title: BMS-536924 reverses IGF-IR-induced transformation of mammary epithelial cells and causes growth inhibition and polarization of MCF7 cells.
abstract: OBJECTIVE
  This study aimed to test the ability of a new insulin-like growth factor receptor (IGF-IR) tyrosine kinase inhibitor, BMS-536924, to reverse the ability of constitutively active IGF-IR (CD8-IGF-IR) to transform MCF10A cells, and to examine the effect of the inhibitor on a range of human breast cancer cell lines.
  
  
  METHODS
  CD8-IGF-IR-MCF10A cells were grown in monolayer culture, three-dimensional (3D) culture, and as xenografts, and treated with BMS-536924. Proliferation, cell cycle, polarity, and apoptosis were measured. Twenty-three human breast cancer cell lines were treated in monolayer culture with BMS-536924, and cell viability was measured. MCF7, MDA-MB-231, and MDA-MB-435 were treated with BMS-536924 in monolayer and 3D culture, and proliferation, migration, polarity, and apoptosis were measured.
  
  
  RESULTS
  Treatment of CD8-IGF-IR-MCF10A cells grown in 3D culture with BMS-536924 caused a blockade of proliferation, restoration of apical-basal polarity, and enhanced apoptosis, resulting in a partial phenotypic reversion to normal acini. In monolayer culture, BMS-536924 induced a dose-dependent inhibition of proliferation, with an accumulation of cells in G(0)/G(1,), and completely blocked CD8-IGF-IR-induced migration, invasion, and anchorage-independent growth. CD8-IGF-IR-MCF10A xenografts treated with BMS-536924 (100 mg/kg/day) showed a 76% reduction in xenograft volume. In a series of 23 human breast cancer cell lines, BMS-536924 inhibited monolayer proliferation of 16 cell lines. Most strikingly, treatment of MCF7 cells grown in 3D culture with BMS-536924 caused blockade of proliferation, and resulted in the formation of hollow polarized lumen.
  
  
  CONCLUSIONS
  These results show that the new small molecule BMS-536924 is an effective inhibitor of IGF-IR, causing a reversion of an IGF-IR - mediated transformed phenotype.
authors.affiliation: Lester and Sue Smith Breast Center, Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Beate C
authors.initials: BC
authors.lastname: Litzenburger
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Isere
authors.initials: I
authors.lastname: Kuiatse
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Attar
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Craig R
authors.initials: CR
authors.lastname: Fairchild
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
mesh_terms: D017209:Apoptosis; D001562:Benzimidazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000187:drug effects*; D011728:Pyridones / Q000494:pharmacology*; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C504983:BMS 536924; D001562:Benzimidazoles; D011728:Pyridones; D017451:Receptors, Somatomedin