RANKL/RANK control Brca1 mutation-driven mammary tumors

Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, usi...

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Detalles Bibliográficos
Autores: Sigl, Verena, Vidal Ocabo, Enrique, Penninger, Josef M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/30835
Acceso en línea:http://hdl.handle.net/10230/30835
http://dx.doi.org/10.1038/cr.2016.69
Access Level:acceso abierto
Palabra clave:BRCA1
RANK
RANKL
Inherited breast cancer
Mammary progenitor cells
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spelling RANKL/RANK control Brca1 mutation-driven mammary tumorsSigl, VerenaVidal Ocabo, EnriquePenninger, Josef M.BRCA1RANKRANKLInherited breast cancerMammary progenitor cellsBreast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients.Nature Publishing Group201720172016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/30835http://dx.doi.org/10.1038/cr.2016.69reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésCell Research. 2016;26:761-74© Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/308352026-05-29T05:05:01Z
dc.title.none.fl_str_mv RANKL/RANK control Brca1 mutation-driven mammary tumors
title RANKL/RANK control Brca1 mutation-driven mammary tumors
spellingShingle RANKL/RANK control Brca1 mutation-driven mammary tumors
Sigl, Verena
BRCA1
RANK
RANKL
Inherited breast cancer
Mammary progenitor cells
title_short RANKL/RANK control Brca1 mutation-driven mammary tumors
title_full RANKL/RANK control Brca1 mutation-driven mammary tumors
title_fullStr RANKL/RANK control Brca1 mutation-driven mammary tumors
title_full_unstemmed RANKL/RANK control Brca1 mutation-driven mammary tumors
title_sort RANKL/RANK control Brca1 mutation-driven mammary tumors
dc.creator.none.fl_str_mv Sigl, Verena
Vidal Ocabo, Enrique
Penninger, Josef M.
author Sigl, Verena
author_facet Sigl, Verena
Vidal Ocabo, Enrique
Penninger, Josef M.
author_role author
author2 Vidal Ocabo, Enrique
Penninger, Josef M.
author2_role author
author
dc.subject.none.fl_str_mv BRCA1
RANK
RANKL
Inherited breast cancer
Mammary progenitor cells
topic BRCA1
RANK
RANKL
Inherited breast cancer
Mammary progenitor cells
description Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients.
publishDate 2016
dc.date.none.fl_str_mv 2016
2017
2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/30835
http://dx.doi.org/10.1038/cr.2016.69
url http://hdl.handle.net/10230/30835
http://dx.doi.org/10.1038/cr.2016.69
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Cell Research. 2016;26:761-74
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
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:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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