title: Association between insulin-like growth factor-1 receptor (IGF1R) negativity and poor prognosis in a cohort of women with primary breast cancer.
abstract: BACKGROUND
  Resistance towards endocrine therapy is a great concern in breast cancer treatment and may partly be explained by the activation of compensatory signaling pathways. The aim of the present study was to investigate if the insulin-like growth factor-1 receptor (IGF1R) signaling pathway was activated or deregulated in breast cancer patients and to explore if any of the markers were prognostic, with or without adjuvant tamoxifen. This signaling pathway has been suggested to cause estrogen independent cell growth and thus contribute to resistance to endocrine treatment in estrogen receptor (ER) positive breast cancer.
  
  
  METHODS
  The protein expression of IGF1R, phosphorylated Mammalian Target of Rapamycin (p-mTOR) and phosphorylated S6 ribosomal protein (p-S6rp) were investigated by immunohistochemistry using tissue microarrays in two patient cohorts. Cohort I (N = 264) consisted of mainly postmenopausal women with stage II breast cancer treated with tamoxifen for 2 years irrespective of ER status. Cohort II (N = 206) consisted of mainly medically untreated, premenopausal patients with node-negative breast cancer. Distant disease-free survival (DDFS) at 5 years was used as end-point for survival analyses.
  
  
  RESULTS
  We found that lower IGF1R expression was associated with worse prognosis for tamoxifen treated, postmenopausal women (HR = 0.70, 95% CI = 0.52 - 0.94, p = 0.016). The effect was seen mainly in ER-negative patients where the prognostic effect was retained after adjustment for other prognostic markers (adjusted HR = 0.49, 95% CI = 0.29 - 0.82, p = 0.007). Expression of IGF1R was associated with ER positivity (p < 0.001) in the same patient cohort.
  
  
  CONCLUSIONS
  Our results support previous studies indicating that IGF1R positivity reflects a well differentiated tumor with low metastatic capacity. An association between lack of IGF1R expression and worse prognosis was mainly seen in the ER-negative part of Cohort I. The lack of co-activation of downstream markers (p-mTOR and p-S6rp) in the IGF1R pathway suggested that the prognostic effect was not due to complete activation of this pathway. Thus, no evidence could be found for a compensatory function of IGF1R signaling in the investigated cohorts.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE-223 81 Lund, Sweden. kristina.aaltonen@med.lu.se.
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Aaltonen
authors.forename: Ann H
authors.initials: AH
authors.lastname: Rosendahl
authors.forename: Hans
authors.initials: H
authors.lastname: Olsson
authors.forename: Per
authors.initials: P
authors.lastname: Malmström
authors.forename: Linda
authors.initials: L
authors.lastname: Hartman
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D042541:Intracellular Space; D008207:Lymphatic Metastasis; D008875:Middle Aged; D011379:Prognosis; D021381:Protein Transport; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D047368:Tumor Burden
chemical_list: D015415:Biomarkers; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases