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

Tomoyo Okada; Surajit Sinha; Ilaria Esposito; Gaia Schiavon; Miguel A López-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

doi:10.1038/ncb3082

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

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

Authors

Tomoyo Okada¹, Surajit Sinha¹, Ilaria Esposito¹, Gaia Schiavon¹, Miguel A López-Lago¹, Wenjing Su¹, Christine A Pratilas², Cristina Abele³, Jonathan M Hernandez⁴, Masahiro Ohara⁵, Morihito Okada⁵, Agnes Viale⁶, Adriana Heguy⁷, Nicholas D Socci⁸, Anna Sapino⁹, Venkatraman E Seshan¹⁰, Stephen Long¹¹, Giorgio Inghirami³, Neal Rosen¹², Filippo G Giancotti¹

Affiliations

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.

PMID: 25531777
PMCID: PMC4374353
DOI: 10.1038/ncb3082

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Adhesion / genetics
Cell Line, Tumor
Cell Polarity / genetics
Cell Proliferation / genetics
Cell Transformation, Neoplastic / genetics*
Cellular Senescence / genetics
Epithelial-Mesenchymal Transition / genetics*
Female
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / secondary
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, SCID
Nerve Tissue Proteins / metabolism
Proto-Oncogene Proteins c-myc / biosynthesis
Receptors, Cell Surface / metabolism
Signal Transduction / genetics
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / pathology*
Tumor Suppressor Protein p53 / genetics
p120 GTPase Activating Protein / biosynthesis
rap1 GTP-Binding Proteins / antagonists & inhibitors
ras GTPase-Activating Proteins / antagonists & inhibitors
rho GTP-Binding Proteins / genetics
rho GTP-Binding Proteins / physiology*

Substances

MYC protein, human
Nerve Tissue Proteins
PLXNB1 protein, human
Proto-Oncogene Proteins c-myc
RND1 protein, human
Receptors, Cell Surface
Tumor Suppressor Protein p53
p120 GTPase Activating Protein
ras GTPase-Activating Proteins
rap1 GTP-Binding Proteins
rho GTP-Binding Proteins

Associated data

GEO/GSE43828
GEO/GSE43885

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding