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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EGenes that confer a survival advantage to primary tumor cells during tumor initiation and also play a role in development of metastases are being identified in breast cancer models. Therapeutic targeting of metastasis genes may have an impact on the prevention and treatment of metastatic diseases, including breast cancer.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Emetastatic trait\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Emechanism of metastasis\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Egenes\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eprevention\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Etreatment\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EUpon receiving the AACR Outstanding Investigator Award for Breast Cancer Research, Yibin Kang, PhD, Princeton University, Princeton, New Jersey, USA, discussed his research into the origin of metastatic traits in breast cancer (BC). Because the majority of patients with BC will develop metastatic disease, identification of the mechanisms of metastasis will provide new therapeutic targets.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EKey questions include, what genes give metastatic tumor cells the ability to escape from the intrinsic constraints of the epithelium and initiate new tumors in a distinct microenvironment, and when does this occur? One level of research involves examining the natural heterogeneity of cells in tumors (intratumoral heterogeneity) to identify metastasis genes.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EAnother level involves looking at intertumoral heterogeneity, important because tumors of the same type from different patients behave differently. One hypothesis for this is the cell-of-origin model, in which tumors develop from different normal cells: aggressive tumors develop from stemlike cells, which become more metastatic after oncogenic events. Other tumors, derived from fully differentiated cells, are less likely to metastasize.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EAnother hypothesis, the oncogenic driver mutation model, suggests that poor-prognosis tumors result from oncogenic driver events during tumor initiation. Tumors may come from the same cell of origin but, through different oncogenic driver events, give rise to tumor cells that have little chance of metastasizing; another oncogenic driver event may lead to formation of highly aggressive metastatic tumors.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EOne amplicon associated with poor prognosis in breast cancer was identified by a computational biology in 8q22 [Hu G et al. \u003Cem\u003ECancer Cell\u003C\/em\u003E. 2009]. This small region contains about a dozen genes, half of which are highly differentially expressed. These were cloned and overexpressed in tumor cells to determine which could drive lung metastases in a mouse model, leading to the identification of one gene, metadherin (MTDH), a poor prognosis marker and functional driver of breast cancer metastasis.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EKnockout of MTDH does not affect embryonic or postnatal development in mice; in a model of a highly aggressive tumor, it slows tumor progression, reduces total tumor burden, and eliminates metastases. Tumor formation in MTDH knockouts in an in vivo model of tumor initiation is shown in \u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E.\u003C\/p\u003E\n         \u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/11613\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/11613\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11613\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-8\u0022 class=\u0022first-child\u0022\u003ETumor Incidence in In Vivo Tumor Initiation Assay\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EStaphylococcal nuclease domain containing 1 (SND1) is associated with poor prognosis and interacts with MTDH. Knockdown of SND1 reduces lung metastases and sensitizes cells to chemotherapy-induced apoptosis [Blanco MA et al. \u003Cem\u003EJ Biol Chem\u003C\/em\u003E. 2011; Wan L et al. \u003Cem\u003ECancer Cell\u003C\/em\u003E. 2014]. Dr Kang\u2019s group has used crystal structural analysis to determine the sites of interaction between MTDH and SND1 [Guo F et al. \u003Cem\u003ECell Reports\u003C\/em\u003E. 2014]. Mutation at either 1 of 2 tryptophans eliminates the binding of MTDH to SND1 and the ability of MTDH to rescue tumor-initiating functions. The group is now screening small molecular compounds to interfere with the cooperative activity of MTDH and SND1 in tumor initiation.\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EGenes that confer survival advantage to primary tumor cells during tumor initiation may play crucial roles in metastasis via several mechanisms, including promotion of the development of tumor-initiating cells or by mediation of crosstalk between tumor cells and their environment. Therapeutic targeting of metastasis genes may have a far-reaching impact on the prevention and treatment of metastatic diseases.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/56\/14.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzo7wp\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_tables.js?nzo7wp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}