Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy
Introduction: The role of the progesterone receptor (PR) in breast cancer remains a major clinical challenge. Although PR induces mammary tumor growth, its presence in breast tumors is a marker of good prognosis. We investigated coordinated PR rapid and nonclassical transcriptional effects governing...
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2013
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_14655411_v15_n6_p_DiazFlaque http://hdl.handle.net/20.500.12110/paper_14655411_v15_n6_p_DiazFlaque |
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paper:paper_14655411_v15_n6_p_DiazFlaque2023-06-08T16:16:50Z Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy CCND1 protein, human cyclin D1 epidermal growth factor receptor 2 ERBB2 protein, human medroxyprogesterone acetate progesterone receptor selective estrogen receptor modulator STAT3 protein Stat3 protein, mouse tamoxifen transcription factor AP 1 animal Bagg albino mouse Breast Neoplasms cell nucleus drug effects female follow up genetics human metabolism mortality pathology phosphorylation promoter region retrospective study treatment outcome Animals Breast Neoplasms Cell Nucleus Cyclin D1 Female Follow-Up Studies Humans Medroxyprogesterone Acetate Mice, Inbred BALB C Phosphorylation Promoter Regions, Genetic Receptor, ErbB-2 Receptors, Progesterone Retrospective Studies Selective Estrogen Receptor Modulators STAT3 Transcription Factor Tamoxifen Transcription Factor AP-1 Treatment Outcome Introduction: The role of the progesterone receptor (PR) in breast cancer remains a major clinical challenge. Although PR induces mammary tumor growth, its presence in breast tumors is a marker of good prognosis. We investigated coordinated PR rapid and nonclassical transcriptional effects governing breast cancer growth and endocrine therapy resistance. Methods: We used breast cancer cell lines expressing wild-type and mutant PRs, cells sensitive and resistant to endocrine therapy, a variety of molecular and cellular biology approaches, in vitro proliferation studies and preclinical models to explore PR regulation of cyclin D1 expression, tumor growth, and response to endocrine therapy. We investigated the clinical significance of activator protein 1 (AP-1) and PR interaction in a cohort of 99 PR-positive breast tumors by an immunofluorescence protocol we developed. The prognostic value of AP-1/PR nuclear colocalization in overall survival (OS) was evaluated using Kaplan-Meier method, and Cox model was used to explore said colocalization as an independent prognostic factor for OS. Results: We demonstrated that at the cyclin D1 promoter and through coordinated rapid and transcriptional effects, progestin induces the assembly of a transcriptional complex among AP-1, Stat3, PR, and ErbB-2 which functions as an enhanceosome to drive breast cancer growth. Our studies in a cohort of human breast tumors identified PR and AP-1 nuclear interaction as a marker of good prognosis and better OS in patients treated with tamoxifen (Tam), an anti-estrogen receptor therapy. Rationale for this finding was provided by our demonstration that Tam inhibits rapid and genomic PR effects, rendering breast cancer cells sensitive to its antiproliferative effects. Conclusions: We here provided novel insight into the paradox of PR action as well as new tools to identify the subgroup of ER+/PR + patients unlikely to respond to ER-targeted therapies. © 2013 Díaz Flaqué et al.; licensee BioMed Central Ltd. 2013 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_14655411_v15_n6_p_DiazFlaque http://hdl.handle.net/20.500.12110/paper_14655411_v15_n6_p_DiazFlaque |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
CCND1 protein, human cyclin D1 epidermal growth factor receptor 2 ERBB2 protein, human medroxyprogesterone acetate progesterone receptor selective estrogen receptor modulator STAT3 protein Stat3 protein, mouse tamoxifen transcription factor AP 1 animal Bagg albino mouse Breast Neoplasms cell nucleus drug effects female follow up genetics human metabolism mortality pathology phosphorylation promoter region retrospective study treatment outcome Animals Breast Neoplasms Cell Nucleus Cyclin D1 Female Follow-Up Studies Humans Medroxyprogesterone Acetate Mice, Inbred BALB C Phosphorylation Promoter Regions, Genetic Receptor, ErbB-2 Receptors, Progesterone Retrospective Studies Selective Estrogen Receptor Modulators STAT3 Transcription Factor Tamoxifen Transcription Factor AP-1 Treatment Outcome |
| spellingShingle |
CCND1 protein, human cyclin D1 epidermal growth factor receptor 2 ERBB2 protein, human medroxyprogesterone acetate progesterone receptor selective estrogen receptor modulator STAT3 protein Stat3 protein, mouse tamoxifen transcription factor AP 1 animal Bagg albino mouse Breast Neoplasms cell nucleus drug effects female follow up genetics human metabolism mortality pathology phosphorylation promoter region retrospective study treatment outcome Animals Breast Neoplasms Cell Nucleus Cyclin D1 Female Follow-Up Studies Humans Medroxyprogesterone Acetate Mice, Inbred BALB C Phosphorylation Promoter Regions, Genetic Receptor, ErbB-2 Receptors, Progesterone Retrospective Studies Selective Estrogen Receptor Modulators STAT3 Transcription Factor Tamoxifen Transcription Factor AP-1 Treatment Outcome Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy |
| topic_facet |
CCND1 protein, human cyclin D1 epidermal growth factor receptor 2 ERBB2 protein, human medroxyprogesterone acetate progesterone receptor selective estrogen receptor modulator STAT3 protein Stat3 protein, mouse tamoxifen transcription factor AP 1 animal Bagg albino mouse Breast Neoplasms cell nucleus drug effects female follow up genetics human metabolism mortality pathology phosphorylation promoter region retrospective study treatment outcome Animals Breast Neoplasms Cell Nucleus Cyclin D1 Female Follow-Up Studies Humans Medroxyprogesterone Acetate Mice, Inbred BALB C Phosphorylation Promoter Regions, Genetic Receptor, ErbB-2 Receptors, Progesterone Retrospective Studies Selective Estrogen Receptor Modulators STAT3 Transcription Factor Tamoxifen Transcription Factor AP-1 Treatment Outcome |
| description |
Introduction: The role of the progesterone receptor (PR) in breast cancer remains a major clinical challenge. Although PR induces mammary tumor growth, its presence in breast tumors is a marker of good prognosis. We investigated coordinated PR rapid and nonclassical transcriptional effects governing breast cancer growth and endocrine therapy resistance. Methods: We used breast cancer cell lines expressing wild-type and mutant PRs, cells sensitive and resistant to endocrine therapy, a variety of molecular and cellular biology approaches, in vitro proliferation studies and preclinical models to explore PR regulation of cyclin D1 expression, tumor growth, and response to endocrine therapy. We investigated the clinical significance of activator protein 1 (AP-1) and PR interaction in a cohort of 99 PR-positive breast tumors by an immunofluorescence protocol we developed. The prognostic value of AP-1/PR nuclear colocalization in overall survival (OS) was evaluated using Kaplan-Meier method, and Cox model was used to explore said colocalization as an independent prognostic factor for OS. Results: We demonstrated that at the cyclin D1 promoter and through coordinated rapid and transcriptional effects, progestin induces the assembly of a transcriptional complex among AP-1, Stat3, PR, and ErbB-2 which functions as an enhanceosome to drive breast cancer growth. Our studies in a cohort of human breast tumors identified PR and AP-1 nuclear interaction as a marker of good prognosis and better OS in patients treated with tamoxifen (Tam), an anti-estrogen receptor therapy. Rationale for this finding was provided by our demonstration that Tam inhibits rapid and genomic PR effects, rendering breast cancer cells sensitive to its antiproliferative effects. Conclusions: We here provided novel insight into the paradox of PR action as well as new tools to identify the subgroup of ER+/PR + patients unlikely to respond to ER-targeted therapies. © 2013 Díaz Flaqué et al.; licensee BioMed Central Ltd. |
| title |
Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy |
| title_short |
Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy |
| title_full |
Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy |
| title_fullStr |
Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy |
| title_full_unstemmed |
Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy |
| title_sort |
progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and erbb-2 governs breast cancer growth and predicts response to endocrine therapy |
| publishDate |
2013 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_14655411_v15_n6_p_DiazFlaque http://hdl.handle.net/20.500.12110/paper_14655411_v15_n6_p_DiazFlaque |
| _version_ |
1768543149816283136 |