Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression

Autores
Buechel, David; Sugiyama, Nami; Rubinstein, Natalia; Saxena, Meera; Kalathur, Ravi K.R.; Lüönd, Fabiana; Vafaizadeh, Vida; Valenta, Tomas; Hausmann, George; Cantù, Claudio; Basler, Konrad; Christofori, Gerhard
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
During malignant progression, epithelial cancer cells dissolve their cell–cell adhesion and gain invasive features. By virtue of its dual function, β-catenin contributes to cadherin-mediated cell–cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bcl9 and Pygopus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of β-catenin’s transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)–PyMT mouse model of metastatic breast cancer, we compared the complete elimination of β-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of β-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of β-catenin’s transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial–mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by β-catenin’s transcriptional activities upon stimulation with Wnt3a or during TGF-β–induced EMT. Our results uncouple the signaling from the adhesion function of β-catenin and underline the importance of Wnt/β-catenin–dependent transcription in malignant tumor progression of breast cancer.
Fil: Buechel, David. Universidad de Basilea; Suiza
Fil: Sugiyama, Nami. Universidad de Basilea; Suiza
Fil: Rubinstein, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional.; Argentina
Fil: Saxena, Meera. Universidad de Basilea; Suiza
Fil: Kalathur, Ravi K.R.. Universidad de Basilea; Suiza. Royal Children’s Hospital; Australia
Fil: Lüönd, Fabiana. Universidad de Basilea; Suiza
Fil: Vafaizadeh, Vida. Universidad de Basilea; Suiza
Fil: Valenta, Tomas. Universitat Zurich; Suiza
Fil: Hausmann, George. Universitat Zurich; Suiza
Fil: Cantù, Claudio. Linköping University; Suecia
Fil: Basler, Konrad. Universitat Zurich; Suiza
Fil: Christofori, Gerhard. Universidad de Basilea; Suiza
Materia
BREAST CANCER
CELL ADHESION
METASTASIS
WNT SIGNALING
Β-CATENIN
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/162604
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progressionBuechel, DavidSugiyama, NamiRubinstein, NataliaSaxena, MeeraKalathur, Ravi K.R.Lüönd, FabianaVafaizadeh, VidaValenta, TomasHausmann, GeorgeCantù, ClaudioBasler, KonradChristofori, GerhardBREAST CANCERCELL ADHESIONMETASTASISWNT SIGNALINGΒ-CATENINhttps://purl.org/becyt/ford/1.7https://purl.org/becyt/ford/1During malignant progression, epithelial cancer cells dissolve their cell–cell adhesion and gain invasive features. By virtue of its dual function, β-catenin contributes to cadherin-mediated cell–cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bcl9 and Pygopus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of β-catenin’s transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)–PyMT mouse model of metastatic breast cancer, we compared the complete elimination of β-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of β-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of β-catenin’s transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial–mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by β-catenin’s transcriptional activities upon stimulation with Wnt3a or during TGF-β–induced EMT. Our results uncouple the signaling from the adhesion function of β-catenin and underline the importance of Wnt/β-catenin–dependent transcription in malignant tumor progression of breast cancer.Fil: Buechel, David. Universidad de Basilea; SuizaFil: Sugiyama, Nami. Universidad de Basilea; SuizaFil: Rubinstein, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional.; ArgentinaFil: Saxena, Meera. Universidad de Basilea; SuizaFil: Kalathur, Ravi K.R.. Universidad de Basilea; Suiza. Royal Children’s Hospital; AustraliaFil: Lüönd, Fabiana. Universidad de Basilea; SuizaFil: Vafaizadeh, Vida. Universidad de Basilea; SuizaFil: Valenta, Tomas. Universitat Zurich; SuizaFil: Hausmann, George. Universitat Zurich; SuizaFil: Cantù, Claudio. Linköping University; SueciaFil: Basler, Konrad. Universitat Zurich; SuizaFil: Christofori, Gerhard. Universidad de Basilea; SuizaNational Academy of Sciences2021-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/162604Buechel, David; Sugiyama, Nami; Rubinstein, Natalia; Saxena, Meera; Kalathur, Ravi K.R.; et al.; Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 118; 34; 8-2021; 1-100027-84241091-6490CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.2020227118info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/doi/10.1073/pnas.2020227118info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:44:11Zoai:ri.conicet.gov.ar:11336/162604instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:44:12.085CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression
title Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression
spellingShingle Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression
Buechel, David
BREAST CANCER
CELL ADHESION
METASTASIS
WNT SIGNALING
Β-CATENIN
title_short Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression
title_full Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression
title_fullStr Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression
title_full_unstemmed Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression
title_sort Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression
dc.creator.none.fl_str_mv Buechel, David
Sugiyama, Nami
Rubinstein, Natalia
Saxena, Meera
Kalathur, Ravi K.R.
Lüönd, Fabiana
Vafaizadeh, Vida
Valenta, Tomas
Hausmann, George
Cantù, Claudio
Basler, Konrad
Christofori, Gerhard
author Buechel, David
author_facet Buechel, David
Sugiyama, Nami
Rubinstein, Natalia
Saxena, Meera
Kalathur, Ravi K.R.
Lüönd, Fabiana
Vafaizadeh, Vida
Valenta, Tomas
Hausmann, George
Cantù, Claudio
Basler, Konrad
Christofori, Gerhard
author_role author
author2 Sugiyama, Nami
Rubinstein, Natalia
Saxena, Meera
Kalathur, Ravi K.R.
Lüönd, Fabiana
Vafaizadeh, Vida
Valenta, Tomas
Hausmann, George
Cantù, Claudio
Basler, Konrad
Christofori, Gerhard
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BREAST CANCER
CELL ADHESION
METASTASIS
WNT SIGNALING
Β-CATENIN
topic BREAST CANCER
CELL ADHESION
METASTASIS
WNT SIGNALING
Β-CATENIN
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.7
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv During malignant progression, epithelial cancer cells dissolve their cell–cell adhesion and gain invasive features. By virtue of its dual function, β-catenin contributes to cadherin-mediated cell–cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bcl9 and Pygopus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of β-catenin’s transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)–PyMT mouse model of metastatic breast cancer, we compared the complete elimination of β-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of β-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of β-catenin’s transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial–mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by β-catenin’s transcriptional activities upon stimulation with Wnt3a or during TGF-β–induced EMT. Our results uncouple the signaling from the adhesion function of β-catenin and underline the importance of Wnt/β-catenin–dependent transcription in malignant tumor progression of breast cancer.
Fil: Buechel, David. Universidad de Basilea; Suiza
Fil: Sugiyama, Nami. Universidad de Basilea; Suiza
Fil: Rubinstein, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional.; Argentina
Fil: Saxena, Meera. Universidad de Basilea; Suiza
Fil: Kalathur, Ravi K.R.. Universidad de Basilea; Suiza. Royal Children’s Hospital; Australia
Fil: Lüönd, Fabiana. Universidad de Basilea; Suiza
Fil: Vafaizadeh, Vida. Universidad de Basilea; Suiza
Fil: Valenta, Tomas. Universitat Zurich; Suiza
Fil: Hausmann, George. Universitat Zurich; Suiza
Fil: Cantù, Claudio. Linköping University; Suecia
Fil: Basler, Konrad. Universitat Zurich; Suiza
Fil: Christofori, Gerhard. Universidad de Basilea; Suiza
description During malignant progression, epithelial cancer cells dissolve their cell–cell adhesion and gain invasive features. By virtue of its dual function, β-catenin contributes to cadherin-mediated cell–cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bcl9 and Pygopus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of β-catenin’s transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)–PyMT mouse model of metastatic breast cancer, we compared the complete elimination of β-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of β-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of β-catenin’s transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial–mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by β-catenin’s transcriptional activities upon stimulation with Wnt3a or during TGF-β–induced EMT. Our results uncouple the signaling from the adhesion function of β-catenin and underline the importance of Wnt/β-catenin–dependent transcription in malignant tumor progression of breast cancer.
publishDate 2021
dc.date.none.fl_str_mv 2021-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/162604
Buechel, David; Sugiyama, Nami; Rubinstein, Natalia; Saxena, Meera; Kalathur, Ravi K.R.; et al.; Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 118; 34; 8-2021; 1-10
0027-8424
1091-6490
CONICET Digital
CONICET
url http://hdl.handle.net/11336/162604
identifier_str_mv Buechel, David; Sugiyama, Nami; Rubinstein, Natalia; Saxena, Meera; Kalathur, Ravi K.R.; et al.; Parsing β-catenin’s cell adhesion and Wnt signaling functions in malignant mammary tumor progression; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 118; 34; 8-2021; 1-10
0027-8424
1091-6490
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.2020227118
info:eu-repo/semantics/altIdentifier/url/https://www.pnas.org/doi/10.1073/pnas.2020227118
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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