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

Abstract

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 virusdriven 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.siGNiFicaNce: 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. Cancer Discovery; 2(1); 68-81.

14-3-3σ stabilizes a complex of soluble actin and intermediate filament to enable breast tumor invasion

“…53). Given the previous reports linking 14-3-3σ with polarity and metastasis suppression in HER2 + mouse mammary gland cancer models (17,18), our data suggest that the functions of this intriguing protein are contingent on the cancer subtype. In agreement with prior reports, we observed only 6% (2 of 28) of HER2 + tumors retained detectable 14-3-3σ expression (Table 1).…”

“…13 and the current study) identified 14-3-3σ (also known as stratifin, SFN) as a protein expressed at higher levels in malignant T4-2 cells relative to its nonmalignant S1 counterpart. The finding that 14-3-3σ expression followed HMT-3522 malignant progression was surprising, given that this molecule is described broadly as a tumor suppressor; in the breast, it is frequently down-modulated through promoter methylation or proteolysis (the latter particularly in ER-positive tumors) (14)(15)(16), and it has been shown also to regulate cell polarity through Par3 association and suppress metastasis in mouse models of HER2-positive mammary cancer (17,18). Additionally, 14-3-3σ functions as an enforcer of the G 2 /M checkpoint in HCT116 colorectal cancer cells by sequestering cyclin B1 and cdc2 from the nucleus (19,20) and facilitates mitotic translation in HeLa and U2OS cells (21).…”

Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

“…Although many of the signaling pathways involved in breast tumors have been elucidated, others are still being discovered. After many years of speculation that polarity disruption is fundamental to cancer, recent data have confirmed that defects in the epithelial polarity machinery accelerate solid tumor progression in mammals (2)(3)(4)(5)(6). The mechanisms by which polarity restrains tumor progression remain largely unknown.…”

“…Three polarity networks are highly conserved in mammalian cells: the Par complex, consisting of PAR3, PAR6, and atypical protein kinase C (aPKC), 2 is situated at tight junctions and the apical surface; the Crumbs complex, containing Crumbs (CRB), PALS1, and PATJ, is essential for specifying the apical membrane; and a group of proteins that includes Scribble (SCRB), Discs-large (DLG), and Lethal Giant Larvae (LGL), localize to the basolateral membrane (7). Members of all three groups have been implicated in tumorigenesis, although mainly through correlative evidence (6, 8 -13).…”

The 14-3-3σ Tumor Suppressor Has Multiple Functions in ErbB2-Induced Breast Cancer

“…What can we learn about 14-3-3σ's role as a tumor suppressor in the article by Ling and colleagues (5) in this issue? First, we need to provide some information on the transgenic models that were used.…”