title: Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis.
abstract: BACKGROUND
  Basal-like breast cancer (BLBC) is an aggressive subtype often characterized by distant metastasis, poor patient prognosis, and limited treatment options. Therefore, the discovery of alternative targets to restrain its metastatic potential is urgently needed. In this study, we aimed to identify novel genes that drive metastasis of BLBC and to elucidate the underlying mechanisms of action.
  
  
  METHODS
  An unbiased approach using gene expression profiling of a BLBC progression model and in silico leveraging of pre-existing tumor transcriptomes were used to uncover metastasis-promoting genes. Lentiviral-mediated knockdown of interleukin-13 receptor alpha 2 (IL13Ralpha2) coupled with whole-body in vivo bioluminescence imaging was performed to assess its role in regulating breast cancer tumor growth and lung metastasis. Gene expression microarray analysis was followed by in vitro validation and cell migration assays to elucidate the downstream molecular pathways involved in this process.
  
  
  RESULTS
  We found that overexpression of the decoy receptor IL13Ralpha2 is significantly enriched in basal compared with luminal primary breast tumors as well as in a subset of metastatic basal-B breast cancer cells. Importantly, breast cancer patients with high-grade tumors and increased IL13Ralpha2 levels had significantly worse prognosis for metastasis-free survival compared with patients with low expression. Depletion of IL13Ralpha2 in metastatic breast cancer cells modestly delayed primary tumor growth but dramatically suppressed lung metastasis in vivo. Furthermore, IL13Ralpha2 silencing was associated with enhanced IL-13-mediated phosphorylation of signal transducer and activator of transcription 6 (STAT6) and impaired migratory ability of metastatic breast cancer cells. Interestingly, genome-wide transcriptional analysis revealed that IL13Ralpha2 knockdown and IL-13 treatment cooperatively upregulated the metastasis suppressor tumor protein 63 (TP63) in a STAT6-dependent manner. These observations are consistent with increased metastasis-free survival of breast cancer patients with high levels of TP63 and STAT6 expression and suggest that the STAT6-TP63 pathway could be involved in impairing metastatic dissemination of breast cancer cells to the lungs.
  
  
  CONCLUSIONS
  Our findings indicate that IL13Ralpha2 could be used as a promising biomarker to predict patient outcome and provide a rationale for assessing the efficacy of anti-IL13Ralpha2 therapies in a subset of highly aggressive basal-like breast tumors as a strategy to prevent metastatic disease.
authors.affiliation: Department of Biological Sciences, School of Pure and Applied Sciences, University of Cyprus, 75 Kallipoleos Ave., 1678, Nicosia, Cyprus. ppapageo@ucy.ac.cy.|Departments of Medicine (Biomedical Genetics Section, Molecular Medicine Program and Cancer Center), Genetics & Genomics and Pathology & Laboratory Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA. ppapageo@ucy.ac.cy.|Department of Health Sciences, European University Cyprus, 6 Diogenis Street, 2404, Nicosia, Cyprus. ppapageo@ucy.ac.cy.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papageorgis
authors.affiliation: Departments of Medicine (Biomedical Genetics Section, Molecular Medicine Program and Cancer Center), Genetics & Genomics and Pathology & Laboratory Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA. saito@bu.edu.
authors.forename: Sait
authors.initials: S
authors.lastname: Ozturk
authors.affiliation: Departments of Medicine (Biomedical Genetics Section, Molecular Medicine Program and Cancer Center), Genetics & Genomics and Pathology & Laboratory Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA. awl2@bu.edu.
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Lambert
authors.affiliation: Department of Biological Sciences, School of Pure and Applied Sciences, University of Cyprus, 75 Kallipoleos Ave., 1678, Nicosia, Cyprus. neophytou.christiana@ucy.ac.cy.
authors.forename: Christiana M
authors.initials: CM
authors.lastname: Neophytou
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University School of Medicine, 2300 I Street NW, Washington, DC, 20037, USA. atzatsos@gwu.edu.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Tzatsos
authors.affiliation: Departments of Medicine (Biomedical Genetics Section, Molecular Medicine Program and Cancer Center), Genetics & Genomics and Pathology & Laboratory Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA. ckwong@bu.edu.
authors.forename: Chen K
authors.initials: CK
authors.lastname: Wong
authors.affiliation: Departments of Medicine (Biomedical Genetics Section, Molecular Medicine Program and Cancer Center), Genetics & Genomics and Pathology & Laboratory Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA. samthia@bu.edu.
authors.forename: Sam
authors.initials: S
authors.lastname: Thiagalingam
authors.affiliation: Department of Biological Sciences, School of Pure and Applied Sciences, University of Cyprus, 75 Kallipoleos Ave., 1678, Nicosia, Cyprus. andreasc@ucy.ac.cy.
authors.forename: Andreas I
authors.initials: AI
authors.lastname: Constantinou
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D011379:Prognosis; D050800:STAT6 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D053663:Interleukin-13 Receptor alpha2 Subunit; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins