The Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase Gene Promoter Is Controlled by Ets and Activating Protein-1 Transcription Factors and Progesterone

Greenland, Karen J.

doi:10.1210/en.141.2.581

Cited by 37 publications

(47 citation statements)

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“…Its presence at higher levels in ERÀ cases suggests other roles in normal breast tissue. The HPGD gene encoding an alcohol dehydrogenase regulated by progesterone is a poor prognostic marker in breast cancer (47), and is overexpressed in ERÀ cell lines and ERÀ tumors (48). The specific roles and interaction of these genes in the genesis of ERÀ tumors clearly needs further work, but just as clearly, point to a heretofore unsuspected role of lipid metabolism abnormalities in the genesis of ERÀ breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Lipid Metabolism Genes in Contralateral Unaffected Breast and Estrogen Receptor Status of Breast Cancer

Wang

Scholtens

Holko

et al. 2013

Cancer Prevention Research

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Risk biomarkers that are specific to estrogen receptor (ER) subtypes of breast cancer would aid the development and implementation of distinct prevention strategies. The contralateral unaffected breast of women with unilateral breast cancer (cases) is a good model for defining subtype-specific risk because women with ER-negative (ERÀ) index primaries are at high risk for subsequent ER-negative primary cancers. We conducted random fine needle aspiration of the unaffected breasts of cases. Samples from 30 subjects [15 ER-positive (ERþ) and 15 ERÀ cases matched for age, race and menopausal status] were used for Illumina expression array analysis. Findings were confirmed using quantitative real-time PCR (qRT-PCR) in the same samples. A validation set consisting of 36 subjects (12 ERþ, 12 ERÀ and 12 standard-risk healthy controls) was used to compare gene expression across groups. ERÀ case samples displayed significantly higher expression of 18 genes/transcripts, 8 of which were associated with lipid metabolism on gene ontology analysis (GO: 0006629). This pattern was confirmed by qRT-PCR in the same samples, and in the 24 cases of the validation set. When compared to the healthy controls in the validation set, significant overexpression of 4 genes (DHRS2, HMGCS2, HPGD and ACSL3) was observed in ERÀ cases, with significantly lower expression of UGT2B11 and APOD in ERþ cases, and decreased expression of UGT2B7 in both subtypes. These data suggest that differential expression of lipid metabolism genes may be involved in the risk for subtypes of breast cancer, and are potential biomarkers of ER-specific breast cancer risk. Cancer Prev Res; 6(4); 321-30. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Lipid Metabolism Genes in Contralateral Unaffected Breast and Estrogen Receptor Status of Breast Cancer

Wang

Scholtens

Holko

et al. 2013

Cancer Prevention Research

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“…Amplification products (introns 2-6) were cloned, partially sequenced from both ends and subjected to restriction analysis. These clones complement a 4·6 kb fragment previously cloned by us that contains 3·5 kb of the 5 -flanking region of the human PGDH gene, exons 1 and 2 and intron 1 (Greenland et al 2000).…”

Section: Cloning Of the Introns Of The Human Pgdh Gene And Determinamentioning

confidence: 94%

“…We have recently isolated 3·5 kb of the 5 -flanking region of the human PGDH gene and reported the presence of several potential binding sites for transcription factors including activating protein-1 (AP-1), Ets and cAMP-responsive element-binding protein (CREB) within 2·4 kb of the 5 -flanking region (Greenland et al 2000). AP-1 belongs to the family of basic region/leucine zipper transcription factors and consists of homo-or heterodimers of Jun, Fos or activating transcription factor (ATF) proteins (Karin et al 1997).…”

Section: Pgdhmentioning

confidence: 99%

“…The PGDH promoter/ luciferase reporter constructs PGDH-2368/luc3 and PGDH-388/luc3 have been described previously (Greenland et al 2000). For construction of the minimal promoter vector PGDH-80/luc3, the fragment 80/ 8 relative to the ATG start codon was created by annealing complementary oligonucleotides with BglII and HindIII overhangs and insertion into the respective sites of pGL3-Basic.…”

Section: Reporter Gene Constructs and Expression Vectorsmentioning

confidence: 99%

“…Within 2·4 kb of the human PGDH promoter several potential binding sites for transcription factors including AP-1, Ets, CREB and CCAAT/ enhancer-binding protein are found in two clusters (Greenland et al 2000). The distal element PGDH-DE ( 2152/ 1944) contains an AP-1 site adjacent to an Ets site and flanked by two CREs (denoted CREB1 and CREB2).…”

Section: Transcriptional Regulation Of the Human Pgdh Genementioning

confidence: 99%

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Genomic structure and transcriptional regulation of the human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase gene

Nandy¹,

Jenatschke²,

Hartung³

et al. 2003

Journal of Molecular Endocrinology

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The NAD + -dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) is a catabolic enzyme that controls the biological activities of prostaglandins by converting them into inactive keto-metabolites. Here we report the genomic organisation of the complete human PGDH gene and characterise its transcriptional regulation. The PGDH gene spans about 31 kb on chromosome 4 and contains 7 exons. Within 2·4 kb of the 5′-flanking sequence we identified two regions with clustered putative transcription factor binding sites. The distal promoter element PGDH-DE (positions−2152/−1944 relative to the start codon) contains binding sites for Ets and activating protein-1 (AP-1) flanked by two cAMP-responsive element-binding protein binding sites (CREB1, CREB2), whereas the proximal element PGDH-PE (−235/−153) includes an Ets and an AP-1 binding sequence. By electrophoretic mobility shift assay, no high affinity binding of Ets or AP-1 factors was observed with PGDH-PE, whereas we confirmed interaction of members of the Ets, AP-1 and CREB families of transcription factors with PGDH-DE. Transcriptional control of the PGDH promoter was assessed by transiently transfecting JEG-3 choriocarcinoma cells. A luciferase reporter gene construct containing the PGDH-PE was not induced by c-jun/c-fos in the absence or presence of co-expressed Ets-1. A construct carrying the PGDH-DE in front of the minimal homologous promoter was activated by co-transfection of expression vectors for AP-1 proteins. Mutation of the AP-1 or CREB2 site reduced the response to c-jun/c-fos, whereas mutation of the Ets site of the distal element reduced basal promoter activity. CREB activated the PGDH-DE construct through the CREB1 site. These results defined the distal element as an integrator of transcriptional regulation by AP-1, Ets and CREB proteins.

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Overexpression of lipid metabolism genes and PBX1 in the contralateral breasts of women with estrogen receptor-negative breast cancer

et al. 2017

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Risk biomarkers for estrogen receptor (ER)-negative breast cancer have clear value for breast cancer prevention. We previously reported a set of lipid metabolism (LiMe) genes with high expression in the contralateral unaffected breasts (CUBs) of ER-negative cancer cases. We now further examine LiMe gene expression in both tumor and CUB, and investigate the role of Pre-B-cell leukemia homeobox-1 (PBX1) as a candidate common transcription factor for LiMe gene expression. mRNA was extracted from laser-capture microdissected epithelium from tumor and CUB of 84 subjects (28 ER-positive cases, 28 ER-negative cases, 28 healthy controls). Gene expression was quantitated by qRT-PCR. Logistic regression models were generated to predict ER status of the contralateral cancer. Protein expression of HMGCS2 and PBX1 was measured using immunohistochemistry. The effect of PBX1 on LiMe gene expression was examined by overexpressing PBX1 in MCF10A cells with or without ER, and by suppressing PBX1 in MDA-MB-453 cells. The expression of DHRS2, HMGCS2, UGT2B7, UGT2B11, ALOX15B, HPGD, UGT2B28 and GLYATL1 was significantly higher in ER-negative versus ER-positive CUBs, and predicted ER status of the tumor in test and validation sets. In contrast, LiMe gene expression was significantly lower in ER-negative than ER-positive tumors. PBX1 overexpression in MCF10A cells up-regulated most LiMe genes, but not in MCF10A cells overexpressing ER. Suppressing PBX1 in MDA-MB-453 cells resulted in decrease of LiMe gene expression. Four binding sites of PBX1 and cofactor were identified in three lipid metabolism genes using ChIP-qPCR. These data suggest a novel role for PBX1 in the regulation of lipid metabolism genes in benign breast, which may contribute to ER-negative tumorigenesis.

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The Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase Gene Promoter Is Controlled by Ets and Activating Protein-1 Transcription Factors and Progesterone

Cited by 37 publications

References 0 publications

Lipid Metabolism Genes in Contralateral Unaffected Breast and Estrogen Receptor Status of Breast Cancer

Lipid Metabolism Genes in Contralateral Unaffected Breast and Estrogen Receptor Status of Breast Cancer

Genomic structure and transcriptional regulation of the human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase gene

Overexpression of lipid metabolism genes and PBX1 in the contralateral breasts of women with estrogen receptor-negative breast cancer

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