TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression

Autores
Daroqui, Maria Cecilia; Vazquez, Paula; Bal, Elisa Dora; Bakin, Andrei V.; Puricelli, Lydia I.
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-beta (TGF-beta) cytokines. In early-stage breast cancers, TGF-beta exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-beta promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-beta are not fully understood. The present study validates the role of TGF-beta signaling in cancer progression and explores mediators of pro-oncogenic TGF-beta activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-beta receptors decreased both basal and TGF-beta-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-beta stimulation of cell motility and invasion. TGF-beta disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-beta. Blockade of Raf-MEK signaling enhanced TGF-beta induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-beta rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-beta stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-beta receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-beta signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-beta-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-beta signaling.
Fil: Daroqui, Maria Cecilia. Montefiore Medical Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Vazquez, Paula. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; Argentina
Fil: Bal, Elisa Dora. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bakin, Andrei V.. Roswell Park Cancer Institute; Estados Unidos
Fil: Puricelli, Lydia I.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; Argentina
Materia
MAMMARY CANCER CELL LINE
TGF B
MAPK SIGNALING PATHWAYS
TUMOR PROGRESSION
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:11336/12865
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/12865
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progressionDaroqui, Maria CeciliaVazquez, PaulaBal, Elisa DoraBakin, Andrei V.Puricelli, Lydia I.MAMMARY CANCER CELL LINETGF BMAPK SIGNALING PATHWAYSTUMOR PROGRESSIONhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-beta (TGF-beta) cytokines. In early-stage breast cancers, TGF-beta exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-beta promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-beta are not fully understood. The present study validates the role of TGF-beta signaling in cancer progression and explores mediators of pro-oncogenic TGF-beta activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-beta receptors decreased both basal and TGF-beta-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-beta stimulation of cell motility and invasion. TGF-beta disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-beta. Blockade of Raf-MEK signaling enhanced TGF-beta induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-beta rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-beta stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-beta receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-beta signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-beta-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-beta signaling.Fil: Daroqui, Maria Cecilia. Montefiore Medical Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vazquez, Paula. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; ArgentinaFil: Bal, Elisa Dora. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bakin, Andrei V.. Roswell Park Cancer Institute; Estados UnidosFil: Puricelli, Lydia I.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; ArgentinaSpandidos Publ Ltd2012-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/12865Daroqui, Maria Cecilia; Vazquez, Paula; Bal, Elisa Dora; Bakin, Andrei V.; Puricelli, Lydia I.; TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression; Spandidos Publ Ltd; Oncology Reports; 28; 2; 8-2012; 567-5751021-335Xenginfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981025/info:eu-repo/semantics/altIdentifier/url/https://www.spandidos-publications.com/or/28/2/567info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:10:22Zoai:ri.conicet.gov.ar:11336/12865instacron: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:34982025-10-22 11:10:22.945CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression
title TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression
spellingShingle TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression
Daroqui, Maria Cecilia
MAMMARY CANCER CELL LINE
TGF B
MAPK SIGNALING PATHWAYS
TUMOR PROGRESSION
title_short TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression
title_full TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression
title_fullStr TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression
title_full_unstemmed TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression
title_sort TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression
dc.creator.none.fl_str_mv Daroqui, Maria Cecilia
Vazquez, Paula
Bal, Elisa Dora
Bakin, Andrei V.
Puricelli, Lydia I.
author Daroqui, Maria Cecilia
author_facet Daroqui, Maria Cecilia
Vazquez, Paula
Bal, Elisa Dora
Bakin, Andrei V.
Puricelli, Lydia I.
author_role author
author2 Vazquez, Paula
Bal, Elisa Dora
Bakin, Andrei V.
Puricelli, Lydia I.
author2_role author
author
author
author
dc.subject.none.fl_str_mv MAMMARY CANCER CELL LINE
TGF B
MAPK SIGNALING PATHWAYS
TUMOR PROGRESSION
topic MAMMARY CANCER CELL LINE
TGF B
MAPK SIGNALING PATHWAYS
TUMOR PROGRESSION
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-beta (TGF-beta) cytokines. In early-stage breast cancers, TGF-beta exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-beta promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-beta are not fully understood. The present study validates the role of TGF-beta signaling in cancer progression and explores mediators of pro-oncogenic TGF-beta activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-beta receptors decreased both basal and TGF-beta-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-beta stimulation of cell motility and invasion. TGF-beta disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-beta. Blockade of Raf-MEK signaling enhanced TGF-beta induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-beta rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-beta stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-beta receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-beta signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-beta-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-beta signaling.
Fil: Daroqui, Maria Cecilia. Montefiore Medical Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Vazquez, Paula. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; Argentina
Fil: Bal, Elisa Dora. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Bakin, Andrei V.. Roswell Park Cancer Institute; Estados Unidos
Fil: Puricelli, Lydia I.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; Argentina
description Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-beta (TGF-beta) cytokines. In early-stage breast cancers, TGF-beta exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-beta promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-beta are not fully understood. The present study validates the role of TGF-beta signaling in cancer progression and explores mediators of pro-oncogenic TGF-beta activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-beta receptors decreased both basal and TGF-beta-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-beta stimulation of cell motility and invasion. TGF-beta disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-beta. Blockade of Raf-MEK signaling enhanced TGF-beta induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-beta rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-beta stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-beta receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-beta signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-beta-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-beta signaling.
publishDate 2012
dc.date.none.fl_str_mv 2012-08
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/11336/12865
Daroqui, Maria Cecilia; Vazquez, Paula; Bal, Elisa Dora; Bakin, Andrei V.; Puricelli, Lydia I.; TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression; Spandidos Publ Ltd; Oncology Reports; 28; 2; 8-2012; 567-575
1021-335X
url http://hdl.handle.net/11336/12865
identifier_str_mv Daroqui, Maria Cecilia; Vazquez, Paula; Bal, Elisa Dora; Bakin, Andrei V.; Puricelli, Lydia I.; TGF-beta autocrine pathway and MAPK signaling promote cell invasiveness and in vivo mammary adenocarcinoma tumor progression; Spandidos Publ Ltd; Oncology Reports; 28; 2; 8-2012; 567-575
1021-335X
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981025/
info:eu-repo/semantics/altIdentifier/url/https://www.spandidos-publications.com/or/28/2/567
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
dc.publisher.none.fl_str_mv Spandidos Publ Ltd
publisher.none.fl_str_mv Spandidos Publ 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
_version_ 1846781463826006016
score 12.982451

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