Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells

M. Mancini, M. B. Gariboldi, E. Taiana, M. C. Bonzi, I. Craparotta, M. Pagin, E. Monti

Research output: Contribution to journalArticlepeer-review

Abstract

Background:Metastatic triple-negative breast cancer is mostly incurable, due to lack of suitable drug targets. The insulin-like growth factor (IGF) system could provide such a target, and IGF-1 receptor (IGF-1R)-directed agents are already available, but seem unable to control all the complexities of the system, including crosstalk with hypoxia-inducible pathways.Methods:Migration of triple-negative MDA-231 breast cancer cells and its modulation by IGFs, the IGF-1R inhibitor NVP-AEW541 and the IGF-2-sequestering monoclonal antibody MAB292 were assessed by the scratch wound healing and Boyden chamber assays; the effect of topotecan (inhibiting hypoxia-inducible factor-1 (HIF-1)) under hypoxia was also evaluated. Constitutive as well as drug-modulated levels of components of the IGF and HIF-1 pathways were evaluated by western blotting and qPCR.Results:IGF-induced migration of MDA-231 cells was not abrogated by the IGF-1R inhibitor NVP-AEW541, whereas IGF-2 sequestration by MAB292 significantly reduced cell migration. Under hypoxia, topotecan was also effective, likely by reducing HIF-1-induced IGF-2 release. Simultaneous targeting of IGF-1R and IGF-2 or HIF-1 completely abolished cell migration.Conclusions:IR activation may account for the failure of NVP-AEW541 to suppress MDA-231 cell migration. Ligand-targeting compounds, or co-inhibition of the IGF and HIF-1 systems, may prevent activation of compensatory signalling, thereby providing a valuable addition to IGF-1R inhibitor-based therapies.

Original languageEnglish
Pages (from-to)2865-2873
Number of pages9
JournalBritish Journal of Cancer
Volume110
Issue number12
DOIs
Publication statusPublished - Jun 10 2014

Keywords

  • Hypoxia
  • IGFs
  • Migration
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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