Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer

Leu, Yu Wei; Yan, Pearlly S.; Fan, Meiyun; Jin, Victor X.; Liu, Joseph C.; Curran, Edward M.; Welshons, Wade V.; Wei, Susan; Davuluri, Ramana V.; Plass, Christoph; Nephew, Kenneth P.; Huang, Tim H.M.

doi:10.1158/0008-5472.can-04-2045

Cited by 172 publications

(147 citation statements)

References 43 publications

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“…Collectively then, the summarised findings suggest that impairment of the HNF1b/ HNF4a signalling network may lead to tumour formation. Similar epigenetic inactivation of a critical regulator of a transcriptional network has been reported for several other genes, including estrogen receptor (Leu et al, 2004) and GATA (Akiyama et al, 2003). Epigenetic inactivation of such transcription factors may affect multiple downstream genes, causing aberrant alteration of signalling pathways involved in a wide array of cellular functions, including growth, differentiation and apoptosis.…”

Section: Discussionsupporting

confidence: 53%

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

et al. 2006

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Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1b (HNF1b), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2 0 deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4a, a transcriptional target of HNF1b, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment.

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Section: Discussionsupporting

confidence: 53%

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

et al. 2006

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“…Silent ERa target gene promoters have also been shown to accumulate DNA methylation following induced depletion of ERa (Leu et al, 2004). Nevertheless the opposite is not true.…”

Section: Discussionmentioning

confidence: 99%

Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells

et al. 2008

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In breast cancer, approximately one-third of tumors express neither the estrogen receptor (ERa) nor estrogen-regulated genes such as the progesterone receptor gene (PR). Our study provides new insights into the mechanism allowing hormone-activated expression of ERa target genes silenced in ERa-negative mammary tumor cells. In cell lines derived from ERa-negative MDA-MB231 cells, stable expression of different levels of ERa from a transgene did not result in transcription of PR. A quantitative comparative analysis demonstrates that inhibiting DNA methyltransferases using 5-aza-2 0 -deoxycytidine or specific disruption of DNMT1 by small interfering RNAs and treatment with the histone-deacetylase inhibitor trichostatin A enabled ERa-mediated hormone-dependent expression of endogenous PR. We show that demethylation of a CpG island located in the first exon of PR was a prerequisite for ERa binding to these regulatory sequences. Although not a general requirement, DNA demethylation is also necessary for derepression of a subset of ERa target genes involved in tumorigenesis. PR transcription did not subsist 4 days after removal of the DNA methyltransferase blocking agents, suggesting that hormone-induced expression of ERa target genes in ERa-negative tumor cells is transient. Our observations support a model where an epigenetic mark confers stable silencing by precluding ERa access to promoters.

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“…53,54 Volpe et al have reported that heterochromatic silencing and histone H3 K9 methylation are regulated by RNAi, 55 and it has been suggested that small interfering RNAs (siRNAs) regulate DNA methylation of promoter regions. 55,56 Hence, it is apparent that DNA methylation, histone modification and RNAi are intimately related to each other, 54,57 and comprehensive epigenetic studies in which these 3 mechanisms are examined will be necessary to confirm the details of regulation of MUC2 gene expression.…”

Section: Discussionmentioning

confidence: 99%

MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer

Yamada

Hamada

Goto

et al. 2006

Intl Journal of Cancer

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Mucins are highly glycosylated proteins that play important roles in carcinogenesis. In pancreatic neoplasia, MUC2 mucin has been demonstrated as a tumor suppressor and we have reported that MUC2 is a favorable prognostic factor. Regulation of MUC2 gene expression is known to be controlled by DNA methylation, but the role of histone modification for MUC2 gene expression has yet to be clarified. Herein, we provide the first report that the histone H3 modification of the MUC2 promoter region regulates MUC2 gene expression. To investigate the histone modification and DNA methylation of the promoter region of the MUC2 gene, we treated 2 human pancreatic cancer cell lines, PANC1 (MUC2-negative) and BxPC3 (MUC2-positive) with the DNA methyltransferase inhibitor 5-azacytidine (5-aza), the histone deacetylase inhibitor trichostatin A (TSA), and a combination of these agents. The DNA methylation level of PANC1 cells was decreased by all 3 treatments, whereas histone H3-K4/K9 methylation and H3-K9/K27 acetylation in PANC1 cells was changed to the level in BxPC3 cells by treatment with TSA alone and with the 5-aza/TSA combination. The expression level of MUC2 mRNA in PANC1 cells exhibited a definite increase when treated with TSA and 5-aza/TSA, whereas 5-aza alone induced only a slight increase. Our results suggest that histone H3 modification in the 5 0 flanking region play an important role in MUC2 gene expression, possibly affecting DNA methylation. An understanding of these intimately correlated epigenetic changes may be of importance for predicting the outcome of patients with pancreatic neoplasms. ' 2006 Wiley-Liss, Inc.

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Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer

Cited by 172 publications

References 43 publications

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

Eliminating epigenetic barriers induces transient hormone-regulated gene expression in estrogen receptor negative breast cancer cells

MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer

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