The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis

Autores
Vafaizadeh vida; Buechel, David; Rubinstein, Natalia; Kalathur, Ravi K. R.; Bazzani, Lorenzo; Saxena, Meera; Valenta, Tomas; Hausmann, George; Cantù, Claudio; Basler, Konrad; Christofori, Gerhard
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Canonical Wnt/β-catenin signaling is an established regulator of cellular state and its critical contributions to tumor initiation, malignant tumor progression and metastasis formation have been demonstrated in various cancer types. Here, we investigated how the binding of β-catenin to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) affected mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9 and Bcl9L resulted into tumor cell death. In contrast, disrupting the interaction of Bcl9/Bcl9L with β-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of β-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the disruption of HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus had only moderate effects. Interestingly, interfering with the β-catenin-Bcl9/Bcl9L-Pygo chain of adapters only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGFβ treatments. Together, the results indicate that Bcl9/Bcl9L modulate but are not critically required for canonical Wnt signaling in its contribution to breast cancer growth and malignant progression, a notion consistent with the “just-right” hypothesis of Wnt-driven tumor progression.
Fil: Vafaizadeh vida. Universidad de Basilea; Suiza
Fil: Buechel, David. Universidad de Basilea; Suiza
Fil: Rubinstein, Natalia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Kalathur, Ravi K. R.. Universidad de Basilea; Suiza
Fil: Bazzani, Lorenzo. Universidad de Basilea; Suiza
Fil: Saxena, Meera. Universidad de Basilea; Suiza
Fil: Valenta, Tomas. Universitat Zurich; Suiza
Fil: Hausmann, George. Universitat Zurich; Suiza
Fil: Cantù, Claudio. Universitat Zurich; Suiza
Fil: Basler, Konrad. Universitat Zurich; Suiza
Fil: Christofori, Gerhard. Universidad de Basilea; Suiza
Materia
breast cancer
bcl9
b catenin
metastasis
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/162718
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/162718
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasisVafaizadeh vidaBuechel, DavidRubinstein, NataliaKalathur, Ravi K. R.Bazzani, LorenzoSaxena, MeeraValenta, TomasHausmann, GeorgeCantù, ClaudioBasler, KonradChristofori, Gerhardbreast cancerbcl9b cateninmetastasishttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Canonical Wnt/β-catenin signaling is an established regulator of cellular state and its critical contributions to tumor initiation, malignant tumor progression and metastasis formation have been demonstrated in various cancer types. Here, we investigated how the binding of β-catenin to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) affected mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9 and Bcl9L resulted into tumor cell death. In contrast, disrupting the interaction of Bcl9/Bcl9L with β-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of β-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the disruption of HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus had only moderate effects. Interestingly, interfering with the β-catenin-Bcl9/Bcl9L-Pygo chain of adapters only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGFβ treatments. Together, the results indicate that Bcl9/Bcl9L modulate but are not critically required for canonical Wnt signaling in its contribution to breast cancer growth and malignant progression, a notion consistent with the “just-right” hypothesis of Wnt-driven tumor progression.Fil: Vafaizadeh vida. Universidad de Basilea; SuizaFil: Buechel, David. Universidad de Basilea; SuizaFil: Rubinstein, Natalia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kalathur, Ravi K. R.. Universidad de Basilea; SuizaFil: Bazzani, Lorenzo. Universidad de Basilea; SuizaFil: Saxena, Meera. Universidad de Basilea; SuizaFil: Valenta, Tomas. Universitat Zurich; SuizaFil: Hausmann, George. Universitat Zurich; SuizaFil: Cantù, Claudio. Universitat Zurich; SuizaFil: Basler, Konrad. Universitat Zurich; SuizaFil: Christofori, Gerhard. Universidad de Basilea; SuizaNature Publishing Group2021-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/162718Vafaizadeh vida; Buechel, David; Rubinstein, Natalia; Kalathur, Ravi K. R.; Bazzani, Lorenzo; et al.; The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis; Nature Publishing Group; Oncogene; 40; 43; 9-2021; 6195-62090950-9232CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41388-021-02016-9?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+onc%2Frss%2Fcurrent+%28Oncogene+-+Issue%29info:eu-repo/semantics/altIdentifier/doi/10.1038/s41388-021-02016-9info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:33:16Zoai:ri.conicet.gov.ar:11336/162718instacron: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:34982025-10-15 15:33:16.416CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis
title The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis
spellingShingle The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis
Vafaizadeh vida
breast cancer
bcl9
b catenin
metastasis
title_short The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis
title_full The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis
title_fullStr The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis
title_full_unstemmed The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis
title_sort The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis
dc.creator.none.fl_str_mv Vafaizadeh vida
Buechel, David
Rubinstein, Natalia
Kalathur, Ravi K. R.
Bazzani, Lorenzo
Saxena, Meera
Valenta, Tomas
Hausmann, George
Cantù, Claudio
Basler, Konrad
Christofori, Gerhard
author Vafaizadeh vida
author_facet Vafaizadeh vida
Buechel, David
Rubinstein, Natalia
Kalathur, Ravi K. R.
Bazzani, Lorenzo
Saxena, Meera
Valenta, Tomas
Hausmann, George
Cantù, Claudio
Basler, Konrad
Christofori, Gerhard
author_role author
author2 Buechel, David
Rubinstein, Natalia
Kalathur, Ravi K. R.
Bazzani, Lorenzo
Saxena, Meera
Valenta, Tomas
Hausmann, George
Cantù, Claudio
Basler, Konrad
Christofori, Gerhard
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv breast cancer
bcl9
b catenin
metastasis
topic breast cancer
bcl9
b catenin
metastasis
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Canonical Wnt/β-catenin signaling is an established regulator of cellular state and its critical contributions to tumor initiation, malignant tumor progression and metastasis formation have been demonstrated in various cancer types. Here, we investigated how the binding of β-catenin to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) affected mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9 and Bcl9L resulted into tumor cell death. In contrast, disrupting the interaction of Bcl9/Bcl9L with β-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of β-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the disruption of HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus had only moderate effects. Interestingly, interfering with the β-catenin-Bcl9/Bcl9L-Pygo chain of adapters only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGFβ treatments. Together, the results indicate that Bcl9/Bcl9L modulate but are not critically required for canonical Wnt signaling in its contribution to breast cancer growth and malignant progression, a notion consistent with the “just-right” hypothesis of Wnt-driven tumor progression.
Fil: Vafaizadeh vida. Universidad de Basilea; Suiza
Fil: Buechel, David. Universidad de Basilea; Suiza
Fil: Rubinstein, Natalia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Biociencias, Biotecnología y Biología Traslacional.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Kalathur, Ravi K. R.. Universidad de Basilea; Suiza
Fil: Bazzani, Lorenzo. Universidad de Basilea; Suiza
Fil: Saxena, Meera. Universidad de Basilea; Suiza
Fil: Valenta, Tomas. Universitat Zurich; Suiza
Fil: Hausmann, George. Universitat Zurich; Suiza
Fil: Cantù, Claudio. Universitat Zurich; Suiza
Fil: Basler, Konrad. Universitat Zurich; Suiza
Fil: Christofori, Gerhard. Universidad de Basilea; Suiza
description Canonical Wnt/β-catenin signaling is an established regulator of cellular state and its critical contributions to tumor initiation, malignant tumor progression and metastasis formation have been demonstrated in various cancer types. Here, we investigated how the binding of β-catenin to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) affected mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9 and Bcl9L resulted into tumor cell death. In contrast, disrupting the interaction of Bcl9/Bcl9L with β-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of β-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the disruption of HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus had only moderate effects. Interestingly, interfering with the β-catenin-Bcl9/Bcl9L-Pygo chain of adapters only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGFβ treatments. Together, the results indicate that Bcl9/Bcl9L modulate but are not critically required for canonical Wnt signaling in its contribution to breast cancer growth and malignant progression, a notion consistent with the “just-right” hypothesis of Wnt-driven tumor progression.
publishDate 2021
dc.date.none.fl_str_mv 2021-09
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/11336/162718
Vafaizadeh vida; Buechel, David; Rubinstein, Natalia; Kalathur, Ravi K. R.; Bazzani, Lorenzo; et al.; The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis; Nature Publishing Group; Oncogene; 40; 43; 9-2021; 6195-6209
0950-9232
CONICET Digital
CONICET
url http://hdl.handle.net/11336/162718
identifier_str_mv Vafaizadeh vida; Buechel, David; Rubinstein, Natalia; Kalathur, Ravi K. R.; Bazzani, Lorenzo; et al.; The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis; Nature Publishing Group; Oncogene; 40; 43; 9-2021; 6195-6209
0950-9232
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41388-021-02016-9?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+onc%2Frss%2Fcurrent+%28Oncogene+-+Issue%29
info:eu-repo/semantics/altIdentifier/doi/10.1038/s41388-021-02016-9
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/vnd.openxmlformats-officedocument.wordprocessingml.document
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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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