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 Gregg, Christopher Moraes, Anne Claude GingrasMorag Park

Research output: Contribution to journalArticle

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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. 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.

Original languageEnglish (US)
Pages (from-to)3191-3205
Number of pages15
JournalCell Reports
Volume22
Issue number12
DOIs
StatePublished - Mar 20 2018

Fingerprint

Triple Negative Breast Neoplasms
Chromosomes
Tumor Suppressor Genes
Genes
Protein Tyrosine Phosphatases
Stem cells
Aberrations
Tumors
Neoplasm Metastasis
Chemical activation
Nuclear Localization Signals
Neoplastic Stem Cells
Oncogenes
Chromosome Aberrations
Mutation
Growth

Keywords

  • chr5q
  • KIBRA
  • mechanotransduction
  • metastasis
  • PTPN14
  • RHOA signaling
  • triple-negative breast cancer
  • tumorspheres
  • WWC1
  • YAP/TAZ

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Knight, J. F., Sung, V. Y. C., Kuzmin, E., Couzens, A. L., de Verteuil, D. A., Ratcliffe, C. D. H., ... Park, M. (2018). KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer. Cell Reports, 22(12), 3191-3205. https://doi.org/10.1016/j.celrep.2018.02.095

KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer. / Knight, Jennifer F.; Sung, Vanessa Y.C.; Kuzmin, Elena; Couzens, Amber L.; de Verteuil, Danielle A.; Ratcliffe, Colin D.H.; Coelho, Paula P.; Johnson, Radia M.; Samavarchi-Tehrani, Payman; Gruosso, Tina; Smith, Harvey W.; Lee, Wontae; Saleh, Sadiq M.; Zuo, Dongmei; Zhao, Hong; Guiot, Marie Christine; Davis, Ryan R.; Gregg, Jeffrey; Moraes, Christopher; Gingras, Anne Claude; Park, Morag.

In: Cell Reports, Vol. 22, No. 12, 20.03.2018, p. 3191-3205.

Research output: Contribution to journalArticle

Knight, JF, Sung, VYC, Kuzmin, E, Couzens, AL, de Verteuil, DA, Ratcliffe, CDH, Coelho, PP, Johnson, RM, Samavarchi-Tehrani, P, Gruosso, T, Smith, HW, Lee, W, Saleh, SM, Zuo, D, Zhao, H, Guiot, MC, Davis, RR, Gregg, J, Moraes, C, Gingras, AC & Park, M 2018, 'KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer', Cell Reports, vol. 22, no. 12, pp. 3191-3205. https://doi.org/10.1016/j.celrep.2018.02.095
Knight JF, Sung VYC, Kuzmin E, Couzens AL, de Verteuil DA, Ratcliffe CDH et al. KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer. Cell Reports. 2018 Mar 20;22(12):3191-3205. https://doi.org/10.1016/j.celrep.2018.02.095
Knight, Jennifer F. ; Sung, Vanessa Y.C. ; Kuzmin, Elena ; Couzens, Amber L. ; de Verteuil, Danielle A. ; Ratcliffe, Colin D.H. ; Coelho, Paula P. ; Johnson, Radia M. ; Samavarchi-Tehrani, Payman ; Gruosso, Tina ; Smith, Harvey W. ; Lee, Wontae ; Saleh, Sadiq M. ; Zuo, Dongmei ; Zhao, Hong ; Guiot, Marie Christine ; Davis, Ryan R. ; Gregg, Jeffrey ; Moraes, Christopher ; Gingras, Anne Claude ; Park, Morag. / KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer. In: Cell Reports. 2018 ; Vol. 22, No. 12. pp. 3191-3205.
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AU - Sung, Vanessa Y.C.

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AU - Couzens, Amber L.

AU - de Verteuil, Danielle A.

AU - Ratcliffe, Colin D.H.

AU - Coelho, Paula P.

AU - Johnson, Radia M.

AU - Samavarchi-Tehrani, Payman

AU - Gruosso, Tina

AU - Smith, Harvey W.

AU - Lee, Wontae

AU - Saleh, Sadiq M.

AU - Zuo, Dongmei

AU - Zhao, Hong

AU - Guiot, Marie Christine

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AB - 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.

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