KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer

Jennifer F. Knight; Vanessa Y.C. Sung; Elena Kuzmin; Amber L. Couzens; Danielle A. de Verteuil; Colin D.H. Ratcliffe; Paula P. Coelho; Radia M. Johnson; Payman Samavarchi-Tehrani; Tina Gruosso; Harvey W. Smith; Wontae Lee; Sadiq M. Saleh; Dongmei Zuo; Hong Zhao; Marie-Christine Guiot; Ryan R. Davis; Jeffrey P. Gregg; Christopher Moraes; Anne-Claude Gingras; Morag Park

Cell Reports (Mar 2018)

KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer

Jennifer F. Knight,
Vanessa Y.C. Sung,
Elena Kuzmin,
Amber L. Couzens,
Danielle A. de Verteuil,
Colin D.H. Ratcliffe,
Paula P. Coelho,
Radia M. Johnson,
Payman Samavarchi-Tehrani,
Tina Gruosso,
Harvey W. Smith,
Wontae Lee,
Sadiq M. Saleh,
Dongmei Zuo,
Hong Zhao,
Marie-Christine Guiot,
Ryan R. Davis,
Jeffrey P. Gregg,
Christopher Moraes,
Anne-Claude Gingras,
Morag Park

Affiliations

Jennifer F. Knight: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada
Vanessa Y.C. Sung: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, Canada
Elena Kuzmin: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, Canada
Amber L. Couzens: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
Danielle A. de Verteuil: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada
Colin D.H. Ratcliffe: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, Canada
Paula P. Coelho: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, Canada
Radia M. Johnson: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada
Payman Samavarchi-Tehrani: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
Tina Gruosso: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada
Harvey W. Smith: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada
Wontae Lee: Department of Biomedical Engineering, McGill University, Montreal, QC H3A 2B4, Canada
Sadiq M. Saleh: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada
Dongmei Zuo: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada
Hong Zhao: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada
Marie-Christine Guiot: Montreal Neurological Institute, Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada
Ryan R. Davis: Department of Pathology and Laboratory Medicine, University of California at Davis School of Medicine, Sacramento, CA 95817, USA
Jeffrey P. Gregg: Department of Pathology and Laboratory Medicine, University of California at Davis School of Medicine, Sacramento, CA 95817, USA
Christopher Moraes: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biomedical Engineering, McGill University, Montreal, QC H3A 2B4, Canada; Department of Chemical Engineering, McGill University, Montreal, QC H3A 0C5, Canada
Anne-Claude Gingras: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
Morag Park: Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, Canada; Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada; Corresponding author

Journal volume & issue: Vol. 22, no. 12
pp. 3191 – 3205

Abstract

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Summary: Triple-negative breast cancers (TNBCs) display a complex spectrum of mutations and chromosomal aberrations. Chromosome 5q (5q) loss is detected in up to 70% of TNBCs, but little is known regarding the genetic drivers associated with this event. Here, we show somatic deletion of a region syntenic with human 5q33.2–35.3 in a mouse model of TNBC. Mechanistically, we identify KIBRA as a major factor contributing to the effects of 5q loss on tumor growth and metastatic progression. Re-expression of KIBRA impairs metastasis in vivo and inhibits tumorsphere formation by TNBC cells in vitro. KIBRA functions co-operatively with the protein tyrosine phosphatase PTPN14 to trigger mechanotransduction-regulated signals that inhibit the nuclear localization of oncogenic transcriptional co-activators YAP/TAZ. Our results argue that the selective advantage produced by 5q loss involves reduced dosage of KIBRA, promoting oncogenic functioning of YAP/TAZ in TNBC. : Triple-negative breast cancers (TNBCs) frequently lose chromosome 5q. Using a TNBC mouse model with spontaneous loss of a syntenic region, Knight et al. identify KIBRA as a metastasis suppressor. Mechanistically, KIBRA suppresses RHOA activation, impairing nuclear translocation of the oncogenes YAP/TAZ, which drive metastatic and cancer stem cell-like behavior. Keywords: KIBRA, WWC1, PTPN14, YAP/TAZ, mechanotransduction, RHOA signaling, triple-negative breast cancer, metastasis, tumorspheres, chr5q

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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