title: IGFBP ratio confers resistance to IGF targeting and correlates with increased invasion and poor outcome in breast tumors.
abstract: OBJECTIVE
  To improve the significance of insulin-like growth factor-binding protein 5 (IGFBP-5) as a prognostic and potentially predictive marker in patients with breast cancer.
  
  
  METHODS
  Increased IGFBP-5 expression was identified in MCF-7 cells resistant (MCF-7R4) to the IGF-1R/insulin receptor (InsR) inhibitor BMS-536924 and its role examined by targeted knockdown and overexpression in multiple experimental models. Protein expression of IGFBP-5 was measured by immunohistochemistry in a cohort of 76 patients with breast cancer to examine correlative associations with invasive tumor fraction and outcome. The use of a combined IGFBP-5/IGFBP-4 (BPR) expression ratio was applied to predict anti-IGF-1R/InsR response in a panel of breast cancer lines and outcome in multiple breast tumor cohorts.
  
  
  RESULTS
  IGFBP-5 knockdown decreased BMS-536924 resistance in MCF-7R4 cells, whereas IGFBP-5 overexpression in MCF-7 cells conferred resistance. When compared with pathologically normal reduction mammoplasty tissue, IGFBP-5 expression levels were upregulated in both invasive and histologically normal adjacent breast cancer tissue. In both univariate and multivariate modeling, metastasis-free survival, recurrence free survival (RFS), and overall survival (OS) were significantly associated with high IGFBP-5 expression. Prognostic power of IGFBP-5 was further increased with the addition of IGFBP-4 where tumors were ranked based upon IGFBP-5/IGFBP-4 expression ratio (BPR). Multiple breast cancer cohorts confirm that BPR (high vs. low) was a strong predictor of RFS and OS.
  
  
  CONCLUSIONS
  IGFBP-5 expression is a marker of poor outcome in patients with breast cancer. An IGFBP-5/IGFBP-4 expression ratio may serve as a surrogate biomarker of IGF pathway activation and predict sensitivity to anti-IGF-1R targeting.
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Becker
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Hou
authors.forename: Sean C
authors.initials: SC
authors.lastname: Harrington
authors.forename: S John
authors.initials: SJ
authors.lastname: Weroha
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Gonzalez
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Jacob
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001562:Benzimidazoles / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011728:Pyridones / Q000627:therapeutic use
chemical_list: C504983:BMS 536924; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D018975:Insulin-Like Growth Factor Binding Protein 5; D011728:Pyridones