Identification of a Novel Estrogen Response Element in the 
 Breast Cancer Resistance Protein
 (
 ABCG2
 ) Gene

Ee, Pui Lai Rachel; Kamalakaran, Sitharthan; Tonetti, Debra A.; He, Xijing; Ross, Douglas D.; Beck, William T.

doi:10.1158/0008-5472.can-03-3583

Cited by 197 publications

(160 citation statements)

References 23 publications

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“…Further interesting evidence was gleaned from our microarray mRNA expression studies coupled with pathway analysis, indicating that the oestrogen receptor may regulate the expression of ABCG2 (data not shown). This hypothesis is supported by recent work that showed the presence of an oestrogen response element in the ABCG2 gene (Ee et al, 2004). Additional studies are necessary to elucidate the role of the oestrogen receptor in ABCG2 overexpression.…”

Section: Discussionmentioning

confidence: 53%

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Calcagno

Fostel²,

et al. 2008

Br J Cancer

111

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Understanding the mechanisms of multidrug resistance (MDR) could improve clinical drug efficacy. Multidrug resistance is associated with ATP binding cassette (ABC) transporters, but the factors that regulate their expression at clinically relevant drug concentrations are poorly understood. We report that a single-step selection with low doses of anti-cancer agents, similar to concentrations reported in vivo, induces MDR that is mediated exclusively by ABCG2. We selected breast, ovarian and colon cancer cells (MCF-7, IGROV-1 and S-1) after exposure to 14 or 21 nM doxorubicin for only 10 days. We found that these cells overexpress ABCG2 at the mRNA and protein levels. RNA interference analysis confirmed that ABCG2 confers drug resistance. Furthermore, ABCG2 upregulation was facilitated by histone hyperacetylation due to weaker histone deacetylase 1-promoter association, indicating that these epigenetic changes elicit changes in ABCG2 gene expression. These studies indicate that the MDR phenotype arises following low-dose, single-step exposure to doxorubicin, and further suggest that ABCG2 may mediate early stages of MDR development. This is the first report to our knowledge of single-step, low-dose selection leading to overexpression of ABCG2 by epigenetic changes in multiple cancer cell lines.

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Section: Discussionmentioning

confidence: 53%

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Calcagno

Fostel²,

et al. 2008

Br J Cancer

111

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“…These genes, their predicted EREs, and position relative to their TSS are listed in Table II. The downregulation of ABCG2/BCRP seems to be cell line-specific because it is, in fact, up-regulated following estrogen treatment in ER-positive T47D:A18 cells, an effect that is mediated by the ERE element identified by PAGen@UIC (26). Thus, by using PAGen@UIC, we have high accuracy for predicting novel estrogen-responsive genes.…”

Section: Fig 1 Strategy Used To Predict Potential Targets Of Transcmentioning

confidence: 94%

Identification of Estrogen-responsive Genes Using a Genome-wide Analysis of Promoter Elements for Transcription Factor Binding Sites

Kamalakaran¹,

Radhakrishnan

Beck

2005

Journal of Biological Chemistry

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We developed a pipeline to identify novel genes regulated by the steroid hormone-dependent transcription factor, estrogen receptor, through a systematic analysis of upstream regions of all human and mouse genes. We built a data base of putative promoter regions for 23,077 human and 19,984 mouse transcripts from National Center for Biotechnology Information annotation and 8793 human and 6785 mouse promoters from the Data Base of Transcriptional Start Sites. We used this data base of putative promoters to identify potential targets of estrogen receptor by identifying estrogen response elements (EREs) in their promoters. Our program correctly identified EREs in genes known to be regulated by estrogen in addition to several new genes whose putative promoters contained EREs. We validated six genes (KIAA1243, NRIP1, MADH9, NME3, TPD52L, and ABCG2) to be estrogen-responsive in MCF7 cells using reverse transcription PCR. To allow for extensibility of our program in identifying targets of other transcription factors, we have built a Web interface to access our data base and programs. Our Web-based program for Promoter Analysis of Genome, PAGen@UIC, allows a user to identify putative target genes for vertebrate transcription factors through the analysis of their upstream sequences. The interface allows the user to search the human and mouse promoter data bases for potential target genes containing one or more listed transcription factor binding sites (TFBSs) in their upstream elements, using either regular expression-based consensus or position weight matrices. The data base can also be searched for promoters harboring user-defined TFBSs given as a consensus or a position weight matrix. Furthermore, the user can retrieve putative promoter sequences for any given gene together with identified TFBSs located on its promoter. Orthologous promoters are also analyzed to determine conserved elements.Estrogens play a critical role in vertebrate reproduction, especially in the development of female sex organs (1). The bulk of estrogen signaling is controlled by estrogen receptors ␣ and ␤ (ER␣ 1 and ER␤), members of the nuclear receptor superfamily (2) of ligand-inducible transcription factors. ER␣ and ER␤ bind to the estrogen response element (ERE) on the promoters of the genes they regulate. The ERE is a palindrome of RG-GTCA motifs separated by 3 bp (3). These elements are bound by ER dimers, with one receptor binding each motif. The sequence and spatial organization of the ERE is important for the specificity of binding. Although a crystal structure of the DNAbound ER is available (4), the unexpected diversity of DNA response elements mediating transcriptional regulation by ERs has made finding EREs in the genome very difficult. In fact, none of the typical estrogen-responsive genes have consensus EREs.

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“…The promoter of ABCG2 has been reported to contain an overlapping estrogen response element and a progesterone response element, which were shown to specifically bind ERα and progesterone receptor A and B (PRA and PRB), respectively. Expression of ABCG2 was reported to be induced by estrogen through ERα; however, enhanced expression of ABCG2 by progesterone was observed only in model cells expressing PRB, whereas PRA was shown to repress PRB activity (Ee et al, 2004;Wang et al, 2008).…”

Section: P0295mentioning

confidence: 97%

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

Hegedüs

Telbisz

Hegedüs

et al. 2015

Advances in Cancer Research

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Identification of a Novel Estrogen Response Element in the Breast Cancer Resistance Protein ( ABCG2 ) Gene

Cited by 197 publications

References 23 publications

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes

Identification of Estrogen-responsive Genes Using a Genome-wide Analysis of Promoter Elements for Transcription Factor Binding Sites

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

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