Author: ["Tomoyo Okada","Surajit Sinha","Ilaria Esposito","Gaia Schiavon","Miguel A. López-Lago","Wenjing Su","Christine A. Pratilas","Cristina Abele","Jonathan M. Hernandez","Masahiro Ohara","Morihito Okada","Agnes Viale","Adriana Heguy","Nicholas D. Socci","Anna Sapino","Venkatraman E. Seshan","Stephen Long","Giorgio Inghirami","Neal Rosen","Filippo G. Giancotti"]
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Abstract
We identified the Rho GTPase Rnd1 as a candidate metastasis suppressor in basal-like and triple-negative breast cancer through bioinformatics analysis. Depletion of Rnd1 disrupted epithelial adhesion and polarity, induced epithelial-to-mesenchymal transition, and cooperated with deregulated expression of c-Myc or loss of p53 to cause neoplastic conversion. Mechanistic studies revealed that Rnd1 suppresses Ras signalling by activating the GAP domain of Plexin B1, which inhibits Rap1. Rap1 inhibition in turn led to derepression of p120 Ras-GAP, which was able to inhibit Ras. Inactivation of Rnd1 in mammary epithelial cells induced highly undifferentiated and invasive tumours in mice. Conversely, Rnd1 expression inhibited spontaneous and experimental lung colonization in mouse models of metastasis. Genomic studies indicated that gene deletion in combination with epigenetic silencing or, more rarely, point mutation inactivates RND1 in human breast cancer. These results reveal a previously unappreciated mechanism through which Rnd1 restrains activation of Ras-MAPK signalling and breast tumour initiation and progression. Giancotti and colleagues report that the Rnd1 Rho GTPase suppresses the epithelial–mesenchymal transition and mammary tumorigenesis by inhibiting Ras-MAPK signalling through a Plexin B1–Rap1–p120 Ras-GAP signalling axis.Cite this article
Okada, T., Sinha, S., Esposito, I. et al. The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling. Nat Cell Biol 17, 81–94 (2015). https://doi.org/10.1038/ncb3082 