PMID- 24853185
OWN - NLM
STAT- MEDLINE
DCOM- 20141003
LR  - 20211021
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 110
IP  - 12
DP  - 2014 Jun 10
TI  - Co-targeting the IGF system and HIF-1 inhibits migration and invasion by 
      (triple-negative) breast cancer cells.
PG  - 2865-73
LID - 10.1038/bjc.2014.269 [doi]
AB  - 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.
FAU - Mancini, M
AU  - Mancini M
AD  - Division of Biomedical Research, Department of Theoretical and Applied Sciences, 
      University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, 
      Italy.
FAU - Gariboldi, M B
AU  - Gariboldi MB
AD  - Division of Biomedical Research, Department of Theoretical and Applied Sciences, 
      University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, 
      Italy.
FAU - Taiana, E
AU  - Taiana E
AD  - Division of Biomedical Research, Department of Theoretical and Applied Sciences, 
      University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, 
      Italy.
FAU - Bonzi, M C
AU  - Bonzi MC
AD  - Division of Biomedical Research, Department of Theoretical and Applied Sciences, 
      University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, 
      Italy.
FAU - Craparotta, I
AU  - Craparotta I
AD  - Division of Biomedical Research, Department of Theoretical and Applied Sciences, 
      University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, 
      Italy.
FAU - Pagin, M
AU  - Pagin M
AD  - Division of Biomedical Research, Department of Theoretical and Applied Sciences, 
      University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, 
      Italy.
FAU - Monti, E
AU  - Monti E
AD  - Division of Biomedical Research, Department of Theoretical and Applied Sciences, 
      University of Insubria, via A. da Giussano 10, Busto Arsizio, Varese 21052, 
      Italy.
LA  - eng
PT  - Journal Article
DEP - 20140522
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (NVP-AEW541)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrroles)
RN  - 0 (Topoisomerase I Inhibitors)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - 67763-97-7 (Insulin-Like Growth Factor II)
RN  - 7M7YKX2N15 (Topotecan)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
SB  - IM
MH  - Antibodies, Monoclonal/pharmacology
MH  - Cell Hypoxia/drug effects
MH  - Cell Line, Tumor
MH  - Cell Movement/*drug effects
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors
MH  - Insulin-Like Growth Factor I
MH  - Insulin-Like Growth Factor II/antagonists & inhibitors/*immunology
MH  - MCF-7 Cells
MH  - Pyrimidines/pharmacology
MH  - Pyrroles/pharmacology
MH  - Receptor, IGF Type 1/*antagonists & inhibitors
MH  - Signal Transduction
MH  - Topoisomerase I Inhibitors/pharmacology
MH  - Topotecan/pharmacology
MH  - Triple Negative Breast Neoplasms/*drug therapy
PMC - PMC4056066
EDAT- 2014/05/24 06:00
MHDA- 2014/10/04 06:00
PMCR- 2015/06/10
CRDT- 2014/05/24 06:00
PHST- 2014/01/03 00:00 [received]
PHST- 2014/04/15 00:00 [revised]
PHST- 2014/04/23 00:00 [accepted]
PHST- 2014/05/24 06:00 [entrez]
PHST- 2014/05/24 06:00 [pubmed]
PHST- 2014/10/04 06:00 [medline]
PHST- 2015/06/10 00:00 [pmc-release]
AID - bjc2014269 [pii]
AID - 10.1038/bjc.2014.269 [doi]
PST - ppublish
SO  - Br J Cancer. 2014 Jun 10;110(12):2865-73. doi: 10.1038/bjc.2014.269. Epub 2014 
      May 22.