Oncogenes* Actions Search in PubMed Search in MeSH Add to Search. Phenotype Actions Search in PubMed Search in MeSH Add to Search. Proto-Oncogene Proteins p21(ras) / metabolism Actions Search in PubMed Search in MeSH Add to Search. Receptor, ErbB-2 Actions Search in PubMed Search in MeSH Add to Search. Spindle Apparatus / metabolism Actions Search in PubMed Search in MeSH Add to Search. Time-Lapse Imaging Actions Search in PubMed Search in MeSH Add to Search. Transgenes Actions Search in PubMed Search in MeSH Add to Search. Substances. Mad2 Proteins Actions Search in PubMed Search in MeSH Add to Search. ERBB2 protein, human Actions Search in PubMed Search in MeSH Add to Search. Receptor, ErbB-2 Actions Search in PubMed Search in MeSH Add to Search. Hras protein, mouse Actions Search in PubMed Search in MeSH Add to Search. Proto-Oncogene Proteins p21(ras) Actions Search in PubMed Search in MeSH Add to Search. Related information. GEO Profiles. Gene. Gene (GeneRIF) MedGen. Nucleotide (RefSeq) Nucleotide (RefSeq) Nucleotide (Weighted) Protein (RefSeq) Protein (Weighted) Taxonomy via GenBank. UniGene. Grant support. 336045/ERC_/European Research Council/International. LinkOut - more resources. Full Text Sources Elsevier Science Europe PubMed Central PubMed Central. Other Literature Sources scite Smart Citations. Medical Genetic Alliance. Molecular Biology Databases Mouse Genome Informatics (MGI) Research Materials NCI CPTC Antibody Characterization Program. Miscellaneous NCI CPTAC Assay Portal.