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 Gingras; Morag Park

doi:10.1016/j.celrep.2018.02.095

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

Pathology and Laboratory Medicine

Research output: Contribution to journal › Article › peer-review

18 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 language	English (US)
Pages (from-to)	3191-3205
Number of pages	15
Journal	Cell Reports
Volume	22
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2018.02.095
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)

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10.1016/j.celrep.2018.02.095

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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

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 › peer-review

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, 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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title = "KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer",

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.",

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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

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.

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KIBRA (WWC1) Is a Metastasis Suppressor Gene Affected by Chromosome 5q Loss in Triple-Negative Breast Cancer

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