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A tumor suppressor role for srGAP3 in mammary epithelial cells

Oncogene volume 32, pages 4854–4860 (2013)Cite this article

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Abstract

srGAP3, a member of the Slit-Robo sub-family of Rho GTPase-activating proteins (Rho GAPs), controls actin and microtubule dynamics through negative regulation of Rac. Here, we describe a potential role for srGAP3 as a tumor suppressor in mammary epithelial cells. We show that RNAi-mediated depletion of srGAP3 promotes Rac dependent, anchorage-independent growth of partially transformed human mammary epithelial cells (HMECs). Furthermore, srGAP3 expression is absent, or significantly reduced in 7/10 breast cancer cell lines compared with normal HMECs. Re-expression of srGAP3 in a subset of these cell lines inhibits both anchorage-independent growth and cell invasion in a GAP-dependent manner, and this is accompanied by an increase in phosphorylation of the ezrin/radixin/moesin (ERM) family proteins and myosin light chain 2 (MLC2). Inhibition of the Rho regulated kinase, ROCK, reduces ERM and MLC2 phosphorylation and restores invasion. We conclude that srGAP3 has tumor suppressor-like activity in HMECs, likely through its activity as a negative regulator of Rac1.

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Acknowledgements

We thank William C Hahn, Dana-Farber Cancer Institute, for providing the cell line HMEC/hTERT/LT/c-myc and John D Scott, University of Washington, for the gift of pCDNA3.1-WRP-V5His and pCDNA3.1-WRPΔGAP-V5His plasmids. We also thank Memorial Sloan-Kettering Cancer Center Molecular Cytogenetics Core facility for performing the FISH assays, the Bioinformatic Core facility for the analysis of the microarray data and Overholtzer laboratories for critical reading of the manuscript and helpful discussions. This work was supported by Fundacion Caja Madrid, Spain (AL) and by an MSKCC Geoffrey Beene Cancer Research Center Grant (AH).

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  1. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    A Lahoz & A Hall

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  1. A Lahoz
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Correspondence to A Hall.

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Lahoz, A., Hall, A. A tumor suppressor role for srGAP3 in mammary epithelial cells. Oncogene 32, 4854–4860 (2013). https://doi.org/10.1038/onc.2012.489

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