Cargando…

Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer

BACKGROUND: Signaling pathways that converge on two different transcription factor complexes, NFκB and AP-1, have been identified in estrogen receptor (ER)-positive breast cancers resistant to the antiestrogen, tamoxifen. METHODS: Two cell line models of tamoxifen-resistant ER-positive breast cancer...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhou, Yamei, Yau, Christina, Gray, Joe W, Chew, Karen, Dairkee, Shanaz H, Moore, Dan H, Eppenberger, Urs, Eppenberger-Castori, Serenella, Benz, Christopher C
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852565/
https://www.ncbi.nlm.nih.gov/pubmed/17407600
http://dx.doi.org/10.1186/1471-2407-7-59
_version_ 1782133061643665408
author Zhou, Yamei
Yau, Christina
Gray, Joe W
Chew, Karen
Dairkee, Shanaz H
Moore, Dan H
Eppenberger, Urs
Eppenberger-Castori, Serenella
Benz, Christopher C
author_facet Zhou, Yamei
Yau, Christina
Gray, Joe W
Chew, Karen
Dairkee, Shanaz H
Moore, Dan H
Eppenberger, Urs
Eppenberger-Castori, Serenella
Benz, Christopher C
author_sort Zhou, Yamei
collection PubMed
description BACKGROUND: Signaling pathways that converge on two different transcription factor complexes, NFκB and AP-1, have been identified in estrogen receptor (ER)-positive breast cancers resistant to the antiestrogen, tamoxifen. METHODS: Two cell line models of tamoxifen-resistant ER-positive breast cancer, MCF7/HER2 and BT474, showing increased AP-1 and NFκB DNA-binding and transcriptional activities, were studied to compare tamoxifen effects on NFκB and AP-1 regulated reporter genes relative to tamoxifen-sensitive MCF7 cells. The model cell lines were treated with the IKK inhibitor parthenolide (PA) or the proteasome inhibitor bortezomib (PS341), alone and in combination with tamoxifen. Expression microarray data available from 54 UCSF node-negative ER-positive breast cancer cases with known clinical outcome were used to search for potential genes signifying upregulated NFκB and AP-1 transcriptional activity in association with tamoxifen resistance. The association of these genes with patient outcome was further evaluated using node-negative ER-positive breast cancer cases identified from three other published data sets (Rotterdam, n = 209; Amsterdam, n = 68; Basel, n = 108), each having different patient age and adjuvant tamoxifen treatment characteristics. RESULTS: Doses of parthenolide and bortezomib capable of sensitizing the two endocrine resistant breast cancer models to tamoxifen were capable of suppressing NFκB and AP-1 regulated gene expression in combination with tamoxifen and also increased ER recruitment of the transcriptional co-repressor, NCoR. Transcript profiles from the UCSF breast cancer cases revealed three NFκB and AP-1 upregulated genes – cyclin D1, uPA and VEGF – capable of dichotomizing node-negative ER-positive cases into early and late relapsing subsets despite adjuvant tamoxfien therapy and most prognostic for younger age cases. Across the four independent sets of node-negative ER-positive breast cancer cases (UCSF, Rotterdam, Amsterdam, Basel), high expression of all three NFκB and AP-1 upregulated genes was associated with earliest metastatic relapse. CONCLUSION: Altogether, these findings implicate increased NFκB and AP-1 transcriptional responses with tamoxifen resistant breast cancer and early metastatic relapse, especially in younger patients. These findings also suggest that agents capable of preventing NFκB and AP-1 gene activation may prove useful in restoring the endocrine responsiveness of such high-risk ER-positive breast cancers.
format Text
id pubmed-1852565
institution National Center for Biotechnology Information
language English
publishDate 2007
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-18525652007-04-18 Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer Zhou, Yamei Yau, Christina Gray, Joe W Chew, Karen Dairkee, Shanaz H Moore, Dan H Eppenberger, Urs Eppenberger-Castori, Serenella Benz, Christopher C BMC Cancer Research Article BACKGROUND: Signaling pathways that converge on two different transcription factor complexes, NFκB and AP-1, have been identified in estrogen receptor (ER)-positive breast cancers resistant to the antiestrogen, tamoxifen. METHODS: Two cell line models of tamoxifen-resistant ER-positive breast cancer, MCF7/HER2 and BT474, showing increased AP-1 and NFκB DNA-binding and transcriptional activities, were studied to compare tamoxifen effects on NFκB and AP-1 regulated reporter genes relative to tamoxifen-sensitive MCF7 cells. The model cell lines were treated with the IKK inhibitor parthenolide (PA) or the proteasome inhibitor bortezomib (PS341), alone and in combination with tamoxifen. Expression microarray data available from 54 UCSF node-negative ER-positive breast cancer cases with known clinical outcome were used to search for potential genes signifying upregulated NFκB and AP-1 transcriptional activity in association with tamoxifen resistance. The association of these genes with patient outcome was further evaluated using node-negative ER-positive breast cancer cases identified from three other published data sets (Rotterdam, n = 209; Amsterdam, n = 68; Basel, n = 108), each having different patient age and adjuvant tamoxifen treatment characteristics. RESULTS: Doses of parthenolide and bortezomib capable of sensitizing the two endocrine resistant breast cancer models to tamoxifen were capable of suppressing NFκB and AP-1 regulated gene expression in combination with tamoxifen and also increased ER recruitment of the transcriptional co-repressor, NCoR. Transcript profiles from the UCSF breast cancer cases revealed three NFκB and AP-1 upregulated genes – cyclin D1, uPA and VEGF – capable of dichotomizing node-negative ER-positive cases into early and late relapsing subsets despite adjuvant tamoxfien therapy and most prognostic for younger age cases. Across the four independent sets of node-negative ER-positive breast cancer cases (UCSF, Rotterdam, Amsterdam, Basel), high expression of all three NFκB and AP-1 upregulated genes was associated with earliest metastatic relapse. CONCLUSION: Altogether, these findings implicate increased NFκB and AP-1 transcriptional responses with tamoxifen resistant breast cancer and early metastatic relapse, especially in younger patients. These findings also suggest that agents capable of preventing NFκB and AP-1 gene activation may prove useful in restoring the endocrine responsiveness of such high-risk ER-positive breast cancers. BioMed Central 2007-04-03 /pmc/articles/PMC1852565/ /pubmed/17407600 http://dx.doi.org/10.1186/1471-2407-7-59 Text en Copyright © 2007 Zhou et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Zhou, Yamei
Yau, Christina
Gray, Joe W
Chew, Karen
Dairkee, Shanaz H
Moore, Dan H
Eppenberger, Urs
Eppenberger-Castori, Serenella
Benz, Christopher C
Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer
title Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer
title_full Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer
title_fullStr Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer
title_full_unstemmed Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer
title_short Enhanced NFκB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer
title_sort enhanced nfκb and ap-1 transcriptional activity associated with antiestrogen resistant breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852565/
https://www.ncbi.nlm.nih.gov/pubmed/17407600
http://dx.doi.org/10.1186/1471-2407-7-59
work_keys_str_mv AT zhouyamei enhancednfkbandap1transcriptionalactivityassociatedwithantiestrogenresistantbreastcancer
AT yauchristina enhancednfkbandap1transcriptionalactivityassociatedwithantiestrogenresistantbreastcancer
AT grayjoew enhancednfkbandap1transcriptionalactivityassociatedwithantiestrogenresistantbreastcancer
AT chewkaren enhancednfkbandap1transcriptionalactivityassociatedwithantiestrogenresistantbreastcancer
AT dairkeeshanazh enhancednfkbandap1transcriptionalactivityassociatedwithantiestrogenresistantbreastcancer
AT mooredanh enhancednfkbandap1transcriptionalactivityassociatedwithantiestrogenresistantbreastcancer
AT eppenbergerurs enhancednfkbandap1transcriptionalactivityassociatedwithantiestrogenresistantbreastcancer
AT eppenbergercastoriserenella enhancednfkbandap1transcriptionalactivityassociatedwithantiestrogenresistantbreastcancer
AT benzchristopherc enhancednfkbandap1transcriptionalactivityassociatedwithantiestrogenresistantbreastcancer