Estrogen-dependent downregulation of hairy and enhancer of split homolog-1 gene expression in breast cancer cells is mediated via a 3′ distal element

Müller, Patrick; Merrell, Kenneth W.; Crofts, Justin D.; Rönnlund, Caroline; Lin, Chin Yo; Gustafsson, Jan‐Åke; Ström, Anders

doi:10.1677/joe-08-0094

Cited by 7 publications

(6 citation statements)

References 15 publications

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“…This is suggests a model in which puberty-specific methylation reduces Hes-1 binding in order to de-repress (ie, activate) the Kiss1 promoter at the time of puberty, which is consistent with recent findings in mice 36. Interestingly, E2 has been shown to repress Hes-1 expression in breast cancer cells 45. Should similar regulation occur in the RP3V Kiss1 neurons, rising E2 levels at puberty could cause Hes-1 to leave the Kiss1 promoter, increasing levels of Kiss1 to increase GnRH release.…”

Section: Discussionsupporting

confidence: 90%

Changes in Methylation Patterns of Kiss1 and Kiss1r Gene Promoters across Puberty

et al. 2013

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The initiation of mammalian puberty is underpinned by an increase in Kisspeptin (Kiss1) signaling via its receptor (Kiss1r/GPR54) on gonadotropin-releasing hormone (GnRH) neurons. Animals and humans with loss-of-function mutations in Kiss1 or Kiss1r fail to go through puberty. The timing of puberty is dependent on environmental factors, and malleability in puberty timing suggests a mechanism that can translate environmental signals into patterns of Kiss1/Kiss1r gene expression. Epigenetics is a powerful mechanism that can control gene expression in an environment-dependent manner. We investigated whether epigenetic DNA methylation is associated with gene expression changes at puberty. We used bisulfite-PCR-pyrosequencing to define the methylation in the promoters of Kiss1 and Kiss1r before and after puberty in female rats. Both Kiss1 and Kiss1r showed highly significant puberty-specific differential promoter methylation patterns. By identifying key differentially methylated residues associated with puberty, these findings will be important for further studies investigating the control of gene expression across the pubertal transition.

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Section: Discussionsupporting

confidence: 90%

Changes in Methylation Patterns of Kiss1 and Kiss1r Gene Promoters across Puberty

et al. 2013

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“…HES1, known to be targeted by ER [42,44] and AHR [43], is a transcription repressor that directly represses E2F1 and it inhibits cell proliferation[42]. Therefore as represented in the network, the down-regulation of human homolog HES1 by estrogen, known to be mediated by a novel type repressive estrogen response element in human [44], appeared to be conserved between fish and human, and this could be pivotal for the up-regulation E2F transcription factors and downstream cell cycle genes (human homologs CDK2, CCNA, CCNE ) that are necessary for G1-S phase transition leading to mitosis. Several E2F transcription factors and cell cycle-related genes have been shown to be up-regulated by estrogen as primary or secondary targets in human breast cancer cell lines [45].…”

Section: Resultsmentioning

confidence: 99%

Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines

et al. 2011

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BackgroundThe zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines.MethodsMicroarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen) and an anti-estrogen (ICI 182,780). Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa).ResultsOur transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE), is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry points for estrogen regulation.ConclusionThe findings demonstrate the use of zebrafish for characterizing estrogen-like environmental carcinogens and anti-estrogen drug screening. From an evolutionary perspective, our findings suggest that estrogen regulation of cell cycle is perhaps one of the earliest forms of steroidal-receptor controlled cellular processes. Our study provides first evidence of molecular conservation of estrogen-responsiveness between zebrafish and human cancer cell lines, hence demonstrating the potential of zebrafish for estrogen-related cancer research.

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“…Also, duplication of ERE half‐palindromes in Notch1 , Notch2 , Notch3 , Dll3, Dll4, and Jagged2 promoters provide a structural basis for estrogenic regulation of these genes. Down regulation of Notch2 , Dll1, and Dll4 in the intact mammary gland compared to mammary glands from ovariectomized mice suggests that certain regulatory sequences and/or chromatin structures are playing a role in regulation of these genes (Strom et al, 2000; Muller et al, 2009). In addition estrogen receptor binding can lead to recruitment of coactivators or co‐repressors (Heldring et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Expression of Notch receptors, ligands, and target genes during development of the mouse mammary gland

et al. 2011

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Notch genes play a critical role in mammary gland growth, development and tumorigenesis. In the present study we have quantitatively determined the levels and mRNA expression patterns of the Notch receptor genes, their ligands and target genes in the postnatal mouse mammary gland. The steady state levels of Notch3 mRNA are the highest among receptor genes, Jagged1 and Dll3 mRNA levels are the highest among ligand genes and Hey2 mRNA levels are highest among expressed Hes/Hey target genes analyzed during different stages of postnatal mammary gland development. Using an immunohistochemical approach with antibodies specific for each Notch receptor, we show that Notch proteins are temporally regulated in mammary epithelial cells during normal mammary gland development in the FVB/N mouse. The loss of ovarian hormones is associated with changes in the levels of Notch receptor mRNAs (Notch2 higher and Notch3 lower) and ligand mRNAs (Dll1 and Dll4 are higher, whereas Dll3 and Jagged1 are lower) in the mammary gland of ovariectomized mice compared to intact mice. These data define expression of the Notch ligand/receptor system throughout development of the mouse mammary gland and help set the stage for genetic analysis of Notch in this context.

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Estrogen-dependent downregulation of hairy and enhancer of split homolog-1 gene expression in breast cancer cells is mediated via a 3′ distal element

Cited by 7 publications

References 15 publications

Changes in Methylation Patterns of Kiss1 and Kiss1r Gene Promoters across Puberty

Changes in Methylation Patterns of Kiss1 and Kiss1r Gene Promoters across Puberty

Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines

Expression of Notch receptors, ligands, and target genes during development of the mouse mammary gland

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