Loss of the 14-3-3σ tumor suppressor is a critical event in ErbB2-mediated tumor progression.

14-3-3 sigma 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 14-3-3 sigma 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 14-3-3 sigma allele lose expression of the remaining 14-3-3 sigma allele, which is associated with epigenetic methylation of the 14-3-3 sigma locus. In addition to accelerated tumor onset, in a mouse mammary tumor virus-driven ErbB2 tumor model, loss of 14-3-3 sigma results in enhanced metastatic phenotype that is correlated with loss of cellular junctions. Taken together, these results provide compelling evidence that 14-3-3 sigma is a potent tumor suppressor involved in ErbB2-driven breast cancer initiation and metastasis. SIGNIFICANCE: 14-3-3 sigma 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 14-3-3 sigma 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. Cancer Discovery; 2(1); 68-81. (C) 2011 AACR.