title: Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer.
abstract: BACKGROUND
  In breast cancer, gene expression analyses have defined five tumor subtypes (luminal A, luminal B, HER2-enriched, basal-like and claudin-low), each of which has unique biologic and prognostic features. Here, we comprehensively characterize the recently identified claudin-low tumor subtype.
  
  
  METHODS
  The clinical, pathological and biological features of claudin-low tumors were compared to the other tumor subtypes using an updated human tumor database and multiple independent data sets. These main features of claudin-low tumors were also evaluated in a panel of breast cancer cell lines and genetically engineered mouse models.
  
  
  RESULTS
  Claudin-low tumors are characterized by the low to absent expression of luminal differentiation markers, high enrichment for epithelial-to-mesenchymal transition markers, immune response genes and cancer stem cell-like features. Clinically, the majority of claudin-low tumors are poor prognosis estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and epidermal growth factor receptor 2 (HER2)-negative (triple negative) invasive ductal carcinomas with a high frequency of metaplastic and medullary differentiation. They also have a response rate to standard preoperative chemotherapy that is intermediate between that of basal-like and luminal tumors. Interestingly, we show that a group of highly utilized breast cancer cell lines, and several genetically engineered mouse models, express the claudin-low phenotype. Finally, we confirm that a prognostically relevant differentiation hierarchy exists across all breast cancers in which the claudin-low subtype most closely resembles the mammary epithelial stem cell.
  
  
  CONCLUSIONS
  These results should help to improve our understanding of the biologic heterogeneity of breast cancer and provide tools for the further evaluation of the unique biology of claudin-low tumors and cell lines.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, 27599, USA.
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.forename: Olga
authors.initials: O
authors.lastname: Karginova
authors.forename: Cheng
authors.initials: C
authors.lastname: Fan
authors.forename: Chad
authors.initials: C
authors.lastname: Livasy
authors.forename: Jason I
authors.initials: JI
authors.lastname: Herschkowitz
authors.forename: Xiaping
authors.initials: X
authors.lastname: He
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D057167:Claudins / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D057167:Claudins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D066246:ErbB Receptors
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