TY - JOUR
T1 - The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling
AU - Okada, Tomoyo
AU - Sinha, Surajit
AU - Esposito, Ilaria
AU - Schiavon, Gaia
AU - López-Lago, Miguel A.
AU - Su, Wenjing
AU - Pratilas, Christine A.
AU - Abele, Cristina
AU - Hernandez, Jonathan M.
AU - Ohara, Masahiro
AU - Okada, Morihito
AU - Viale, Agnes
AU - Heguy, Adriana
AU - Socci, Nicholas D.
AU - Sapino, Anna
AU - Seshan, Venkatraman E.
AU - Long, Stephen
AU - Inghirami, Giorgio
AU - Rosen, Neal
AU - Giancotti, Filippo G.
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
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U2 - 10.1038/ncb3082
DO - 10.1038/ncb3082
M3 - Article
C2 - 25531777
AN - SCOPUS:84926184821
SN - 1465-7392
VL - 17
SP - 81
EP - 94
JO - Nature cell biology
JF - Nature cell biology
IS - 1
ER -