Negative Selection and Chromosome Instability Induced by Mad2 Overexpression Delay Breast Cancer but Facilitate Oncogene-Independent Outgrowth.
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.
Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy.
Konstantina
K
Rowald
Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy.
Martina
M
Mantovan
Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy.
Joana
J
Passos
Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Christopher
C
Buccitelli
Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Balca R
BR
Mardin
Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Jan O
JO
Korbel
Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy.
Martin
M
Jechlinger
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.
Rocio
R
Sotillo
D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002478:Cells, Cultured; D043171:Chromosomal Instability; D020090:Chromosome Segregation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D064246:Mad2 Proteins / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008938:Mitosis; D009857:Oncogenes; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases; D008941:Spindle Apparatus / Q000378:metabolism; D059008:Time-Lapse Imaging; D019076:Transgenes
D064246:Mad2 Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C495971:Hras protein, mouse