title: Differential expression of HIF-1α in CD44+CD24-/low breast ductal carcinomas.
abstract: BACKGROUND
  Cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self-renewing cell populations that constitute the bulk of tumor. Stem cells renewal and differentiation can be directly influenced by the oxygen levels of determined tissues, probably by the reduction of oxidative DNA damage in hypoxic regions, thus leading to a friendlier microenvironment, regarding to clonal expansion and for resistance to chemotherapeutic regimens. Furthermore, there have been strong data indicating a pivotal role of hypoxic niche in cancer stem cells development. There are evidence that hypoxia could drive the maintenance of CSC, via HIF-1α expression, but it still to be determined whether hypoxia markers are expressed in breast tumors presenting CD44+CD24-/low immunophenotype.
  
  
  METHODS
  Immunohistochemical analysis of CD44+CD24-/low expression and its relationship with hypoxia markers and clinical outcome were evaluated in 253 samples of breast ductal carcinomas. Double-immunolabeling was performed using EnVision Doublestain System (Dako, Carpinteria, CA, USA). Slides were then scanned into high-resolution images using Aperio ScanScope XT and then, visualized in the software Image Scope (Aperio, Vista, CA, USA).
  
  
  RESULTS
  In univariate analysis, CD44+CD24-/low expression showed association with death due to breast cancer (p = 0.035). Breast tumors expressing CD44+CD24-/low immunophenotype showed relationship with HIF-1α (p = 0.039) and negativity for HER-2 (p = 0.013).
  
  
  CONCLUSIONS
  Considering that there are strong evidences that the fraction of a tumour considered to be cancer stem cells is plastic depending upon microenvironmental signals, our findings provide further evidence that hypoxia might be related to the worse prognosis found in CD44+CD24-/low positive breast tumors.
authors.affiliation: Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Oliveira-Costa
authors.forename: Juliana S
authors.initials: JS
authors.lastname: Zanetti
authors.forename: Giórgia G
authors.initials: GG
authors.lastname: Silveira
authors.forename: Danilo F
authors.initials: DF
authors.lastname: Soave
authors.forename: Lucinei R
authors.initials: LR
authors.lastname: Oliveira
authors.forename: Verônica A
authors.initials: VA
authors.lastname: Zorgetto
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Soares
authors.forename: Sérgio
authors.initials: S
authors.lastname: Zucoloto
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ribeiro-Silva
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D001938:Brazil; D001943:Breast Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D051927:CD24 Antigen / Q000032:analysis*; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D015687:Cell Hypoxia; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis*; D007150:Immunohistochemistry; D016130:Immunophenotyping / Q000379:methods; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000737:chemistry* / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D018570:Risk Assessment; D012307:Risk Factors; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D051927:CD24 Antigen; D018960:Hyaluronan Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018719:Erb-b2 Receptor Tyrosine Kinases; C497889:CD24 protein, human; C497483:CD44 protein, human; C497442:HIF1A protein, human; C508053:ERBB2 protein, human