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

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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., 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