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


Authors: Okada, T.; Sinha, S.; Esposito, I.; Schiavon, G.; Lopez Lago, M. A.; Su, W. J.; Pratilas, C. A.; Abele, C.; Hernandez, J. M.; Ohara, M.; Okada, M.; Viale, A.; Heguy, A.; Socci, N. D.; Sapino, A.; Seshan, V. E.; Long, S.; Inghirami, G.; Rosen, N.; Giancotti, F. G.
Article Title: The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling
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.
Keywords: receptor; tyrosine kinase; comparative genomic hybridization; domain; epithelial-cells; human breast-cancer; effector; tumor-suppressor; activating protein; b-raf; gene-expression analysis; induced senescence
Journal Title: Nature Cell Biology
Volume: 17
Issue: 1
ISSN: 1465-7392
Publisher: Nature Publishing Group  
Date Published: 2015-01-01
Start Page: 81
End Page: +
Language: English
ACCESSION: WOS:000346823900010
DOI: 10.1038/ncb3082
PROVIDER: wos
PUBMED: 25531777
PMCID: PMC4374353
Notes: Correction issued, see DOI: 10.1038/s41556-019-0288-3 -- Article -- Source: Wos
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MSK Authors
  1. Venkatraman Ennapadam Seshan
    288 Seshan
  2. Adriana Heguy
    85 Heguy
  3. Neal Rosen
    366 Rosen
  4. Tomoyo Okada
    14 Okada
  5. Agnes Viale
    205 Viale
  6. Nicholas D Socci
    188 Socci
  7. Stephen Barstow Long
    26 Long
  8. Surajit Sinha
    4 Sinha
  9. Wenjing Su
    6 Su