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

13 Scopus citations

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

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)

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  • Cite this

    Knight, J. F., Sung, V. Y. C., Kuzmin, E., Couzens, A. L., de Verteuil, D. A., Ratcliffe, C. D. H., Coelho, P. P., Johnson, R. M., Samavarchi-Tehrani, P., Gruosso, T., Smith, H. W., Lee, W., Saleh, S. M., Zuo, D., Zhao, H., Guiot, M. C., Davis, R. R., Gregg, J., Moraes, C., ... 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