IQ Motif-Containing GTPase-Activating Protein 2 Inhibits Breast Cancer Angiogenesis by Suppressing VEGFR2-AKT Signaling

Antiangiogenesis cancer therapies are facing setbacks due to side effects and resistance. Parallel targeting of multiple pathways can help in the development of more effective therapies. This requires the discovery of new molecules that can regulate multiple cellular processes. Our study has recentl...

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Bibliographic Details
Published in:Molecular cancer research 2022-01, Vol.20 (1), p.77-91
Main Authors: Kumar, Dinesh, Patel, Saket Awadhesbhai, Khan, Rehan, Chawla, Saurabh, Mohapatra, Nachiketa, Dixit, Manjusha
Format: Article
Language:English
Subjects:
Animals
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Cell Line, Tumor
Cell Proliferation
Chick Embryo
Female
Humans
Mice
Neovascularization, Pathologic - genetics
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction
Transfection
Vascular Endothelial Growth Factor Receptor-2 - metabolism
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Summary:Antiangiogenesis cancer therapies are facing setbacks due to side effects and resistance. Parallel targeting of multiple pathways can help in the development of more effective therapies. This requires the discovery of new molecules that can regulate multiple cellular processes. Our study has recently established the association of reduced IQGAP2 expression in breast cancer with EMT and poor prognosis of the patient. Existing literature indirectly suggests the role of IQGAP2 in angiogenesis that is still unexplored. In this study, we searched the role of IQGAP2 in tumor angiogenesis in a comprehensive manner using cell culture, patients, and animal models. Depletion of IQGAP2 in breast cancer cells increased proliferation, migration, and tubulogenesis of HUVECs. Findings were validated in CAM, Matrigel plug and skin wound-healing assays in mouse model, showing that the reduction of IQGAP2 significantly increased angiogenesis. As a confirmation, IHC analysis of the patient's tissues showed a negative correlation of IQGAP2 expression with the microvessel density. Mechanistically, loss of IQGAP2 appeared to activate VEGF-A via ERK activation in tumor cells, which activated the VEGFR2-AKT axis in HUVECs. IMPLICATIONS: The findings of this study suggest the antiangiogenic properties of IQGAP2 in breast cancer. The Dual effect of IQGAP2 on EMT and angiogenesis makes it a potential target for anticancer therapy.
ISSN:1541-7786
1557-3125
DOI:10.1158/1541-7786.MCR-20-1044