KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer
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 syn...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471830305X |
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| language |
English |
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Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer Cell Reports |
| author_facet |
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 |
| author_sort |
Jennifer F. Knight |
| title |
KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer |
| title_short |
KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer |
| title_full |
KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer |
| title_fullStr |
KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer |
| title_full_unstemmed |
KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer |
| title_sort |
kibra (wwc1) is a metastasis suppressor gene affected by chromosome 5q loss in triple-negative breast cancer |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2018-03-01 |
| description |
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 |
| url |
http://www.sciencedirect.com/science/article/pii/S221112471830305X |
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doaj-f4500191f8be42e7bd824f4c692561b22020-11-24T21:47:22ZengElsevierCell Reports2211-12472018-03-01221231913205KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast CancerJennifer F. Knight0Vanessa Y.C. Sung1Elena Kuzmin2Amber L. Couzens3Danielle A. de Verteuil4Colin D.H. Ratcliffe5Paula P. Coelho6Radia M. Johnson7Payman Samavarchi-Tehrani8Tina Gruosso9Harvey W. Smith10Wontae Lee11Sadiq M. Saleh12Dongmei Zuo13Hong Zhao14Marie-Christine Guiot15Ryan R. Davis16Jeffrey P. Gregg17Christopher Moraes18Anne-Claude Gingras19Morag Park20Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, CanadaLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, QC H2W 1S6, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, CanadaLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, Canada; Department of Oncology, McGill University, Montreal, QC H2W 1S6, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, CanadaDepartment of Biomedical Engineering, McGill University, Montreal, QC H3A 2B4, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, CanadaGoodman Cancer Research Centre, McGill University, Montreal, QC H3G 0B1, CanadaMontreal Neurological Institute, Department of Pathology, McGill University, Montreal, QC H3A 2B4, CanadaDepartment of Pathology and Laboratory Medicine, University of California at Davis School of Medicine, Sacramento, CA 95817, USADepartment of Pathology and Laboratory Medicine, University of California at Davis School of Medicine, Sacramento, CA 95817, USAGoodman 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, CanadaLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaGoodman 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 authorSummary: 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, chr5qhttp://www.sciencedirect.com/science/article/pii/S221112471830305X |