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.

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

SAPINO, Anna;INGHIRAMI, Giorgio;
2015-01-01

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.
2015
17
1
81
94
http://www.nature.com./ncb/journal/v17/n1/full/ncb3082.html#affil-auth
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374353/
Tomoyo Okada;Surajit Sinha;Ilaria Esposito;Gaia Schiavon;Miguel A. L?pez-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
File in questo prodotto:
File Dimensione Formato  
figura 2.pdf

Open Access dal 24/06/2015

Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 285.48 kB
Formato Adobe PDF
285.48 kB Adobe PDF Visualizza/Apri
figure 6.pdf

Open Access dal 24/06/2015

Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 210.56 kB
Formato Adobe PDF
210.56 kB Adobe PDF Visualizza/Apri
figura 3.pdf

Open Access dal 24/06/2015

Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 312.91 kB
Formato Adobe PDF
312.91 kB Adobe PDF Visualizza/Apri
figure 7.pdf

Open Access dal 24/06/2015

Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 344.92 kB
Formato Adobe PDF
344.92 kB Adobe PDF Visualizza/Apri
figure 8.pdf

Open Access dal 24/06/2015

Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 259.86 kB
Formato Adobe PDF
259.86 kB Adobe PDF Visualizza/Apri
figure 4.pdf

Open Access dal 24/06/2015

Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 296.71 kB
Formato Adobe PDF
296.71 kB Adobe PDF Visualizza/Apri
supplementary tables.pdf

Open Access dal 24/06/2015

Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 701.67 kB
Formato Adobe PDF
701.67 kB Adobe PDF Visualizza/Apri
figura 1.pdf

Open Access dal 24/06/2015

Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 306.29 kB
Formato Adobe PDF
306.29 kB Adobe PDF Visualizza/Apri
1414227_aperto.pdf

Open Access dal 24/06/2015

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 218.55 kB
Formato Adobe PDF
218.55 kB Adobe PDF Visualizza/Apri
figure 5.pdf

Open Access dal 24/06/2015

Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 282.3 kB
Formato Adobe PDF
282.3 kB Adobe PDF Visualizza/Apri
1414227_chiuso.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 5.69 MB
Formato Adobe PDF
5.69 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Rnd-Nature_Cell_Biology.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 5.88 MB
Formato Adobe PDF
5.88 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/152877
Citazioni
  • ???jsp.display-item.citation.pmc??? 60
  • Scopus 94
  • ???jsp.display-item.citation.isi??? 90
social impact