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Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer.

ABSTRACT: Estrogen receptors (ER) and nuclear factor-kappaB (NF-kappaB) are known to play important roles in breast cancer, but these factors are generally thought to repress each other's activity. However, we have recently found that ER and NF-kappaB can also act together in a positive manner to synergistically increase gene transcription. To examine the extent of cross-talk between ER and NF-kappaB, a microarray study was conducted in which MCF-7 breast cancer cells were treated with 17beta-estradiol (E(2)), tumor necrosis factor alpha (TNFalpha), or both. Follow-up studies with an ER antagonist and NF-kappaB inhibitors show that cross-talk between E(2) and TNFalpha is mediated by these two factors. We find that although transrepression between ER and NF-kappaB does occur, positive cross-talk is more prominent with three gene-specific patterns of regulation: (a) TNFalpha enhances E(2) action on approximately 30% of E(2)-upregulated genes; (b) E(2) enhances TNFalpha activity on approximately 15% of TNFalpha-upregulated genes; and (c) E(2) + TNFalpha causes a more than additive upregulation of approximately 60 genes. Consistent with their prosurvival roles, ER and NF-kappaB and their target gene, BIRC3, are involved in protecting breast cancer cells against apoptosis. Furthermore, genes positively regulated by E(2) + TNFalpha are clinically relevant because they are enriched in luminal B breast tumors and their expression profiles can distinguish a cohort of patients with poor outcome following endocrine treatment. Taken together, our findings suggest that positive cross-talk between ER and NF-kappaB is more extensive than anticipated and that these factors may act together to promote survival of breast cancer cells and progression to a more aggressive phenotype.

SUBMITTER: Frasor J

PROVIDER: S-EPMC2996265 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer.

Frasor Jonna J Weaver Aisha A Pradhan Madhumita M Dai Yang Y Miller Lance D LD Lin Chin-Yo CY Stanculescu Adina A

Cancer research 20091117 23

Estrogen receptors (ER) and nuclear factor-kappaB (NF-kappaB) are known to play important roles in breast cancer, but these factors are generally thought to repress each other's activity. However, we have recently found that ER and NF-kappaB can also act together in a positive manner to synergistically increase gene transcription. To examine the extent of cross-talk between ER and NF-kappaB, a microarray study was conducted in which MCF-7 breast cancer cells were treated with 17beta-estradiol (E ...[more]

PMID: 19920189

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Project description:BackgroundAmong women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERβ plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERβ agonists without ERα activity has limited the exploration of ERβ activation as a strategy for ERα+ breast cancer.MethodsWe measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERβ agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERβ agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERβ agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2-regulated genes.ResultsIn this study, we demonstrate the efficacy of highly selective ERβ agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERβ agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERβ agonists and ERα antagonists suggested that the efficacy of ERβ agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERβ gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples.ConclusionOur results demonstrate that highly selective ERβ agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer.

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Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer.

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Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer.

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