title: Altered expression of insulin receptor isoforms in breast cancer.
abstract: OBJECTIVE
  Insulin-like growth factor (IGF) signaling through human insulin receptor isoform A (IR-A) contributes to tumorigenesis and intrinsic resistance to anti-IGF1R therapy. In the present study, we (a) developed quantitative TaqMan real time-PCR-based assays (qRT-PCR) to measure human insulin receptor isoforms with high specificity, (b) evaluated isoform expression levels in molecularly-defined breast cancer subtypes, and (c) identified the IR-A:IR-B mRNA ratio as a potential biomarker guiding patient stratification for anti-IGF therapies.
  
  
  METHODS
  mRNA expression levels of IR-A and IR-B were measured in 42 primary breast cancers and 19 matched adjacent normal tissues with TaqMan qRT-PCR assays. The results were further confirmed in 165 breast cancers. The tumor samples were profiled using whole genome microarrays and subsequently subtyped using the PAM50 breast cancer gene signature. The relationship between the IR-A:IR-B ratio and cancer subtype, as well as markers of proliferation were characterized.
  
  
  RESULTS
  The mRNA expression levels of IR-A in the breast tumors were similar to those observed in the adjacent normal tissues, while the mRNA levels of IR-B were significantly decreased in tumors. The IR-A:IR-B ratio was significantly higher in luminal B breast cancer than in luminal A. Strong concordance between the IR-A:IR-B ratio and the composite Oncotype DX proliferation score was observed for stratifying the latter two breast cancer subtypes.
  
  
  CONCLUSIONS
  The reduction in IR-B expression is the key to the altered IR-A:IR-B ratio observed in breast cancer. The IR-A:IR-B ratio may have biomarker utility in guiding a patient stratification strategy for an anti-IGF therapeutic.
authors: MedImmune, LLC, Gaithersburg, Maryland, United States of America.
authors: Jiaqi
authors: J
authors: Huang
authors: Chris
authors: C
authors: Morehouse
authors: Katie
authors: K
authors: Streicher
authors: Brandon W
authors: BW
authors: Higgs
authors: Jin
authors: J
authors: Gao
authors: Meggan
authors: M
authors: Czapiga
authors: Anmarie
authors: A
authors: Boutrin
authors: Wei
authors: W
authors: Zhu
authors: Philip
authors: P
authors: Brohawn
authors: Yong
authors: Y
authors: Chang
authors: Jaye
authors: J
authors: Viner
authors: Theresa
authors: T
authors: LaVallee
authors: Laura
authors: L
authors: Richman
authors: Bahija
authors: B
authors: Jallal
authors: Yihong
authors: Y
authors: Yao
mesh_terms: D015703:Antigens, CD / Q000032:analysis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000032:analysis / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D020033:Protein Isoforms; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; C435941:INSR protein, human; D011972:Receptor, Insulin