Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells
Interactions between steroid hormone receptors and signal transducer and activator of transcription (Stat)-mediated signaling pathways have already been described. In the present study, we explored the capacity of progestins to modulate Stat3 transcriptional activation in an experimental model of ho...
Guardado en:
| Autores principales: | , , , , , , , , , , |
|---|---|
| Formato: | Artículo publishedVersion |
| Publicado: |
2005
|
| Materias: | |
| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_02707306_v25_n12_p4826_Proietti https://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=artiaex&d=paper_02707306_v25_n12_p4826_Proietti_oai |
| Aporte de: |
| id |
I28-R145-paper_02707306_v25_n12_p4826_Proietti_oai |
|---|---|
| record_format |
dspace |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-145 |
| collection |
Repositorio Digital de la Universidad de Buenos Aires (UBA) |
| topic |
4 amino 7 tert butyl 5 (4 chlorophenyl)pyrazolo[3,4 d]pyrimidine antigestagen Janus kinase Janus kinase 1 Janus kinase 2 medroxyprogesterone acetate mifepristone mutant protein progesterone derivative protein tyrosine kinase STAT3 protein steroid receptor animal cell animal experiment animal model animal tissue article breast adenocarcinoma breast cancer cancer cell cancer model cell growth cell proliferation controlled study enzyme activity enzyme inhibition expression vector female gene induction genetic transfection hormonal carcinogenesis hormonal regulation mouse nonhuman oncogene src priority journal protein DNA binding protein expression protein phosphorylation protein protein interaction protein targeting signal transduction transcription initiation tumor growth Active Transport, Cell Nucleus Animals Antineoplastic Agents, Hormonal Breast Neoplasms Cell Line, Tumor DNA DNA-Binding Proteins Epithelial Cells Female Humans Janus Kinase 1 Janus Kinase 2 Medroxyprogesterone 17-Acetate Mice Mice, Inbred BALB C Progestins Protein-Tyrosine Kinases Proto-Oncogene Proteins Receptors, Progesterone src-Family Kinases STAT3 Transcription Factor Trans-Activation (Genetics) Trans-Activators |
| spellingShingle |
4 amino 7 tert butyl 5 (4 chlorophenyl)pyrazolo[3,4 d]pyrimidine antigestagen Janus kinase Janus kinase 1 Janus kinase 2 medroxyprogesterone acetate mifepristone mutant protein progesterone derivative protein tyrosine kinase STAT3 protein steroid receptor animal cell animal experiment animal model animal tissue article breast adenocarcinoma breast cancer cancer cell cancer model cell growth cell proliferation controlled study enzyme activity enzyme inhibition expression vector female gene induction genetic transfection hormonal carcinogenesis hormonal regulation mouse nonhuman oncogene src priority journal protein DNA binding protein expression protein phosphorylation protein protein interaction protein targeting signal transduction transcription initiation tumor growth Active Transport, Cell Nucleus Animals Antineoplastic Agents, Hormonal Breast Neoplasms Cell Line, Tumor DNA DNA-Binding Proteins Epithelial Cells Female Humans Janus Kinase 1 Janus Kinase 2 Medroxyprogesterone 17-Acetate Mice Mice, Inbred BALB C Progestins Protein-Tyrosine Kinases Proto-Oncogene Proteins Receptors, Progesterone src-Family Kinases STAT3 Transcription Factor Trans-Activation (Genetics) Trans-Activators Proietti, C. Salatino, M. Rosemblit, C. Carnevale, R. Pecci, A. Kornblihtt, A.R. Molinolo, A.A. Frahm, I. Charreau, E.H. Schillaci, R. Elizalde, P.V. Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells |
| topic_facet |
4 amino 7 tert butyl 5 (4 chlorophenyl)pyrazolo[3,4 d]pyrimidine antigestagen Janus kinase Janus kinase 1 Janus kinase 2 medroxyprogesterone acetate mifepristone mutant protein progesterone derivative protein tyrosine kinase STAT3 protein steroid receptor animal cell animal experiment animal model animal tissue article breast adenocarcinoma breast cancer cancer cell cancer model cell growth cell proliferation controlled study enzyme activity enzyme inhibition expression vector female gene induction genetic transfection hormonal carcinogenesis hormonal regulation mouse nonhuman oncogene src priority journal protein DNA binding protein expression protein phosphorylation protein protein interaction protein targeting signal transduction transcription initiation tumor growth Active Transport, Cell Nucleus Animals Antineoplastic Agents, Hormonal Breast Neoplasms Cell Line, Tumor DNA DNA-Binding Proteins Epithelial Cells Female Humans Janus Kinase 1 Janus Kinase 2 Medroxyprogesterone 17-Acetate Mice Mice, Inbred BALB C Progestins Protein-Tyrosine Kinases Proto-Oncogene Proteins Receptors, Progesterone src-Family Kinases STAT3 Transcription Factor Trans-Activation (Genetics) Trans-Activators |
| description |
Interactions between steroid hormone receptors and signal transducer and activator of transcription (Stat)-mediated signaling pathways have already been described. In the present study, we explored the capacity of progestins to modulate Stat3 transcriptional activation in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in BALB/c mice and in the human breast cancer cell line T47D. We found that C4HD epithelial cells, from the MPA-induced mammary tumor model, expressed Stat3 and that MPA treatment of C4HD cells up-regulated Stat3 protein expression. In addition, MPA induced rapid, nongenomic Stat3, Jak1, and Jak2 tyrosine phosphorylation in C4HD and T47D cells. MPA treatment of C4HD cells also resulted in rapid c-Src tyrosine phosphorylation. These effects were completely abolished by the progestin antagonist RU486. Abrogation of Jak1 and Jak2 activity by transient transaction of C4HD cells with dominant negative (DN) Jak1 or DN Jak2 vectors, or inhibition of Src activity by preincubation of cells with the Src family kinase inhibitor PP2, blocked the capacity of MPA to induce Stat3 phosphorylation. Treatment of C4HD cells with MPA induced Stat3 binding to DNA. In addition, MPA promoted strong Stat3 transcriptional activation in C4HD and T47D cells that was inhibited by RU486 and by blockage of Jak1, Jak2, and Src activities. To investigate the correlation between MPA-induced Stat3 activation and cell growth, C4HD cells were transiently transfected with a DN Stat3 expression vector, Stat3Y705-F, or with a constitutively activated Stat3 mutant, Stat3-C. While expression of Stat3Y705-F mutant had an inhibitory effect on MPA-induced growth of C4HD cells, transfection with the constitutively activated Stat3-C vector resulted in MPA-independent proliferation. Finally, we addressed the effect of targeting Stat3 in in vivo growth of C4HD breast tumors. Blockage of Stat3 activation by transfection of C4HD cells with the DN Stat3Y705-F expression vector significantly inhibited these cells' ability to form tumors in syngeneic mice. Our results have for the first time demonstrated that progestins are able to induce Stat3 transcriptional activation, which is in turn an obligatory requirement for progestin stimulation of both in vitro and in vivo breast cancer growth. Copyright © 2005, American Society for Microbiology. All Rights Reserved. |
| format |
Artículo Artículo publishedVersion |
| author |
Proietti, C. Salatino, M. Rosemblit, C. Carnevale, R. Pecci, A. Kornblihtt, A.R. Molinolo, A.A. Frahm, I. Charreau, E.H. Schillaci, R. Elizalde, P.V. |
| author_facet |
Proietti, C. Salatino, M. Rosemblit, C. Carnevale, R. Pecci, A. Kornblihtt, A.R. Molinolo, A.A. Frahm, I. Charreau, E.H. Schillaci, R. Elizalde, P.V. |
| author_sort |
Proietti, C. |
| title |
Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells |
| title_short |
Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells |
| title_full |
Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells |
| title_fullStr |
Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells |
| title_full_unstemmed |
Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells |
| title_sort |
progestins induce transcriptional activation of signal transducer and activator of transcription 3 (stat3) via a jak- and src-dependent mechanism in breast cancer cells |
| publishDate |
2005 |
| url |
http://hdl.handle.net/20.500.12110/paper_02707306_v25_n12_p4826_Proietti https://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=artiaex&d=paper_02707306_v25_n12_p4826_Proietti_oai |
| work_keys_str_mv |
AT proiettic progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells AT salatinom progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells AT rosemblitc progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells AT carnevaler progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells AT peccia progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells AT kornblihttar progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells AT molinoloaa progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells AT frahmi progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells AT charreaueh progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells AT schillacir progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells AT elizaldepv progestinsinducetranscriptionalactivationofsignaltransducerandactivatoroftranscription3stat3viaajakandsrcdependentmechanisminbreastcancercells |
| _version_ |
1809357219449274368 |
| spelling |
I28-R145-paper_02707306_v25_n12_p4826_Proietti_oai2024-08-16 Proietti, C. Salatino, M. Rosemblit, C. Carnevale, R. Pecci, A. Kornblihtt, A.R. Molinolo, A.A. Frahm, I. Charreau, E.H. Schillaci, R. Elizalde, P.V. 2005 Interactions between steroid hormone receptors and signal transducer and activator of transcription (Stat)-mediated signaling pathways have already been described. In the present study, we explored the capacity of progestins to modulate Stat3 transcriptional activation in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in BALB/c mice and in the human breast cancer cell line T47D. We found that C4HD epithelial cells, from the MPA-induced mammary tumor model, expressed Stat3 and that MPA treatment of C4HD cells up-regulated Stat3 protein expression. In addition, MPA induced rapid, nongenomic Stat3, Jak1, and Jak2 tyrosine phosphorylation in C4HD and T47D cells. MPA treatment of C4HD cells also resulted in rapid c-Src tyrosine phosphorylation. These effects were completely abolished by the progestin antagonist RU486. Abrogation of Jak1 and Jak2 activity by transient transaction of C4HD cells with dominant negative (DN) Jak1 or DN Jak2 vectors, or inhibition of Src activity by preincubation of cells with the Src family kinase inhibitor PP2, blocked the capacity of MPA to induce Stat3 phosphorylation. Treatment of C4HD cells with MPA induced Stat3 binding to DNA. In addition, MPA promoted strong Stat3 transcriptional activation in C4HD and T47D cells that was inhibited by RU486 and by blockage of Jak1, Jak2, and Src activities. To investigate the correlation between MPA-induced Stat3 activation and cell growth, C4HD cells were transiently transfected with a DN Stat3 expression vector, Stat3Y705-F, or with a constitutively activated Stat3 mutant, Stat3-C. While expression of Stat3Y705-F mutant had an inhibitory effect on MPA-induced growth of C4HD cells, transfection with the constitutively activated Stat3-C vector resulted in MPA-independent proliferation. Finally, we addressed the effect of targeting Stat3 in in vivo growth of C4HD breast tumors. Blockage of Stat3 activation by transfection of C4HD cells with the DN Stat3Y705-F expression vector significantly inhibited these cells' ability to form tumors in syngeneic mice. Our results have for the first time demonstrated that progestins are able to induce Stat3 transcriptional activation, which is in turn an obligatory requirement for progestin stimulation of both in vitro and in vivo breast cancer growth. Copyright © 2005, American Society for Microbiology. All Rights Reserved. Fil:Proietti, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Salatino, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Rosemblit, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Carnevale, R. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Pecci, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Kornblihtt, A.R. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Charreau, E.H. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Elizalde, P.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. application/pdf http://hdl.handle.net/20.500.12110/paper_02707306_v25_n12_p4826_Proietti info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar Mol. Cell. Biol. 2005;25(12):4826-4840 4 amino 7 tert butyl 5 (4 chlorophenyl)pyrazolo[3,4 d]pyrimidine antigestagen Janus kinase Janus kinase 1 Janus kinase 2 medroxyprogesterone acetate mifepristone mutant protein progesterone derivative protein tyrosine kinase STAT3 protein steroid receptor animal cell animal experiment animal model animal tissue article breast adenocarcinoma breast cancer cancer cell cancer model cell growth cell proliferation controlled study enzyme activity enzyme inhibition expression vector female gene induction genetic transfection hormonal carcinogenesis hormonal regulation mouse nonhuman oncogene src priority journal protein DNA binding protein expression protein phosphorylation protein protein interaction protein targeting signal transduction transcription initiation tumor growth Active Transport, Cell Nucleus Animals Antineoplastic Agents, Hormonal Breast Neoplasms Cell Line, Tumor DNA DNA-Binding Proteins Epithelial Cells Female Humans Janus Kinase 1 Janus Kinase 2 Medroxyprogesterone 17-Acetate Mice Mice, Inbred BALB C Progestins Protein-Tyrosine Kinases Proto-Oncogene Proteins Receptors, Progesterone src-Family Kinases STAT3 Transcription Factor Trans-Activation (Genetics) Trans-Activators Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells info:eu-repo/semantics/article info:ar-repo/semantics/artículo info:eu-repo/semantics/publishedVersion https://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=artiaex&d=paper_02707306_v25_n12_p4826_Proietti_oai |