Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways
Accumulating evidence indicates that progestins are involved in controlling mammary gland tumorigenesis. Here, we assessed the molecular mechanisms of progestin action in breast cancer models with different phenotypes. We examined C4HD cells, an estrogen (ER) and progesterone (PR) receptor-positive...
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2007
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08888809_v21_n6_p1335_Carnevale http://hdl.handle.net/20.500.12110/paper_08888809_v21_n6_p1335_Carnevale |
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paper:paper_08888809_v21_n6_p1335_Carnevale2023-06-08T15:47:02Z Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways DNA binding protein estrogen receptor gelatinase A gelatinase B gestagen mitogen activated protein kinase mutant protein phosphatidylinositol 3 kinase progesterone receptor protein kinase B transcription factor urokinase animal cell animal experiment animal model article breast cancer breast carcinogenesis cancer cell culture cancer model cell growth cell proliferation controlled study cytoplasm enzyme activation female hormonal regulation hormone response human human cell metastasis modulation mouse nonhuman null allele phenotype priority journal protein function signal transduction wild type 1-Phosphatidylinositol 3-Kinase Animals Breast Neoplasms Cell Line, Tumor Cell Proliferation Cytoplasm Matrix Metalloproteinase 2 Matrix Metalloproteinase 9 Mice Mitogen-Activated Protein Kinase Kinases Neoplasm Metastasis Peptide Hydrolases Progestins Receptors, Progesterone Signal Transduction Urinary Plasminogen Activator Murinae Accumulating evidence indicates that progestins are involved in controlling mammary gland tumorigenesis. Here, we assessed the molecular mechanisms of progestin action in breast cancer models with different phenotypes. We examined C4HD cells, an estrogen (ER) and progesterone (PR) receptor-positive murine breast cancer model in which progestins exert sustained proliferative response, the LM3 murine metastatic mammary tumor cell line, which lacks PR and ER expression, and human PR null T47D-Y breast cancer cells. In addition to acting as a transcription factor, PR can also function as an activator of signaling pathways. To explore which of these two functions were involved in progestin responses, reconstitution experiments in the PR-negative models were performed with wild-type PR-B, with a DNA binding mutant C587A-PR, and with mutant PR-BmPro, which lacks the ability to activate cytoplasm signaling pathways. We found that in a cell context either ER-positive or -negative, progestins induced cell growth and modulation of matrix metalloproteinases-9 (MMP-9) and -2 (MMP-2), and urokinase-type plasminogen activator (uPA) activities, via MAPK and phosphatidylinositol 3-kinase/Akt pathways, in cells expressing wildtype PR-B or DNA binding mutant C587A-PR. In contrast, in cells expressing mutant PR-BmPro, progestins did not induce growth. We also found that unliganded PR expression conferred breast cancer cells an in vitro less proliferative phenotype, as compared with cells lacking PR expression. Modulation of this behavior occurred when PR was functioning either as transcription factor or as signaling activator. Finally, we for the first time demonstrated that progestins favor development of breast tumor metastasis via PR function as activator of signaling pathways. Our present findings provide mechanistic support to the design of a novel therapeutic intervention in PR-positive breast tumors involving blockage of PR capacity to activate cytoplasmic signaling. Copyright © 2007 by The Endocrine Society. 2007 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08888809_v21_n6_p1335_Carnevale http://hdl.handle.net/20.500.12110/paper_08888809_v21_n6_p1335_Carnevale |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
DNA binding protein estrogen receptor gelatinase A gelatinase B gestagen mitogen activated protein kinase mutant protein phosphatidylinositol 3 kinase progesterone receptor protein kinase B transcription factor urokinase animal cell animal experiment animal model article breast cancer breast carcinogenesis cancer cell culture cancer model cell growth cell proliferation controlled study cytoplasm enzyme activation female hormonal regulation hormone response human human cell metastasis modulation mouse nonhuman null allele phenotype priority journal protein function signal transduction wild type 1-Phosphatidylinositol 3-Kinase Animals Breast Neoplasms Cell Line, Tumor Cell Proliferation Cytoplasm Matrix Metalloproteinase 2 Matrix Metalloproteinase 9 Mice Mitogen-Activated Protein Kinase Kinases Neoplasm Metastasis Peptide Hydrolases Progestins Receptors, Progesterone Signal Transduction Urinary Plasminogen Activator Murinae |
| spellingShingle |
DNA binding protein estrogen receptor gelatinase A gelatinase B gestagen mitogen activated protein kinase mutant protein phosphatidylinositol 3 kinase progesterone receptor protein kinase B transcription factor urokinase animal cell animal experiment animal model article breast cancer breast carcinogenesis cancer cell culture cancer model cell growth cell proliferation controlled study cytoplasm enzyme activation female hormonal regulation hormone response human human cell metastasis modulation mouse nonhuman null allele phenotype priority journal protein function signal transduction wild type 1-Phosphatidylinositol 3-Kinase Animals Breast Neoplasms Cell Line, Tumor Cell Proliferation Cytoplasm Matrix Metalloproteinase 2 Matrix Metalloproteinase 9 Mice Mitogen-Activated Protein Kinase Kinases Neoplasm Metastasis Peptide Hydrolases Progestins Receptors, Progesterone Signal Transduction Urinary Plasminogen Activator Murinae Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways |
| topic_facet |
DNA binding protein estrogen receptor gelatinase A gelatinase B gestagen mitogen activated protein kinase mutant protein phosphatidylinositol 3 kinase progesterone receptor protein kinase B transcription factor urokinase animal cell animal experiment animal model article breast cancer breast carcinogenesis cancer cell culture cancer model cell growth cell proliferation controlled study cytoplasm enzyme activation female hormonal regulation hormone response human human cell metastasis modulation mouse nonhuman null allele phenotype priority journal protein function signal transduction wild type 1-Phosphatidylinositol 3-Kinase Animals Breast Neoplasms Cell Line, Tumor Cell Proliferation Cytoplasm Matrix Metalloproteinase 2 Matrix Metalloproteinase 9 Mice Mitogen-Activated Protein Kinase Kinases Neoplasm Metastasis Peptide Hydrolases Progestins Receptors, Progesterone Signal Transduction Urinary Plasminogen Activator Murinae |
| description |
Accumulating evidence indicates that progestins are involved in controlling mammary gland tumorigenesis. Here, we assessed the molecular mechanisms of progestin action in breast cancer models with different phenotypes. We examined C4HD cells, an estrogen (ER) and progesterone (PR) receptor-positive murine breast cancer model in which progestins exert sustained proliferative response, the LM3 murine metastatic mammary tumor cell line, which lacks PR and ER expression, and human PR null T47D-Y breast cancer cells. In addition to acting as a transcription factor, PR can also function as an activator of signaling pathways. To explore which of these two functions were involved in progestin responses, reconstitution experiments in the PR-negative models were performed with wild-type PR-B, with a DNA binding mutant C587A-PR, and with mutant PR-BmPro, which lacks the ability to activate cytoplasm signaling pathways. We found that in a cell context either ER-positive or -negative, progestins induced cell growth and modulation of matrix metalloproteinases-9 (MMP-9) and -2 (MMP-2), and urokinase-type plasminogen activator (uPA) activities, via MAPK and phosphatidylinositol 3-kinase/Akt pathways, in cells expressing wildtype PR-B or DNA binding mutant C587A-PR. In contrast, in cells expressing mutant PR-BmPro, progestins did not induce growth. We also found that unliganded PR expression conferred breast cancer cells an in vitro less proliferative phenotype, as compared with cells lacking PR expression. Modulation of this behavior occurred when PR was functioning either as transcription factor or as signaling activator. Finally, we for the first time demonstrated that progestins favor development of breast tumor metastasis via PR function as activator of signaling pathways. Our present findings provide mechanistic support to the design of a novel therapeutic intervention in PR-positive breast tumors involving blockage of PR capacity to activate cytoplasmic signaling. Copyright © 2007 by The Endocrine Society. |
| title |
Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways |
| title_short |
Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways |
| title_full |
Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways |
| title_fullStr |
Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways |
| title_full_unstemmed |
Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways |
| title_sort |
progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways |
| publishDate |
2007 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_08888809_v21_n6_p1335_Carnevale http://hdl.handle.net/20.500.12110/paper_08888809_v21_n6_p1335_Carnevale |
| _version_ |
1768543427799023616 |