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Toca-1 is suppressed by p53 to limit breast cancer cell invasion and tumor metastasis

dc.contributor.authorChander, Harish
dc.contributor.authorBrien, Colin D
dc.contributor.authorTruesdell, Peter
dc.contributor.authorKathleen, Watt
dc.contributor.authorMeens, Jalna
dc.contributor.authorSchick, Colleen
dc.contributor.authorGermain, Doris
dc.contributor.authorCraig, Andrew WB
dc.date.accessioned2018-07-10T07:30:32Z
dc.date.available2018-07-10T07:30:32Z
dc.date.issued2014
dc.identifier.citationChander, H., Brien, C. D., Truesdell, P., Watt, K., Meens, J., Schick, C., . . . Craig, A. W. B. (2014). Toca-1 is suppressed by p53 to limit breast cancer cell invasion and tumor metastasis. Breast Cancer Research, 16(1). doi: 10.1186/s13058-014-0503-xen_US
dc.identifier.issn14655411
dc.identifier.urihttp://kr.cup.edu.in/handle/32116/1070
dc.description.abstractIntroduction: Transducer of Cdc42-dependent actin assembly-1 (Toca-1) recruits actin regulatory proteins to invadopodia, and promotes breast tumor metastasis. Since metastatic breast tumors frequently harbor mutations in the tumor suppressor p53, we tested whether p53 regulates Toca-1 expression. Methods: Normal mammary epithelial cells (HBL-100, MCF10A) and breast cancer cell lines expressing wild-type (WT) p53 (DU4475, MTLn3) were treated with camptothecin or Nutlin-3 to stabilize p53 to test effects on Toca-1 mRNA and protein levels. Chromatin immunoprecipitation (ChIP) assays were performed to identify p53 binding site in Toca-1 gene. Stable silencing of p53 and Toca-1 were performed in MTLn3 cells to test effects on invadopodia and cell invasion in vitro, and tumor metastasis in vivo. Results: We observed that breast cancer cell lines with mutant p53 have high levels of Toca-1 compared to those with WT p53. Stabilization of WT p53 led to further reduction in Toca-1 mRNA and protein levels in normal breast epithelial cells and breast cancer cells. ChIP assays revealed p53 binding within intron 2 of toca1, and reduced histone acetylation within its promoter region upon p53 upregulation or activation. Stable silencing of WT p53 in MTLn3 cells led to increased extracellular matrix degradation and cell invasion compared to control cells. Interestingly, the combined silencing of p53 and Toca-1 led to a partial rescue of these effects of p53 silencing in vitro and reduced lung metastases in mice. In human breast tumors, Toca-1 levels were high in subtypes with frequent p53 mutations, and high Toca-1 transcript levels correlated with increased risk of relapse. Conclusions: Based on these findings, we conclude that loss of p53 tumor suppressor function in breast cancers leads to upregulation of Toca-1, and results in enhanced risk of developing metastatic disease. ? Chander et al.en_US
dc.language.isoen_USen_US
dc.publisherBioMed Central Ltd.en_US
dc.subjectcamptothecin; messenger RNA; nutlin 3; protein p21; protein p53; regulator protein; short hairpin RNA; transducer of Cdc42 dependent actin assembly 1; unclassified drug; carrier protein; FNBP1L protein, human; messenger RNA; protein p53; Toca-1 protein, rat; TP53 protein, human; vesicular transport adaptor protein; animal experiment; Article; breast cancer; cancer cell culture; chromatin immunoprecipitation; controlled study; human; human cell; immunoblotting; immunohistochemistry; in vitro studen_US
dc.titleToca-1 is suppressed by p53 to limit breast cancer cell invasion and tumor metastasisen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/s13058-014-0503-x
dc.identifier.urlhttps://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-014-0503-x
dc.title.journalBreast Cancer Research


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