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
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
