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 language | English (US) |
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Pages (from-to) | 3191-3205 |
Number of pages | 15 |
Journal | Cell Reports |
Volume | 22 |
Issue number | 12 |
DOIs | |
State | Published - 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)