title: Upregulation of Claudin-4, CAIX and GLUT-1 in distant breast cancer metastases.
abstract: BACKGROUND
  Several studies have shown that the immunophenotype of distant breast cancer metastases may differ significantly from that of the primary tumor, especially with regard to differences in the level of hormone receptor protein expression, a process known as receptor conversion. This study aimed to compare expression levels of several membrane proteins between primary breast tumors and their corresponding distant metastases in view of their potential applicability for molecular imaging and drug targeting.
  
  
  METHODS
  Expression of Claudin-4, EGFR, CAIX, GLUT-1 and IGF1R was assessed by immunohistochemistry on tissue microarrays composed of 97 paired primary breast tumors and their distant (non-bone) metastases.
  
  
  RESULTS
  In both the primary cancers and the metastases, Claudin-4 was most frequently expressed, followed by GLUT-1, CAIX and EGFR.From primary breast cancers to their distant metastases there was positive to negative conversion, e.g. protein expression in the primary tumor with no expression in its paired metastasis, in 6%, 19%, 12%, 38%, and 0% for Claudin-4 (n.s), GLUT-1 (n.s), CAIX (n.s), EGFR (n.s) and IGF1R (n.s) respectively. Negative to positive conversion was seen in 65%, 47%, 43%, 9% and 0% of cases for Claudin-4 (p = 0.049), GLUT-1 (p = 0.024), CAIX (p = 0.002), EGFR (n.s.) and IGF1R (n.s.) respectively. Negative to positive conversion of Claudin-4 in the metastasis was significantly associated with tumor size (p = 0.015), negative to positive conversion of EGFR with negative PR status (p = 0.046) and high MAI (p = 0.047) and GLUT-1 negative to positive conversion with (neo)adjuvant chemotherapy (p = 0.039) and time to metastasis formation (p = 0.034). CAIX and GLUT-1 expression in the primary tumor were significantly associated with high MAI (p = 0.008 and p = 0.038 respectively).
  
  
  CONCLUSIONS
  Claudin-4 is frequently expressed in primary breast cancers but especially in their metastases and is thereby an attractive membrane bound molecular imaging and drug target. Conversion in expression of the studied proteins from the primary tumor to metastases was fairly frequent, except for IGF1R, implying that the expression status of metastases cannot always be reliably predicted from the primary tumor, thereby necessitating biopsy for reliable assessment.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Jiwa
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
authors.forename: Laurien D
authors.initials: LD
authors.lastname: Hoefnagel
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, Utrecht 3508GA, The Netherlands. cmoelans@umcutrecht.nl.
authors.forename: Cathy B
authors.initials: CB
authors.lastname: Moelans
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D062506:Claudin-4 / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D009362:Neoplasm Metastasis; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D062506:Claudin-4; D051272:Glucose Transporter Type 1; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1