Co-targeting the IGF system and HIF-1 inhibits migration and invasion by (triple-negative) breast cancer cells.
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.
Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
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Mancini
Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
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Gariboldi
Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
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Taiana
Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
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Bonzi
Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
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Craparotta
Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
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Pagin
Division of Biomedical Research, Department of Theoretical and Applied Sciences, University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, Italy.
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Monti
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors / Q000276:immunology*; D061986:MCF-7 Cells; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D059004:Topoisomerase I Inhibitors; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D019772:Topotecan; D017526:Receptor, IGF Type 1