Data from Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

Abstract

<div>Abstract<p>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 <i>14-3-3</i>σ allele results in accelerated mammary and salivary tumorigenesis in mice expressing an activated <i>erbB2</i> oncogene under the endogenous <i>erbB2</i> promoter. Significantly, the majority of tumors bearing a single conditional <i>14-3-3</i>σ allele lose expression of the remaining <i>14-3-3</i>σ allele, which is associated with epigenetic methylation of the <i>14-3-3</i>σ 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.</p><p><b>Significance:</b> 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. <i>Cancer Discovery; 2(1)</i>; 68–81. <i>©2011 AACR</i>.</p><p>Read the Commentary on this article by Hynes and Smirnova, p. 19</p><p>This article is highlighted in the In This Issue feature, p. 1</p></div>