title: The expression and significance of insulin-like growth factor-1 receptor and its pathway on breast cancer stem/progenitors.
abstract: BACKGROUND
  Dysregulation of the insulin-like growth factor-1 receptor (IGF-1R)/phosphatidylinositol-3-kinase (PI3K)/Akt pathway was shown to correlate with breast cancer disease progression. Cancer stem cells are a subpopulation within cancer cells that participate in tumor initiation, radio/chemoresistance and metastasis. In breast cancer, breast cancer stem cells (BCSCs) were identified as CD24-CD44+ cells or cells with high intracellular aldehyde dehydrogenase activity (ALDH+). Elucidation of the role of IGF-1R in BCSCs is crucial to the design of breast cancer therapies targeting BCSCs.
  
  
  METHODS
  IGF-1R expression in BCSCs and noncancer stem cells sorted from xenografts of human primary breast cancers was examined by fluorescence-activated cell sorting (FACS), western blot analysis and immunoprecipitation. The role of IGF-1R in BCSCs was assessed by IGF-1R blockade with chemical inhibitor and gene silencing. Involvement of PI3K/Akt/mammalian target of rapamycin (mTOR) as the downstream pathway was studied by their phosphorylation status upon IGF-1R inhibition and the effects of chemical inhibitors of these signaling molecules on BCSCs. We also studied 16 clinical specimens of breast cancer for the expression of phosphor-Akt in the BCSCs by FACS.
  
  
  RESULTS
  Expression of phosphorylated IGF-1R was greater in BCSCs than in non-BCSCs from xenografts of human breast cancer, which were supported by western blot and immunoprecipitation experiments. The sorted IGF-1R-expressing cells displayed features of cancer stem/progenitors such as mammosphere formation in vitro and tumorigenicity in vivo, both of which were suppressed by knockdown of IGF-1R. A specific inhibitor of the IGF-1R, picropodophyllin suppressed phospho-AktSer473 and preferentially decreased ALDH+ BCSC populations of human breast cancer cells. Furthermore, picropodophyllin inhibited the capacity of CD24-CD44+ BCSCs to undergo the epithelial-mesenchymal transition process with downregulation of mesenchymal markers. Inhibitors of signal molecules downstream of IGF-1R including PI3K/Akt/mTOR also reduced the ALDH+ population of breast cancer cells. Furthermore, the mTOR inhibitor, rapamycin, suppressed BCSCs in vitro and in vivo.
  
  
  CONCLUSIONS
  Our data support the notion that IGF-1R is a marker of stemness, and IGF-1R and its downstream PI3K/Akt/mTOR pathway are attractive targets for therapy directed against breast cancer stem/progenitors.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Chang
authors.forename: Ruey-Jen
authors.initials: RJ
authors.lastname: Lin
authors.forename: John
authors.initials: J
authors.lastname: Yu
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Chang
authors.forename: Chiung-Hui
authors.initials: CH
authors.lastname: Fu
authors.forename: Alan
authors.initials: A
authors.lastname: Lai
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
authors.forename: Alice L
authors.initials: AL
authors.lastname: Yu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D011034:Podophyllotoxin / Q000008:administration & dosage / Q000031:analogs & derivatives; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C415032:picropodophyllin; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D011034:Podophyllotoxin