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Phosphoinositide conversion inactivates R-RAS and drives metastases in breast cancer

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Item Type:Article
Title:Phosphoinositide conversion inactivates R-RAS and drives metastases in breast cancer
Creators Name:Li, H. and Prever, L. and Hsu, M.Y. and Lo, W.T. and Margaria, J.P. and De Santis, M.C. and Zanini, C. and Forni, M. and Novelli, F. and Pece, S. and Di Fiore, P.P. and Porporato, P.E. and Martini, M. and Belabed, H. and Nazare, M. and Haucke, V. and Gulluni, F. and Hirsch, E.
Abstract:Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R-RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof-of-concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α-overexpressing breast cancer, thereby suggesting a novel strategy for anti-breast cancer therapy.
Keywords:PI3KC2a, R-RAS, RASA3, Breast Cancer, Focal Adhesions, Metastases, Migration
Source:Advanced Science
ISSN:2198-3844
Publisher:Wiley
Volume:9
Number:9
Page Range:e2103249
Date:25 March 2022
Official Publication:https://doi.org/10.1002/advs.202103249
PubMed:View item in PubMed

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