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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/12865
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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 Técnicas2025-09-29T09:41:46Zoai: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:34982025-09-29 09:41:46.659CONICET 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 |
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1844613317547524096 |
score |
13.070432 |