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Nat Cell Biol. 2015 Jan;17(1):81-94. doi: 10.1038/ncb3082. Epub 2014 Dec 22.

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

Author information

1
Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
2
1] Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Department of Pediatrics, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
3
Department of Biomedical Sciences and Human Oncology, Center of Experimental Medicine and Research, University of Torino, Torino 10126, Italy.
4
1] Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Department of Surgery, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
5
Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
6
Genomics Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
7
Geoffrey Beene Translational Oncology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
8
Bioinformatics Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
9
Department of Medical Sciences, Center of Experimental Medicine and Research, University of Torino, Torino 10126, Italy.
10
Department of Epidemiology and Biostatistics, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
11
Structural Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
12
1] Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Department of Medicine, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

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.

PMID:
25531777
PMCID:
PMC4374353
DOI:
10.1038/ncb3082
[Indexed for MEDLINE]
Free PMC Article

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