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Indole-3-Carbinol Triggers Aryl Hydrocarbon Receptor-dependent Estrogen Receptor (ER)α Protein Degradation in Breast Cancer Cells Disrupting an ERα-GATA3 Transcriptional Cross-Regulatory Loop

Estrogen receptor (ER)α is a critical target of therapeutic strategies to control the proliferation of hormone-dependent breast cancers. Preferred clinical options have significant adverse side effects that can lead to treatment resistance due to the persistence of active estrogen receptors. We have...

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Detalles Bibliográficos
Autores principales: Marconett, Crystal N., Sundar, Shyam N., Poindexter, Kevin M., Stueve, Theresa R., Bjeldanes, Leonard F., Firestone, Gary L.
Formato: Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847521/
https://www.ncbi.nlm.nih.gov/pubmed/20130088
http://dx.doi.org/10.1091/mbc.E09-08-0689
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author Marconett, Crystal N.
Sundar, Shyam N.
Poindexter, Kevin M.
Stueve, Theresa R.
Bjeldanes, Leonard F.
Firestone, Gary L.
author_facet Marconett, Crystal N.
Sundar, Shyam N.
Poindexter, Kevin M.
Stueve, Theresa R.
Bjeldanes, Leonard F.
Firestone, Gary L.
author_sort Marconett, Crystal N.
collection PubMed
description Estrogen receptor (ER)α is a critical target of therapeutic strategies to control the proliferation of hormone-dependent breast cancers. Preferred clinical options have significant adverse side effects that can lead to treatment resistance due to the persistence of active estrogen receptors. We have established the cellular mechanism by which indole-3-carbinol (I3C), a promising anticancer phytochemical from Brassica vegetables, ablates ERα expression, and we have uncovered a critical role for the GATA3 transcription factor in this indole-regulated cascade. I3C-dependent activation of the aryl hydrocarbon receptor (AhR) initiates Rbx-1 E3 ligase-mediated ubiquitination and proteasomal degradation of ERα protein. I3C inhibits endogenous binding of ERα with the 3′-enhancer region of GATA3 and disrupts endogenous GATA3 interactions with the ERα promoter, leading to a loss of GATA3 and ERα expression. Ectopic expression of GATA3 has no effect on I3C-induced ERα protein degradation but does prevent I3C inhibition of ERα promoter activity, demonstrating the importance of GATA3 in this I3C-triggered cascade. Our preclinical results implicate I3C as a novel anticancer agent in human cancers that coexpress ERα, GATA3, and AhR, a combination found in a large percentage of breast cancers but not in other critical ERα target tissues essential to patient health.
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spelling pubmed-28475212010-06-16 Indole-3-Carbinol Triggers Aryl Hydrocarbon Receptor-dependent Estrogen Receptor (ER)α Protein Degradation in Breast Cancer Cells Disrupting an ERα-GATA3 Transcriptional Cross-Regulatory Loop Marconett, Crystal N. Sundar, Shyam N. Poindexter, Kevin M. Stueve, Theresa R. Bjeldanes, Leonard F. Firestone, Gary L. Mol Biol Cell Articles Estrogen receptor (ER)α is a critical target of therapeutic strategies to control the proliferation of hormone-dependent breast cancers. Preferred clinical options have significant adverse side effects that can lead to treatment resistance due to the persistence of active estrogen receptors. We have established the cellular mechanism by which indole-3-carbinol (I3C), a promising anticancer phytochemical from Brassica vegetables, ablates ERα expression, and we have uncovered a critical role for the GATA3 transcription factor in this indole-regulated cascade. I3C-dependent activation of the aryl hydrocarbon receptor (AhR) initiates Rbx-1 E3 ligase-mediated ubiquitination and proteasomal degradation of ERα protein. I3C inhibits endogenous binding of ERα with the 3′-enhancer region of GATA3 and disrupts endogenous GATA3 interactions with the ERα promoter, leading to a loss of GATA3 and ERα expression. Ectopic expression of GATA3 has no effect on I3C-induced ERα protein degradation but does prevent I3C inhibition of ERα promoter activity, demonstrating the importance of GATA3 in this I3C-triggered cascade. Our preclinical results implicate I3C as a novel anticancer agent in human cancers that coexpress ERα, GATA3, and AhR, a combination found in a large percentage of breast cancers but not in other critical ERα target tissues essential to patient health. The American Society for Cell Biology 2010-04-01 /pmc/articles/PMC2847521/ /pubmed/20130088 http://dx.doi.org/10.1091/mbc.E09-08-0689 Text en © 2010 by The American Society for Cell Biology
spellingShingle Articles
Marconett, Crystal N.
Sundar, Shyam N.
Poindexter, Kevin M.
Stueve, Theresa R.
Bjeldanes, Leonard F.
Firestone, Gary L.
Indole-3-Carbinol Triggers Aryl Hydrocarbon Receptor-dependent Estrogen Receptor (ER)α Protein Degradation in Breast Cancer Cells Disrupting an ERα-GATA3 Transcriptional Cross-Regulatory Loop
title Indole-3-Carbinol Triggers Aryl Hydrocarbon Receptor-dependent Estrogen Receptor (ER)α Protein Degradation in Breast Cancer Cells Disrupting an ERα-GATA3 Transcriptional Cross-Regulatory Loop
title_full Indole-3-Carbinol Triggers Aryl Hydrocarbon Receptor-dependent Estrogen Receptor (ER)α Protein Degradation in Breast Cancer Cells Disrupting an ERα-GATA3 Transcriptional Cross-Regulatory Loop
title_fullStr Indole-3-Carbinol Triggers Aryl Hydrocarbon Receptor-dependent Estrogen Receptor (ER)α Protein Degradation in Breast Cancer Cells Disrupting an ERα-GATA3 Transcriptional Cross-Regulatory Loop
title_full_unstemmed Indole-3-Carbinol Triggers Aryl Hydrocarbon Receptor-dependent Estrogen Receptor (ER)α Protein Degradation in Breast Cancer Cells Disrupting an ERα-GATA3 Transcriptional Cross-Regulatory Loop
title_short Indole-3-Carbinol Triggers Aryl Hydrocarbon Receptor-dependent Estrogen Receptor (ER)α Protein Degradation in Breast Cancer Cells Disrupting an ERα-GATA3 Transcriptional Cross-Regulatory Loop
title_sort indole-3-carbinol triggers aryl hydrocarbon receptor-dependent estrogen receptor (er)α protein degradation in breast cancer cells disrupting an erα-gata3 transcriptional cross-regulatory loop
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847521/
https://www.ncbi.nlm.nih.gov/pubmed/20130088
http://dx.doi.org/10.1091/mbc.E09-08-0689
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