The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling.

TitleThe Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling.
Publication TypeJournal Article
Year of Publication2015
AuthorsOkada T, Sinha S, Esposito I, Schiavon G, López-Lago MA, Su W, Pratilas CA, Abele C, Hernandez JM, Ohara M, Okada M, Viale A, Heguy A, Socci ND, Sapino A, Seshan VE, Long S, Inghirami G, Rosen N, Giancotti FG
JournalNat Cell Biol
Volume17
Issue1
Pagination81-94
Date Published2015 Jan
ISSN1476-4679
KeywordsAnimals, Cell Adhesion, Cell Line, Tumor, Cell Polarity, Cell Proliferation, Cell Transformation, Neoplastic, Cellular Senescence, Epithelial-Mesenchymal Transition, Female, Humans, Lung Neoplasms, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, SCID, Nerve Tissue Proteins, p120 GTPase Activating Protein, Proto-Oncogene Proteins c-myc, rap1 GTP-Binding Proteins, ras GTPase-Activating Proteins, Receptors, Cell Surface, rho GTP-Binding Proteins, Signal Transduction, Triple Negative Breast Neoplasms, Tumor Suppressor Protein p53
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.

DOI10.1038/ncb3082
Alternate JournalNat Cell Biol
PubMed ID25531777
PubMed Central IDPMC4374353
Grant ListT32 CA009501 / CA / NCI NIH HHS / United States
R01 CA113996 / CA / NCI NIH HHS / United States
P30 CA08748 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA058976 / CA / NCI NIH HHS / United States
R01 CA078901 / CA / NCI NIH HHS / United States
P01 CA094060 / CA / NCI NIH HHS / United States
Related Faculty: 
Giorgio Inghirami, M.D.

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