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

doi:10.1016/j.celrep.2018.02.095

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

Cell Rep. 2018 Mar 20;22(12):3191-3205. doi: 10.1016/j.celrep.2018.02.095.

Authors

Jennifer F Knight¹, Vanessa Y C Sung², Elena Kuzmin², Amber L Couzens³, Danielle A de Verteuil¹, Colin D H Ratcliffe², Paula P Coelho², Radia M Johnson¹, Payman Samavarchi-Tehrani³, Tina Gruosso⁴, Harvey W Smith¹, Wontae Lee⁵, Sadiq M Saleh¹, Dongmei Zuo¹, Hong Zhao¹, Marie-Christine Guiot⁶, Ryan R Davis⁷, Jeffrey P Gregg⁷, Christopher Moraes⁸, Anne-Claude Gingras⁹, Morag Park¹⁰

Affiliations

¹ Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada.
² Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, Canada.
³ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
⁴ Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada.
⁵ Department of Biomedical Engineering, McGill University, Montreal, QC H3A 2B4, Canada.
⁶ Montreal Neurological Institute, Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada.
⁷ Department of Pathology and Laboratory Medicine, University of California at Davis School of Medicine, Sacramento, CA 95817, USA.
⁸ 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.
⁹ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
¹⁰ 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. Electronic address: [email protected].

Abstract

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.

Keywords: KIBRA; PTPN14; RHOA signaling; WWC1; YAP/TAZ; chr5q; mechanotransduction; metastasis; triple-negative breast cancer; tumorspheres.

Publication types

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

MeSH terms

Anemia, Macrocytic / genetics*
Animals
Chromosome Deletion
Chromosomes, Human, Pair 5 / genetics
Disease Models, Animal
Female
Genes, Tumor Suppressor*
Humans
Intracellular Signaling Peptides and Proteins / genetics*
Intracellular Signaling Peptides and Proteins / metabolism
Mammary Neoplasms, Experimental / genetics*
Mammary Neoplasms, Experimental / metabolism
Mammary Neoplasms, Experimental / pathology
Mice
Neoplasm Metastasis
Phosphoproteins / genetics*
Phosphoproteins / metabolism
Triple Negative Breast Neoplasms / genetics*
Triple Negative Breast Neoplasms / metabolism
Triple Negative Breast Neoplasms / pathology

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding