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) |
|---|---|
| Pages (from-to) | 3191-3205 |
| Number of pages | 15 |
| Journal | Cell Reports |
| Volume | 22 |
| Issue number | 12 |
| DOIs | |
| State | Published - 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
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 journal › Article
}
TY - JOUR
T1 - KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer
AU - Knight, Jennifer F.
AU - Sung, Vanessa Y.C.
AU - Kuzmin, Elena
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
AU - Davis, Ryan R.
AU - Gregg, Jeffrey
AU - Moraes, Christopher
AU - Gingras, Anne Claude
AU - Park, Morag
PY - 2018/3/20
Y1 - 2018/3/20
N2 - 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.
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.
KW - chr5q
KW - KIBRA
KW - mechanotransduction
KW - metastasis
KW - PTPN14
KW - RHOA signaling
KW - triple-negative breast cancer
KW - tumorspheres
KW - WWC1
KW - YAP/TAZ
UR - http://www.scopus.com/inward/record.url?scp=85044160134&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044160134&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2018.02.095
DO - 10.1016/j.celrep.2018.02.095
M3 - Article
C2 - 29562176
AN - SCOPUS:85044160134
VL - 22
SP - 3191
EP - 3205
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 12
ER -