Abstract | BACKGROUND: METHODS: Two cell line models of tamoxifen-resistant ER-positive breast cancer, MCF7/HER2 and BT474, showing increased AP-1 and NFkappaB DNA-binding and transcriptional activities, were studied to compare tamoxifen effects on NFkappaB 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 NFkappaB 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 NFkappaB 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 NFkappaB 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 NFkappaB and AP-1 upregulated genes was associated with earliest metastatic relapse. CONCLUSION: Altogether, these findings implicate increased NFkappaB 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 NFkappaB and AP-1 gene activation may prove useful in restoring the endocrine responsiveness of such high-risk ER-positive breast cancers.
|
Authors | Yamei Zhou, Christina Yau, Joe W Gray, Karen Chew, Shanaz H Dairkee, Dan H Moore, Urs Eppenberger, Serenella Eppenberger-Castori, Christopher C Benz |
Journal | BMC cancer
(BMC Cancer)
Vol. 7
Pg. 59
(Apr 03 2007)
ISSN: 1471-2407 [Electronic] England |
PMID | 17407600
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Estrogen Antagonists
- NF-kappa B
- Transcription Factor AP-1
- Tamoxifen
|
Topics |
- Breast Neoplasms
(drug therapy, genetics, metabolism)
- Cell Line, Tumor
- Drug Resistance, Neoplasm
(genetics)
- Estrogen Antagonists
(pharmacology, therapeutic use)
- Humans
- NF-kappa B
(genetics, metabolism)
- Tamoxifen
(pharmacology, therapeutic use)
- Transcription Factor AP-1
(genetics, metabolism)
|