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To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population.<\/jats:p>","DOI":"10.1073\/pnas.1120605109","type":"journal-article","created":{"date-parts":[[2012,1,19]],"date-time":"2012-01-19T20:27:14Z","timestamp":1327004834000},"page":"2078-2083","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":234,"title":["Three differentiation states risk-stratify bladder cancer into distinct subtypes"],"prefix":"10.1073","volume":"109","author":[{"given":"Jens-Peter","family":"Volkmer","sequence":"first","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine,"},{"name":"Department of Urology,"},{"name":"Department of Urology, Heinrich Heine University, D\u00fcsseldorf, NRW 40225, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debashis","family":"Sahoo","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K.","family":"Chin","sequence":"additional","affiliation":[{"name":"Department of Radiation and Cellular Oncology, University of Chicago Medical Center, Chicago, IL 60637;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip Levy","family":"Ho","sequence":"additional","affiliation":[{"name":"Scott Department of Urology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad","family":"Tang","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonina V.","family":"Kurtova","sequence":"additional","affiliation":[{"name":"Scott Department of Urology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen B.","family":"Willingham","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senthil K.","family":"Pazhanisamy","sequence":"additional","affiliation":[{"name":"Scott Department of Urology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Humberto","family":"Contreras-Trujillo","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa A.","family":"Storm","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair","family":"Lotan","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9110;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew H.","family":"Beck","sequence":"additional","affiliation":[{"name":"Department of Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin I.","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Urology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ash A.","family":"Alizadeh","sequence":"additional","affiliation":[{"name":"Division of Hematology, and Department of Internal Medicine, Stanford University, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme","family":"Godoy","sequence":"additional","affiliation":[{"name":"Scott Department of Urology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth P.","family":"Lerner","sequence":"additional","affiliation":[{"name":"Scott Department of Urology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"van de Rijn","sequence":"additional","affiliation":[{"name":"Department of Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda D.","family":"Shortliffe","sequence":"additional","affiliation":[{"name":"Department of Urology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irving L.","family":"Weissman","sequence":"additional","affiliation":[{"name":"Institute of Stem Cell Biology and Regenerative Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith S.","family":"Chan","sequence":"additional","affiliation":[{"name":"Scott Department of Urology, and"},{"name":"Department of Molecular and Cellular Biology, Dan L. 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