Dataset Information

P120 Catenin Isoforms Differentially Associate with Breast Cancer Invasion and Metastasis.

ABSTRACT: Tumor metastasis is the endpoint of tumor progression and depends on the ability of tumor cells to locally invade tissue, transit through the bloodstream and ultimately to colonize secondary organs at distant sites. P120 catenin (P120) has been implicated as an important regulator of metastatic dissemination because of its roles in cell-cell junctional stability, cytoskeletal dynamics, growth and survival. However, conflicting roles for P120 in different tumor models and steps of metastasis have been reported, and the understanding of P120 functions is confounded by the differential expression of P120 isoforms, which differ in N-terminal length, tissue localization and, likely, function. Here, we used in silico exon expression analyses, in vitro invasion assays and both RT-PCR and immunofluorescence of human tumors. We show that alternative exon usage favors expression of short isoform P120-3 in 1098 breast tumors and correlates with poor prognosis. P120-3 is upregulated at the invasive front of breast cancer cells migrating as collective groups in vitro. Furthermore, we demonstrate in histological sections of 54 human breast cancer patients that P120-3 expression is maintained throughout the metastatic cascade, whereas P120-1 is differentially expressed and diminished during invasion and in metastases. These data suggest specific regulation and functions of P120-3 in breast cancer invasion and metastasis.

SUBMITTER: Venhuizen JH

PROVIDER: S-EPMC6826419 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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P120 Catenin Isoforms Differentially Associate with Breast Cancer Invasion and Metastasis.

Venhuizen Jan-Hendrik JH Span Paul N PN van den Dries Koen K Sommer Sebastian S Friedl Peter P Zegers Mirjam M MM

Cancers 20190929 10

Tumor metastasis is the endpoint of tumor progression and depends on the ability of tumor cells to locally invade tissue, transit through the bloodstream and ultimately to colonize secondary organs at distant sites. P120 catenin (P120) has been implicated as an important regulator of metastatic dissemination because of its roles in cell-cell junctional stability, cytoskeletal dynamics, growth and survival. However, conflicting roles for P120 in different tumor models and steps of metastasis have ...[more]

PMID: 31569498

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Project description:BackgroundDespite recent advances in the diagnosis and treatment of breast cancer, metastasis remains the main cause of death. Since migration of tumor cells is considered a prerequisite for tumor cell invasion and metastasis, a pressing goal in tumor biology has been to elucidate factors regulating their migratory activity. Protein kinase C alpha (PKC?) is a serine-threonine protein kinase implicated in cancer metastasis and associated with poor prognosis in breast cancer patients. In this study, we set out to define the signaling axis mediated by PKC? to promote breast cancer cell migration.MethodsOncomine™ overexpression analysis was used to probe for PRKCA (PKC?) and FOXC2 expression in mRNA datasets. The heat map of PRKCA, FOXC2, and CTNND1 were obtained from the UC Santa Cruz platform. Survival data were obtained by PROGgene and available at http://www.compbio.iupui.edu/proggene . Markers for EMT and adherens junction were assessed by Western blotting and quantitative polymerase chain reaction. Effects of PKC? and FOXC2 on migration and invasion were assessed in vitro by transwell migration and invasion assays respectively. Cellular localization of E-cadherin and p120-catenin was determined by immunofluorescent staining. Promoter activity of p120-catenin was determined by dual luciferase assay using a previously validated p120-catenin reporter construct. Interaction between FOXC2 and p120-catenin promoter was verified by chromatin immunoprecipitation assay.ResultsWe determined that PKC? expression is necessary to maintain the migratory and invasive phenotype of both endocrine resistant and triple negative breast cancer cell lines. FOXC2 acts as a transcriptional repressor downstream of PKC?, and represses p120-catenin expression. Consequently, loss of p120-catenin leads to destabilization of E-cadherin at the adherens junction. Inhibition of either PKC? or FOXC2 is sufficient to rescue p120-catenin expression and trigger relocalization of p120-catenin and E-cadherin to the cell membrane, resulting in reduced tumor cell migration and invasion.ConclusionsTaken together, these results suggest that breast cancer metastasis may partially be controlled through PKC?/FOXC2-dependent repression of p120-catenin and highlight the potential for PKC? signal transduction networks to be targeted for the treatment of endocrine resistant and triple negative breast cancer.

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P120 Catenin Isoforms Differentially Associate with Breast Cancer Invasion and Metastasis.

Publications

P120 Catenin Isoforms Differentially Associate with Breast Cancer Invasion and Metastasis.

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