Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2

Autores
Díaz Flaqué, María Celeste; Vicario, Rocío; Proietti Anastasi, Cecilia Jazmín; Izzo, Franco; Schillaci, Roxana; Elizalde, Patricia Virginia
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Cell cycle regulator p21CIP1 has controversial biological effects in breast cancer since in spite of its role as cell cycle inhibitor and promoter of cellular senescence, it also induces cell proliferation and chemoteraphy resistance. We here explored the molecular mechanisms involved in progestin regulation of p21CIP1 expression. We also investigated the biological effects of p21CIP1 in breast cancer cells. We found that the synthetic progestin medroxyprogesterone acetate (MPA) upregulates p21CIP1 protein expression via c-Src, signal transducer and activator of transcription 3 (Stat3) and ErbB-2 phosphorylation. Notably, we also found that ErbB-2 nuclear function plays a key role in MPA-induction of p21CIP1 expression. Interestingly, we determined that progestin drives p21CIP1 transcriptional activation via a novel nonclassical transcriptional mechanism in which progesterone receptor is recruited along with Stat3 and ErbB-2 to a Stat3 binding site at p21CIP1 promoter. Our findings revealed that ErbB-2 functions as a coactivator of Stat3 in progestin induction of p21CIP1 transcriptional activation. Furthermore, we demonstrated that blockage of p21CIP1 expression strongly inhibited in vitro and in vivo progestin-induced breast cancer cell proliferation. These results further support the hypothesis that according to cell context and type of stimulus, p21CIP1 is capable of inducing cell cycle progression. Moreover, we provided evidence that Stat3 and nuclear ErbB-2 are key players in progestin-induced p21CIP1 regulation.
Fil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Vicario, Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Izzo, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Materia
Progesterone Receptor
Sta3
P21cip1
Breast Cancer
Erb-2
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/5537
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/5537
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2Díaz Flaqué, María CelesteVicario, RocíoProietti Anastasi, Cecilia JazmínIzzo, FrancoSchillaci, RoxanaElizalde, Patricia VirginiaProgesterone ReceptorSta3P21cip1Breast CancerErb-2https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Cell cycle regulator p21CIP1 has controversial biological effects in breast cancer since in spite of its role as cell cycle inhibitor and promoter of cellular senescence, it also induces cell proliferation and chemoteraphy resistance. We here explored the molecular mechanisms involved in progestin regulation of p21CIP1 expression. We also investigated the biological effects of p21CIP1 in breast cancer cells. We found that the synthetic progestin medroxyprogesterone acetate (MPA) upregulates p21CIP1 protein expression via c-Src, signal transducer and activator of transcription 3 (Stat3) and ErbB-2 phosphorylation. Notably, we also found that ErbB-2 nuclear function plays a key role in MPA-induction of p21CIP1 expression. Interestingly, we determined that progestin drives p21CIP1 transcriptional activation via a novel nonclassical transcriptional mechanism in which progesterone receptor is recruited along with Stat3 and ErbB-2 to a Stat3 binding site at p21CIP1 promoter. Our findings revealed that ErbB-2 functions as a coactivator of Stat3 in progestin induction of p21CIP1 transcriptional activation. Furthermore, we demonstrated that blockage of p21CIP1 expression strongly inhibited in vitro and in vivo progestin-induced breast cancer cell proliferation. These results further support the hypothesis that according to cell context and type of stimulus, p21CIP1 is capable of inducing cell cycle progression. Moreover, we provided evidence that Stat3 and nuclear ErbB-2 are key players in progestin-induced p21CIP1 regulation.Fil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Vicario, Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Izzo, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaElsevier2013-06-30info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/5537Díaz Flaqué, María Celeste; Vicario, Rocío; Proietti Anastasi, Cecilia Jazmín; Izzo, Franco; Schillaci, Roxana; et al.; Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2; Elsevier; Steroids; 78; 6; 30-6-2013; 559-5670039-128X1878-5867enginfo:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/altIdentifier/pmid/23178160info:eu-repo/semantics/altIdentifier/doi/d10.1016/j.steroids.2012.11.003info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0039128X12003030info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:37:10Zoai:ri.conicet.gov.ar:11336/5537instacron: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 10:37:11.197CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2
title Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2
spellingShingle Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2
Díaz Flaqué, María Celeste
Progesterone Receptor
Sta3
P21cip1
Breast Cancer
Erb-2
title_short Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2
title_full Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2
title_fullStr Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2
title_full_unstemmed Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2
title_sort Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2
dc.creator.none.fl_str_mv Díaz Flaqué, María Celeste
Vicario, Rocío
Proietti Anastasi, Cecilia Jazmín
Izzo, Franco
Schillaci, Roxana
Elizalde, Patricia Virginia
author Díaz Flaqué, María Celeste
author_facet Díaz Flaqué, María Celeste
Vicario, Rocío
Proietti Anastasi, Cecilia Jazmín
Izzo, Franco
Schillaci, Roxana
Elizalde, Patricia Virginia
author_role author
author2 Vicario, Rocío
Proietti Anastasi, Cecilia Jazmín
Izzo, Franco
Schillaci, Roxana
Elizalde, Patricia Virginia
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Progesterone Receptor
Sta3
P21cip1
Breast Cancer
Erb-2
topic Progesterone Receptor
Sta3
P21cip1
Breast Cancer
Erb-2
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Cell cycle regulator p21CIP1 has controversial biological effects in breast cancer since in spite of its role as cell cycle inhibitor and promoter of cellular senescence, it also induces cell proliferation and chemoteraphy resistance. We here explored the molecular mechanisms involved in progestin regulation of p21CIP1 expression. We also investigated the biological effects of p21CIP1 in breast cancer cells. We found that the synthetic progestin medroxyprogesterone acetate (MPA) upregulates p21CIP1 protein expression via c-Src, signal transducer and activator of transcription 3 (Stat3) and ErbB-2 phosphorylation. Notably, we also found that ErbB-2 nuclear function plays a key role in MPA-induction of p21CIP1 expression. Interestingly, we determined that progestin drives p21CIP1 transcriptional activation via a novel nonclassical transcriptional mechanism in which progesterone receptor is recruited along with Stat3 and ErbB-2 to a Stat3 binding site at p21CIP1 promoter. Our findings revealed that ErbB-2 functions as a coactivator of Stat3 in progestin induction of p21CIP1 transcriptional activation. Furthermore, we demonstrated that blockage of p21CIP1 expression strongly inhibited in vitro and in vivo progestin-induced breast cancer cell proliferation. These results further support the hypothesis that according to cell context and type of stimulus, p21CIP1 is capable of inducing cell cycle progression. Moreover, we provided evidence that Stat3 and nuclear ErbB-2 are key players in progestin-induced p21CIP1 regulation.
Fil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Vicario, Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Izzo, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
description Cell cycle regulator p21CIP1 has controversial biological effects in breast cancer since in spite of its role as cell cycle inhibitor and promoter of cellular senescence, it also induces cell proliferation and chemoteraphy resistance. We here explored the molecular mechanisms involved in progestin regulation of p21CIP1 expression. We also investigated the biological effects of p21CIP1 in breast cancer cells. We found that the synthetic progestin medroxyprogesterone acetate (MPA) upregulates p21CIP1 protein expression via c-Src, signal transducer and activator of transcription 3 (Stat3) and ErbB-2 phosphorylation. Notably, we also found that ErbB-2 nuclear function plays a key role in MPA-induction of p21CIP1 expression. Interestingly, we determined that progestin drives p21CIP1 transcriptional activation via a novel nonclassical transcriptional mechanism in which progesterone receptor is recruited along with Stat3 and ErbB-2 to a Stat3 binding site at p21CIP1 promoter. Our findings revealed that ErbB-2 functions as a coactivator of Stat3 in progestin induction of p21CIP1 transcriptional activation. Furthermore, we demonstrated that blockage of p21CIP1 expression strongly inhibited in vitro and in vivo progestin-induced breast cancer cell proliferation. These results further support the hypothesis that according to cell context and type of stimulus, p21CIP1 is capable of inducing cell cycle progression. Moreover, we provided evidence that Stat3 and nuclear ErbB-2 are key players in progestin-induced p21CIP1 regulation.
publishDate 2013
dc.date.none.fl_str_mv 2013-06-30
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/11336/5537
Díaz Flaqué, María Celeste; Vicario, Rocío; Proietti Anastasi, Cecilia Jazmín; Izzo, Franco; Schillaci, Roxana; et al.; Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2; Elsevier; Steroids; 78; 6; 30-6-2013; 559-567
0039-128X
1878-5867
url http://hdl.handle.net/11336/5537
identifier_str_mv Díaz Flaqué, María Celeste; Vicario, Rocío; Proietti Anastasi, Cecilia Jazmín; Izzo, Franco; Schillaci, Roxana; et al.; Progestin drives breast cancer growth by inducing p21CIP1 expression through the assembly of a transcriptional complex among Stat3, progesterone receptor and ErbB-2; Elsevier; Steroids; 78; 6; 30-6-2013; 559-567
0039-128X
1878-5867
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/
info:eu-repo/semantics/altIdentifier/pmid/23178160
info:eu-repo/semantics/altIdentifier/doi/d10.1016/j.steroids.2012.11.003
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0039128X12003030
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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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