title: Loss of the 14-3-3σ tumor suppressor is a critical event in ErbB2-mediated tumor progression.
abstract: 14-3-3σ is a putative tumor suppressor involved in cell-cycle progression and epithelial polarity. We demonstrate that loss of one or both copies of the conditional 14-3-3σ allele results in accelerated mammary and salivary tumorigenesis in mice expressing an activated erbB2 oncogene under the endogenous erbB2 promoter. Significantly, the majority of tumors bearing a single conditional 14-3-3σ allele lose expression of the remaining 14-3-3σ allele, which is associated with epigenetic methylation of the 14-3-3σ locus. In addition to accelerated tumor onset, in a mouse mammary tumor virus-driven ErbB2 tumor model, loss of 14-3-3σ results in enhanced metastatic phenotype that is correlated with loss of cellular junctions. Taken together, these results provide compelling evidence that 14-3-3σ is a potent tumor suppressor involved in ErbB2-driven breast cancer initiation and metastasis.
  
  
  CONCLUSIONS
  14-3-3σ has been identified as a normal mammary epithelial cell marker frequently downregulated during neoplastic development. Consistent with its potential role as a tumor suppressor, we demonstrate that targeted disruption of 14-3-3σ in a number of epithelial tissues can profoundly impact both the initiation and metastatic phases of ErbB2-mediated tumor progression through modulation of a number of distinct signaling networks.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Chen
authors.initials: C
authors.lastname: Ling
authors.forename: Vi-Minh-Tri
authors.initials: VM
authors.lastname: Su
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zuo
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
mesh_terms: D048948:14-3-3 Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018450:Disease Progression; D005260:Female; D016147:Genes, Tumor Suppressor; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C499130:Sfn protein, mouse