CCAAT/Enhancer Binding Protein δ Up-regulates Aromatase Promoters I.3/II in Breast Cancer Epithelial Cells

Kijima, Ikuko; Ye, Jingjing; Glackin, Carlotta A.; Chen, Shiuan

doi:10.1158/0008-5472.can-07-3249

Cited by 15 publications

(7 citation statements)

References 49 publications

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“…Recently, through in vivo footprinting analysis, we identified an important regulatory site at which C/EBPδ binds and up-regulates breast cancer-specific aromatase promoters I.3/II in breast cancer epithelial cells (44). Our review of the literature on HDAC inhibitors revealed that adiponectin gene expression can be suppressed by the HDAC inhibitor valproic acid, which decreases C/EBPα levels and lessens binding of C/EBPα to the adiponectin promoter (45).…”

Section: Lbh589 Suppresses Aromatase Expression Through Promoters I3mentioning

confidence: 93%

The HDAC inhibitor LBH589 (panobinostat) is an inhibitory modulator of aromatase gene expression

Chen

Kijima

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Aromatase converts androgens to estrogens. Although thirdgeneration aromatase inhibitors (AIs) are important drugs in hormonal therapy for breast cancer in postmenopausal women, there are concerns about the side effects associated with the estrogen deprivation achieved with AIs. Expression of aromatase in breast cancer tissue is driven by different promoters than those in noncancer tissues; thus, suppression of aromatase expression in cancer tissues through the down-regulation of breast tumorspecific promoters would reduce the side effects associated with whole-body suppression of estrogen biosynthesis by AIs. We report that histone deacetylase inhibitor LBH589 (panobinostat) is a potent inhibitor of aromatase expression (with an IC 50 value < 25 nM). LBH589 selectively suppresses human aromatase gene promoters I.3/II, which are preferentially used in breast cancer tissue. Furthermore, using the H295R cell culture model, we found that achieving the same degree of inhibition of aromatase activity required only one-fifth as much letrozole (an AI) in the presence of 25 nM LBH589 as in the absence of LBH589. We also used an H295R/MCF7 coculture model to demonstrate the synergistic interaction of LBH589 + letrozole in suppressing the proliferation of hormone-responsive breast cancer cells. Finally, our results also indicate that LBH589 down-regulates the activity of promoters I.3/ II in an epigenetic fashion. LBH589 reduces the levels of C/EBPδ, decreases the binding of C/EBPδ, and increases the levels and binding of acetyl-histones to the promoters I.3/II. These findings provide an important basis for future clinical evaluations of LBH589 in hormone-dependent breast cancer.

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Section: Lbh589 Suppresses Aromatase Expression Through Promoters I3mentioning

confidence: 93%

The HDAC inhibitor LBH589 (panobinostat) is an inhibitory modulator of aromatase gene expression

Chen

Kijima

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The role of aromatase in promoting breast cancer is well defined; factors derived from malignant epithelial cells such as prostaglandin E 2 as well as trans-acting transcription factors such as Liver Receptor Homologue (LRH-1/NR5A2), cAMP response element binding protein (CREB), Activating Transcription Factor 2 (ATF2/CREB2) and CCAAT/enhancer binding protein δ (C/EBPδ) increase aromatase levels within the epithelial cells and surrounding adipose stromal fibroblasts [9-11]. Additionally in breast cancers, the tumour inhibits adipose stromal fibroblast differentiation while in normal breast tissues differentiation into mature adipocytes reduces aromatase expression [10,12].…”

Section: Introductionmentioning

confidence: 99%

Aromatase expression is increased in BRCA1mutation carriers

2009

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BackgroundUntil recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of BRCA1 gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression in vitro. Our objective was to characterise aromatase gene (CYP19A1) and its promoter expression in breast adipose and ovarian tissue in BRCA1 mutation carriers and unaffected controls.MethodsWe measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women.ResultsWe demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of BRCA1 mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts.ConclusionUnderstanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in BRCA1 mutation carriers.

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“…The regulation of aromatase expression is complex, but one of its key regulators is cAMP. cAMP activates the cAMP-responsive element binding protein (CREB), which interacts with CRE sites in the aromatase promoter I.3/II, inducing its transcription [36,37]. cAMP treatment of MCF-7 cells caused an approximately twofold increase in aromatase mRNA levels (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The model systems used in this study, JEG-3 human placental cells used as a source of microsomal aromatase and the estrogen-receptorpositive MCF-7 human mammary cancer cell line, have been used extensively in aromatase research [30][31][32][33]37,38] and thus are appropriate in vitro models. Plasma concentrations of ROH reach 2-3 μM in humans [2,39].…”

Section: Discussionmentioning

confidence: 99%