Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer

Autores
Parker, B. S.; Ciocca, Daniel Ramon; Bidwell, B. N.; Gago, Francisco Eduardo; Fanelli, Mariel Andrea; George, J.; Slavin, J. L.; Möller, A.; Steel, R.; Pouliot, N.; Eckhardt, B. L.; Henderson, M. A.; Anderson, R. L.
Año de publicación
2008
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Using the clinically relevant 4T1-derived syngeneic murine model of spontaneous mammary metastasis to bone, we have identified the cysteine cathepsin inhibitor Stefin A as a gene differentially expressed in primary and metastatic mammary tumours. In primary tumours, Stefin A expression correlated inversely with metastatic potential in 4T1-derived lines and was not detected in tumour cells in culture, indicating induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metastatic 4T1.2 cell line significantly reduced spontaneous bone metastasis following orthotopic injection into the mammary gland. Consistent with the mouse data, Stefin A expression correlated with disease-free survival (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test, p = 0.0075). In a multivariate disease-free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p = 0.0014), along with grade and progesterone receptor (PR) status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2 mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. Using immunohistology, the cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases in both the murine model and human tissues. We conclude that Stefin A expression reduces distant metastasis in breast cancer and propose that this may be due to the inhibition of cysteine cathepsins, such as cathepsin B.
Fil: Parker, B. S.. University of Melbourne; Australia
Fil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Bidwell, B. N.. University of Melbourne; Australia
Fil: Gago, Francisco Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: George, J.. Peter MacCallum Cancer Centre; Australia
Fil: Slavin, J. L.. University of Melbourne; Australia
Fil: Möller, A.. Peter MacCallum Cancer; Australia. , University of Melbourne; Australia
Fil: Steel, R.. Peter MacCallum Cancer; Australia. University of Melbourne; Australia
Fil: Pouliot, N.. Peter MacCallum Cancer; Australia. University of Melbourne; Australia
Fil: Eckhardt, B. L.. Peter MacCallum Cancer; Australia. University of Melbourne; Australia
Fil: Henderson, M. A.. Peter MacCallum Cancer; Australia
Fil: Anderson, R. L.. Peter MacCallum Cancer; Australia. University of Melbourne; Australia
Materia
BONE METASTASIS
BREAST CANCER
CYSTEINE CATHEPSINS
STEFIN A
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:11336/130099
Acceder
id CONICETDig_86ff048e27132762e3e1dcd16c7a3dbb
oai_identifier_str oai:ri.conicet.gov.ar:11336/130099
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancerParker, B. S.Ciocca, Daniel RamonBidwell, B. N.Gago, Francisco EduardoFanelli, Mariel AndreaGeorge, J.Slavin, J. L.Möller, A.Steel, R.Pouliot, N.Eckhardt, B. L.Henderson, M. A.Anderson, R. L.BONE METASTASISBREAST CANCERCYSTEINE CATHEPSINSSTEFIN Ahttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Using the clinically relevant 4T1-derived syngeneic murine model of spontaneous mammary metastasis to bone, we have identified the cysteine cathepsin inhibitor Stefin A as a gene differentially expressed in primary and metastatic mammary tumours. In primary tumours, Stefin A expression correlated inversely with metastatic potential in 4T1-derived lines and was not detected in tumour cells in culture, indicating induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metastatic 4T1.2 cell line significantly reduced spontaneous bone metastasis following orthotopic injection into the mammary gland. Consistent with the mouse data, Stefin A expression correlated with disease-free survival (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test, p = 0.0075). In a multivariate disease-free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p = 0.0014), along with grade and progesterone receptor (PR) status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2 mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. Using immunohistology, the cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases in both the murine model and human tissues. We conclude that Stefin A expression reduces distant metastasis in breast cancer and propose that this may be due to the inhibition of cysteine cathepsins, such as cathepsin B.Fil: Parker, B. S.. University of Melbourne; AustraliaFil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Bidwell, B. N.. University of Melbourne; AustraliaFil: Gago, Francisco Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: George, J.. Peter MacCallum Cancer Centre; AustraliaFil: Slavin, J. L.. University of Melbourne; AustraliaFil: Möller, A.. Peter MacCallum Cancer; Australia. , University of Melbourne; AustraliaFil: Steel, R.. Peter MacCallum Cancer; Australia. University of Melbourne; AustraliaFil: Pouliot, N.. Peter MacCallum Cancer; Australia. University of Melbourne; AustraliaFil: Eckhardt, B. L.. Peter MacCallum Cancer; Australia. University of Melbourne; AustraliaFil: Henderson, M. A.. Peter MacCallum Cancer; AustraliaFil: Anderson, R. L.. Peter MacCallum Cancer; Australia. University of Melbourne; AustraliaJohn Wiley & Sons Ltd2008-10info: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/11336/130099Parker, B. S.; Ciocca, Daniel Ramon; Bidwell, B. N.; Gago, Francisco Eduardo; Fanelli, Mariel Andrea; et al.; Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer; John Wiley & Sons Ltd; Journal of Pathology; 214; 3; 10-2008; 337-3460022-3417CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1002/path.2265info:eu-repo/semantics/altIdentifier/doi/10.1002/path.2265info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:49:03Zoai:ri.conicet.gov.ar:11336/130099instacron: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:34982025-09-29 09:49:04.145CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer
title Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer
spellingShingle Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer
Parker, B. S.
BONE METASTASIS
BREAST CANCER
CYSTEINE CATHEPSINS
STEFIN A
title_short Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer
title_full Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer
title_fullStr Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer
title_full_unstemmed Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer
title_sort Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer
dc.creator.none.fl_str_mv Parker, B. S.
Ciocca, Daniel Ramon
Bidwell, B. N.
Gago, Francisco Eduardo
Fanelli, Mariel Andrea
George, J.
Slavin, J. L.
Möller, A.
Steel, R.
Pouliot, N.
Eckhardt, B. L.
Henderson, M. A.
Anderson, R. L.
author Parker, B. S.
author_facet Parker, B. S.
Ciocca, Daniel Ramon
Bidwell, B. N.
Gago, Francisco Eduardo
Fanelli, Mariel Andrea
George, J.
Slavin, J. L.
Möller, A.
Steel, R.
Pouliot, N.
Eckhardt, B. L.
Henderson, M. A.
Anderson, R. L.
author_role author
author2 Ciocca, Daniel Ramon
Bidwell, B. N.
Gago, Francisco Eduardo
Fanelli, Mariel Andrea
George, J.
Slavin, J. L.
Möller, A.
Steel, R.
Pouliot, N.
Eckhardt, B. L.
Henderson, M. A.
Anderson, R. L.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BONE METASTASIS
BREAST CANCER
CYSTEINE CATHEPSINS
STEFIN A
topic BONE METASTASIS
BREAST CANCER
CYSTEINE CATHEPSINS
STEFIN A
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Using the clinically relevant 4T1-derived syngeneic murine model of spontaneous mammary metastasis to bone, we have identified the cysteine cathepsin inhibitor Stefin A as a gene differentially expressed in primary and metastatic mammary tumours. In primary tumours, Stefin A expression correlated inversely with metastatic potential in 4T1-derived lines and was not detected in tumour cells in culture, indicating induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metastatic 4T1.2 cell line significantly reduced spontaneous bone metastasis following orthotopic injection into the mammary gland. Consistent with the mouse data, Stefin A expression correlated with disease-free survival (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test, p = 0.0075). In a multivariate disease-free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p = 0.0014), along with grade and progesterone receptor (PR) status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2 mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. Using immunohistology, the cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases in both the murine model and human tissues. We conclude that Stefin A expression reduces distant metastasis in breast cancer and propose that this may be due to the inhibition of cysteine cathepsins, such as cathepsin B.
Fil: Parker, B. S.. University of Melbourne; Australia
Fil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Bidwell, B. N.. University of Melbourne; Australia
Fil: Gago, Francisco Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina
Fil: George, J.. Peter MacCallum Cancer Centre; Australia
Fil: Slavin, J. L.. University of Melbourne; Australia
Fil: Möller, A.. Peter MacCallum Cancer; Australia. , University of Melbourne; Australia
Fil: Steel, R.. Peter MacCallum Cancer; Australia. University of Melbourne; Australia
Fil: Pouliot, N.. Peter MacCallum Cancer; Australia. University of Melbourne; Australia
Fil: Eckhardt, B. L.. Peter MacCallum Cancer; Australia. University of Melbourne; Australia
Fil: Henderson, M. A.. Peter MacCallum Cancer; Australia
Fil: Anderson, R. L.. Peter MacCallum Cancer; Australia. University of Melbourne; Australia
description Using the clinically relevant 4T1-derived syngeneic murine model of spontaneous mammary metastasis to bone, we have identified the cysteine cathepsin inhibitor Stefin A as a gene differentially expressed in primary and metastatic mammary tumours. In primary tumours, Stefin A expression correlated inversely with metastatic potential in 4T1-derived lines and was not detected in tumour cells in culture, indicating induction only within the tumour microenvironment. Enforced expression of Stefin A in the highly metastatic 4T1.2 cell line significantly reduced spontaneous bone metastasis following orthotopic injection into the mammary gland. Consistent with the mouse data, Stefin A expression correlated with disease-free survival (absence of distant metastasis) in a cohort of 142 primary tumours from breast cancer patients. This was most significant for patients with invasive ductal carcinoma expressing Stefin A, who were less likely to develop distant metastases (log rank test, p = 0.0075). In a multivariate disease-free survival analysis (Cox proportional hazards model), Stefin A expression remained a significant independent prognostic factor in patients with invasive ductal carcinoma (p = 0.0014), along with grade and progesterone receptor (PR) status. In human lung and bone metastases, we detected irregular Stefin A staining patterns, with expression often localizing to micrometastases (<0.2 mm) in direct contact with the stroma. We propose that Stefin A, as a cysteine cathepsin inhibitor, may be a marker of increased cathepsin activity in metastases. Using immunohistology, the cathepsin inhibitor was detected co-expressed with cathepsin B in lung and bone metastases in both the murine model and human tissues. We conclude that Stefin A expression reduces distant metastasis in breast cancer and propose that this may be due to the inhibition of cysteine cathepsins, such as cathepsin B.
publishDate 2008
dc.date.none.fl_str_mv 2008-10
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/11336/130099
Parker, B. S.; Ciocca, Daniel Ramon; Bidwell, B. N.; Gago, Francisco Eduardo; Fanelli, Mariel Andrea; et al.; Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer; John Wiley & Sons Ltd; Journal of Pathology; 214; 3; 10-2008; 337-346
0022-3417
CONICET Digital
CONICET
url http://hdl.handle.net/11336/130099
identifier_str_mv Parker, B. S.; Ciocca, Daniel Ramon; Bidwell, B. N.; Gago, Francisco Eduardo; Fanelli, Mariel Andrea; et al.; Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer; John Wiley & Sons Ltd; Journal of Pathology; 214; 3; 10-2008; 337-346
0022-3417
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://onlinelibrary.wiley.com/doi/abs/10.1002/path.2265
info:eu-repo/semantics/altIdentifier/doi/10.1002/path.2265
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 John Wiley & Sons Ltd
publisher.none.fl_str_mv John Wiley & Sons Ltd
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 13.070432

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