Cargando…
The Organochlorine o,p’-DDT Plays a Role in Coactivator-Mediated MAPK Crosstalk in MCF-7 Breast Cancer Cells
Background: The organochlorine dichlorodiphenyltrichloroethane (DDT), a known estrogen mimic and endocrine disruptor, has been linked to animal and human disorders. However, the detailed mechanism(s) by which DDT affects cellular physiology remains incompletely defined. Objectives: We and others hav...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Institute of Environmental Health Sciences
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440107/ https://www.ncbi.nlm.nih.gov/pubmed/22609851 http://dx.doi.org/10.1289/ehp.1104296 |
_version_ | 1782243119768535040 |
---|---|
author | Bratton, Melyssa R. Frigo, Daniel E. Segar, H. Chris Nephew, Kenneth P. McLachlan, John A. Wiese, Thomas E. Burow, Matthew E. |
author_facet | Bratton, Melyssa R. Frigo, Daniel E. Segar, H. Chris Nephew, Kenneth P. McLachlan, John A. Wiese, Thomas E. Burow, Matthew E. |
author_sort | Bratton, Melyssa R. |
collection | PubMed |
description | Background: The organochlorine dichlorodiphenyltrichloroethane (DDT), a known estrogen mimic and endocrine disruptor, has been linked to animal and human disorders. However, the detailed mechanism(s) by which DDT affects cellular physiology remains incompletely defined. Objectives: We and others have shown that DDT activates cell-signaling cascades, culminating in the activation of estrogen receptor-dependent and -independent gene expression. Here, we identify a mechanism by which DDT alters cellular signaling and gene expression, independent of the estrogen receptor. Methods: We performed quantitative polymerase chain reaction array analysis of gene expression in MCF-7 breast cancer cells using either estradiol (E(2)) or o,p´-DDT to identify distinct cellular gene expression responses. To elucidate the mechanisms by which DDT regulates cell signaling, we used molecular and pharmacological techniques. Results: E(2) and DDT treatment both altered the expression of many of the genes assayed, but up-regulation of vascular endothelial growth factor A (VEGFA) was observed only after DDT treatment, and this increase was not affected by the pure estrogen receptor α antagonist ICI 182780. Furthermore, DDT increased activation of the HIF-1 response element (HRE), a known enhancer of the VEGFA gene. This DDT-mediated increase in HRE activity was augmented by the coactivator CBP (CREB-binding protein) and was dependent on the p38 pathway. Conclusions: DDT up-regulated the expression of several genes in MCF-7 breast cancer cells that were not altered by treatment with E(2), including VEGFA. We propose that this DDT-initiated, ER-independent stimulation of gene expression is due to DDT’s ability to initiate crosstalk between MAPK (mitogen-activated protein kinase) signaling pathways and transcriptional coactivators. |
format | Online Article Text |
id | pubmed-3440107 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | National Institute of Environmental Health Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-34401072012-10-04 The Organochlorine o,p’-DDT Plays a Role in Coactivator-Mediated MAPK Crosstalk in MCF-7 Breast Cancer Cells Bratton, Melyssa R. Frigo, Daniel E. Segar, H. Chris Nephew, Kenneth P. McLachlan, John A. Wiese, Thomas E. Burow, Matthew E. Environ Health Perspect Research Background: The organochlorine dichlorodiphenyltrichloroethane (DDT), a known estrogen mimic and endocrine disruptor, has been linked to animal and human disorders. However, the detailed mechanism(s) by which DDT affects cellular physiology remains incompletely defined. Objectives: We and others have shown that DDT activates cell-signaling cascades, culminating in the activation of estrogen receptor-dependent and -independent gene expression. Here, we identify a mechanism by which DDT alters cellular signaling and gene expression, independent of the estrogen receptor. Methods: We performed quantitative polymerase chain reaction array analysis of gene expression in MCF-7 breast cancer cells using either estradiol (E(2)) or o,p´-DDT to identify distinct cellular gene expression responses. To elucidate the mechanisms by which DDT regulates cell signaling, we used molecular and pharmacological techniques. Results: E(2) and DDT treatment both altered the expression of many of the genes assayed, but up-regulation of vascular endothelial growth factor A (VEGFA) was observed only after DDT treatment, and this increase was not affected by the pure estrogen receptor α antagonist ICI 182780. Furthermore, DDT increased activation of the HIF-1 response element (HRE), a known enhancer of the VEGFA gene. This DDT-mediated increase in HRE activity was augmented by the coactivator CBP (CREB-binding protein) and was dependent on the p38 pathway. Conclusions: DDT up-regulated the expression of several genes in MCF-7 breast cancer cells that were not altered by treatment with E(2), including VEGFA. We propose that this DDT-initiated, ER-independent stimulation of gene expression is due to DDT’s ability to initiate crosstalk between MAPK (mitogen-activated protein kinase) signaling pathways and transcriptional coactivators. National Institute of Environmental Health Sciences 2012-05-18 2012-09 /pmc/articles/PMC3440107/ /pubmed/22609851 http://dx.doi.org/10.1289/ehp.1104296 Text en http://creativecommons.org/publicdomain/mark/1.0/ Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, ?Reproduced with permission from Environmental Health Perspectives?); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright. |
spellingShingle | Research Bratton, Melyssa R. Frigo, Daniel E. Segar, H. Chris Nephew, Kenneth P. McLachlan, John A. Wiese, Thomas E. Burow, Matthew E. The Organochlorine o,p’-DDT Plays a Role in Coactivator-Mediated MAPK Crosstalk in MCF-7 Breast Cancer Cells |
title | The Organochlorine o,p’-DDT Plays a Role in Coactivator-Mediated MAPK Crosstalk in MCF-7 Breast Cancer Cells |
title_full | The Organochlorine o,p’-DDT Plays a Role in Coactivator-Mediated MAPK Crosstalk in MCF-7 Breast Cancer Cells |
title_fullStr | The Organochlorine o,p’-DDT Plays a Role in Coactivator-Mediated MAPK Crosstalk in MCF-7 Breast Cancer Cells |
title_full_unstemmed | The Organochlorine o,p’-DDT Plays a Role in Coactivator-Mediated MAPK Crosstalk in MCF-7 Breast Cancer Cells |
title_short | The Organochlorine o,p’-DDT Plays a Role in Coactivator-Mediated MAPK Crosstalk in MCF-7 Breast Cancer Cells |
title_sort | organochlorine o,p’-ddt plays a role in coactivator-mediated mapk crosstalk in mcf-7 breast cancer cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440107/ https://www.ncbi.nlm.nih.gov/pubmed/22609851 http://dx.doi.org/10.1289/ehp.1104296 |
work_keys_str_mv | AT brattonmelyssar theorganochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT frigodaniele theorganochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT segarhchris theorganochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT nephewkennethp theorganochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT mclachlanjohna theorganochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT wiesethomase theorganochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT burowmatthewe theorganochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT brattonmelyssar organochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT frigodaniele organochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT segarhchris organochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT nephewkennethp organochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT mclachlanjohna organochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT wiesethomase organochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells AT burowmatthewe organochlorineopddtplaysaroleincoactivatormediatedmapkcrosstalkinmcf7breastcancercells |