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. 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.
Highlights
Breast cancer is a prevalent and poorly understood disease thought to arise through the accumulation of numerous genetic alterations that confer growth and survival advantages to tumor cells
Given the potential role of 14-3-3σ in regulating epithelial polarity and epithelial migration, we evaluated whether targeted disruption of 14-3-3σ could impact the metastatic properties of ErbB2 tumors by crossing it to a separate mouse strain expressing both activated ErbB2 and Cre recombinase under the constitutive mammary tumor virus (MMTV) promoter [29]
Histological analyses of the mammary tumors revealed that 14-3-3σ–deficient tumors exhibited typical adenocarcinoma features as found in the parental ErbB2KI strain, they possessed a higher degree of collagen-rich stroma (Supplementary Fig. S1C)
Summary
Breast cancer is a prevalent and poorly understood disease thought to arise through the accumulation of numerous genetic alterations that confer growth and survival advantages to tumor cells. One genetic alteration associated with poor outcome in patients with breast cancer is amplification and overexpression of the erbB2 proto-oncogene, a member of the epidermal growth factor receptor (EGFR) transmembrane receptor family [1,2,3]. Mammary epithelial expression of the EGFR or its ligand TGF-α in transgenic mice results in the frequent induction of mammary adenocarcinomas [4,5,6,7]. Mammary epithelial-specific expression of activated erbB2 results in the rapid induction of metastatic multifocal mammary tumors [8,9,10,11,12]. Mammary epithelial expression of the erbB2 proto-oncogene is capable of efficiently inducing multifocal mammary tumors, no comparable activating mutations have been detected in human erbB2 [13]. It is likely that the primary mechanism by which ErbB2 induces mammary tumorigenesis in human breast cancer is through elevated expression of the wild-type receptor
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