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GREB1 (growth regulation by estrogen in breast cancer 1)

Written2012-09Kevin C Knower, Chantal B Magne Nde, Kyren Lazarus, Sarah Q To, Zhe Zhao, Ashwini L Chand, Colin D Clyne
Cancer Drug Discovery Laboratory, Prince Henry's Institute, Clayton, Victoria, Australia

(Note : for Links provided by Atlas : click)


HGNC Alias symbKIAA0575
HGNC Alias namegene regulated by estrogen in breast cancer
HGNC Previous namegrowth regulation by estrogen in breast cancer 1
LocusID (NCBI) 9687
Atlas_Id 40751
Location 2p25.1  [Link to chromosome band 2p25]
Location_base_pair Starts at 11539819 and ends at 11588229 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping GREB1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
GREB1 (2p25.1)::E2F6 (2p25.1)GREB1 (2p25.1)::PDE1A (2q32.1)


  Figure 1. (a) The genomic location of GREB1 on the short arm of chromosome 2. (b) The 3 primary splice variants of GREB1, GREB1a, GREB1b and GREB1c. Green boxes represent exons, red lines introns. Numbers below exons indicate exon number. Numbers either side of variant indicate genomic location of the start and end of each transcript.
Description The GREB1 gene is located on the short arm of chromosome 2, at 2q25.1, between the genomic sites for E2F transcription factor 6 and neurotensin receptor 2 (Entrez gene 9687). It is encoded on the plus strand covering 108.68 kb from 11674242 to 11782912 (UCSC). The gene structure consists of 60 exons/alternative exons and 40 distinct introns.
Transcription The GREB1 gene contains a distal enhancer 20 kb upstream of the transcription start site containing 3 estrogen response elements (EREs), which bind estrogen receptor α (ERα) in the presence of estrogen. In breast cancer cells, the steroid receptor co-activator SRC-3, phosphorylated RNA polymerase II and actylated histones are also bound in the presence of estrogen. Chromatin loops link the three distal EREs and the transcription start site, indicating the distal enhancer plays a potent role in GREB1 estrogen responsiveness (Deschênes et al., 2007; Sun et al., 2007).
Three primary representative complete cDNA clones have been isolated from an MCF7 (ER+ breast cancer cell line) cDNA library, designated GREB1a, GREB1b and GREB1c respectively (Ghosh et al., 2000). The longest transcript variant is GREB1a, consisting of 8482 bp spliced from 33 exons. GREB1b is 2521 bp in length and is spliced from 11 exons, whilst GREB1c is 2432 bp long spliced from 10 exons. All three variants differ in their 5' and 3' UTRs and contain distinct c-terminus regions. In addition, up to 10 additional splice variants have been identified amongst clones from breast, uterus, prostate and brain (Dias Neto et al., 2000; Nagase et al., 1998). Expression of GREB1 variants have also been detected in the ovary, prostate and pancreas (NCBI).


  Table 1. Isoforms of GREB1. 1=present, 0=absent.
Description GREB1 protein has 7 isoforms containing a transmembrane domain and/or N-myristoylation domain. The three well documented isoforms of GREB1 protein, GREB1a, GREB1b and GREB1c contain 1949, 457 and 409 amino acids, respectively (Table 1). They share N-terminus end region and containing diverging C-terminus end. The divergence between 1a and 1b start from 450 aa. GREB1c shares first 386 amino acids with GREB1a and differs from 387 to 409 amino acids (Ghosh et al., 2000).
Expression GREB1 protein expression is found in both normal and cancerous tissues. Its regulation is not only correlated with the presence of a subset of nuclear receptors such as ERα (Deschênes et al., 2007; Hnatyszyn et al., 2010; Lin et al., 2004; Pellegrini et al., 2012), androgen receptor (AR) (Rae et al., 2006) and Liver receptor Homolog 1 (LRH-1) (Chand et al., 2012) but also depends on their activation. In breast cancers, GREB1 protein is detected in ERalpha+ but not ERalpha-negative breast tumour tissue (Hnatyszyn et al., 2010).
In addition GREB1, regulated by androgens is expressed in proliferating prostatic tissue and prostate cancer (Rae et al., 2006).
Localisation GREB1 protein expression is predominantly nuclear with some cytoplasmic appearance (Hnatyszyn et al., 2010).
Function The role of GREB1 is emerging as a hormone-dependent mediator of tumour cell proliferation. It has been reported to elicit estrogen and androgen-stimulated cell proliferation in breast and prostate tumours (Rae et al., 2006; Rae et al., 2005; Antunes et al., 2012). Whether the three variants have the same cellular function is unclear and its precise mechanistic action within the cell has still not been demonstrated.
The exact roles that GREB1 have in normal tissue are poorly defined.
Homology GREB1 protein together with his paralogue GREB1-like located on chromosome 18 belong to the GREB1 family (Nagase et al., 2000). The GREB1 gene sequence is conserved in chimpanzee, dog, cow, mouse, chicken and monkey (HomoloGene).

Implicated in

Entity Breast cancers
Note A family of estrogen responsive genes discovered in MCF7 cells were designated GREB (genes regulated by estrogen in breast cancer) (Ghosh et al., 2000). Of these novel genes, GREB-1 was identified to have a strong correlation with ERα in breast cancer cells (Ghosh et al., 2000; Rae et al., 2005). Interestingly, GREB-1 was significantly induced by E2 in MCF-7 cells and its suppression blocked E2 induced growth (Rae et al., 2005). Furthermore, the GREB-1 regulatory region was found to possess three crucial estrogen response elements (EREs) (Lin et al., 2004). In addition, ChIP analysis revealed the binding of ERα, the steroid receptor coactivator-3, acetylated histones and phosphorylated RNA polymerase II to all three EREs in the presence of E2 (Deschênes et al., 2007). Subsequently, GREB-1 is now a well characterised estrogen responsive gene used to identify ERα activity (Cai et al., 2011; Chand et al., 2012; Gupta et al., 2012; Liu et al., 2012; Rae et al., 2005; Sun et al., 2007; Woodfield et al., 2010). Hnatyszyn, et al developed a novel GREB-1 antibody which was used to detect GREB-1 protein expression in ERα+ve breast cancer cells and tissue (Hnatyszyn et al., 2010).
This positive correlation of GREB1 expression with ERα expression is validated in clinical cohorts (Ghosh et al., 2000). Another cohort of ER positive breast cancers in postmenopausal women (n=104) has shown a strong correlation of GREB-1 gene expression with plasma E2 levels (Dunbier et al., 2010). In a cohort of breast cancer patients (n=64) compared to healthy women (n=79) GREB-1 gene expression correlated positively with serum E2 levels (Haakensen et al., 2011). Furthermore in-vivo studies involving the transplantation of human breast tissue into female athymic mice (Balb/c nu/nu mice) has also demonstrated the induction of GREB-1 in response to E2 treatment (Wilson et al., 2006).
Entity Prostate cancer
Note High levels of GREB1 mRNA ,comparable to levels in breast cancer MCF-7 cells, were found in prostatic tissues and prostate tumours (Rae et al., 2006). GREB1 was found to be also expressed in the AR-positive cell line LNCaP but absent in the AR-negative cell line PC-3 (Rae et al., 2006). GREB1 expression was responsive to androgens via androgen response elements (ARE) located ~3.3 kb upstream of the promoter. Knock-down of GREB1 in LNCaP cells led to the suppression of hormone-induced growth. Using microarray and qRT-PCR analysis of 33 prostate cancer patients, GREB1 was found to be over-expressed 13-fold compared to normal (Antunes et al., 2012). GREB1 transcript was significantly higher among patients with later stage prostate cancers.
Entity Lung cancer
Note Following exposure to 2R4F tobacco mainstream smoke (MSS), GREB1 expression was elevated in normal human bronchial epithelial (NHBE) cells (Parsanejad et al., 2008). Using human saliva samples from 42 lung cancer patients and 74 healthy control subjects, transcriptomes were analyzed by gene microarray and revealed that GREB1 was one of five biomarkers found to be elevated in lung cancer patients (Zhang et al., 2012).
Entity Ovarian cancer
Note To identify epigenetic changes associated with progression-free interval of ovarian cancer, 20 samples of advanced ovarian cancer with a predominantly serous papillary histological subtype were subjected to DNA methylation profiling. GREB1 promoter hypomethylation was associated with longer survival (Bauerschlag et al., 2011).
Entity Hypertension
Note A SNP, 45718A>G, was significantly associated with hypertension and blood pressure level in men, and this SNP was in linkage disequilibrium with a SNP present at the 3' splice site of intron 11 (Kamide et al., 2005).


GREB1 tissue expression is associated with organ-confined prostate cancer.
Antunes AA, Leite KR, Reis ST, Sousa-Canavez JM, Camara-Lopes LH, Dall'oglio MF, Srougi M.
Urol Oncol. 2012 Jan-Feb;30(1):16-20. doi: 10.1016/j.urolonc.2009.09.014. Epub 2009 Nov 27.
PMID 19945309
Progression-free survival in ovarian cancer is reflected in epigenetic DNA methylation profiles.
Bauerschlag DO, Ammerpohl O, Brautigam K, Schem C, Lin Q, Weigel MT, Hilpert F, Arnold N, Maass N, Meinhold-Heerlein I, Wagner W.
Oncology. 2011;80(1-2):12-20. doi: 10.1159/000327746. Epub 2011 May 16.
PMID 21577013
The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor a.
Cai W, Kramarova TV, Berg P, Korbonits M, Pongratz I.
PLoS One. 2011;6(10):e25201. doi: 10.1371/journal.pone.0025201. Epub 2011 Oct 3.
PMID 21984905
The orphan nuclear receptor LRH-1 and ERa activate GREB1 expression to induce breast cancer cell proliferation.
Chand AL, Wijayakumara DD, Knower KC, Herridge KA, Howard TL, Lazarus KA, Clyne CD.
PLoS One. 2012;7(2):e31593. doi: 10.1371/journal.pone.0031593. Epub 2012 Feb 16.
PMID 22359603
Regulation of GREB1 transcription by estrogen receptor alpha through a multipartite enhancer spread over 20 kb of upstream flanking sequences.
Deschenes J, Bourdeau V, White JH, Mader S.
J Biol Chem. 2007 Jun 15;282(24):17335-9. Epub 2007 Apr 26.
PMID 17463000
Shotgun sequencing of the human transcriptome with ORF expressed sequence tags.
Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W Jr, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ.
Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3491-6.
PMID 10737800
Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women.
Dunbier AK, Anderson H, Ghazoui Z, Folkerd EJ, A'hern R, Crowder RJ, Hoog J, Smith IE, Osin P, Nerurkar A, Parker JS, Perou CM, Ellis MJ, Dowsett M.
J Clin Oncol. 2010 Mar 1;28(7):1161-7. doi: 10.1200/JCO.2009.23.9616. Epub 2010 Feb 1.
PMID 20124184
PDZK1 and GREB1 are estrogen-regulated genes expressed in hormone-responsive breast cancer.
Ghosh MG, Thompson DA, Weigel RJ.
Cancer Res. 2000 Nov 15;60(22):6367-75.
PMID 11103799
Janus kinase 2--a novel negative regulator of estrogen receptor a function.
Gupta N, Grebhardt S, Mayer D.
Cell Signal. 2012 Jan;24(1):151-61. doi: 10.1016/j.cellsig.2011.08.016. Epub 2011 Sep 1.
PMID 21907792
Serum estradiol levels associated with specific gene expression patterns in normal breast tissue and in breast carcinomas.
Haakensen VD, Bjoro T, Luders T, Riis M, Bukholm IK, Kristensen VN, Troester MA, Homen MM, Ursin G, Borresen-Dale AL, Helland A.
BMC Cancer. 2011 Aug 3;11:332. doi: 10.1186/1471-2407-11-332.
PMID 21812955
Correlation of GREB1 mRNA with protein expression in breast cancer: validation of a novel GREB1 monoclonal antibody.
Hnatyszyn HJ, Liu M, Hilger A, Herbert L, Gomez-Fernandez CR, Jorda M, Thomas D, Rae JM, El-Ashry D, Lippman ME.
Breast Cancer Res Treat. 2010 Jul;122(2):371-80. doi: 10.1007/s10549-009-0584-x. Epub 2009 Oct 20.
PMID 19842031
Hypertension susceptibility genes on chromosome 2p24-p25 in a general Japanese population.
Kamide K, Kokubo Y, Yang J, Tanaka C, Hanada H, Takiuchi S, Inamoto N, Banno M, Kawano Y, Okayama A, Tomoike H, Miyata T.
J Hypertens. 2005 May;23(5):955-60.
PMID 15834280
Discovery of estrogen receptor alpha target genes and response elements in breast tumor cells.
Lin CY, Strom A, Vega VB, Kong SL, Yeo AL, Thomsen JS, Chan WC, Doray B, Bangarusamy DK, Ramasamy A, Vergara LA, Tang S, Chong A, Bajic VB, Miller LD, Gustafsson JA, Liu ET.
Genome Biol. 2004;5(9):R66. Epub 2004 Aug 12.
PMID 15345050
TRIM29 functions as a tumor suppressor in nontumorigenic breast cells and invasive ER+ breast cancer.
Liu J, Welm B, Boucher KM, Ebbert MT, Bernard PS.
Am J Pathol. 2012 Feb;180(2):839-47. doi: 10.1016/j.ajpath.2011.10.020. Epub 2011 Dec 2.
PMID 22138580
Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.
Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O.
DNA Res. 1998 Feb 28;5(1):31-9.
PMID 9628581
Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.
Nagase T, Kikuno R, Hattori A, Kondo Y, Okumura K, Ohara O.
DNA Res. 2000 Dec 31;7(6):347-55.
PMID 11214970
The time course of expression of genes involved in specific pathways in normal human bronchial epithelial cells following exposure to cigarette smoke.
Parsanejad R, Fields WR, Morgan WT, Bombick BR, Doolittle DJ.
Exp Lung Res. 2008 Oct;34(8):513-30. doi: 10.1080/01902140802271826.
PMID 18850377
The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis.
Pellegrini C, Gori I, Achtari C, Hornung D, Chardonnens E, Wunder D, Fiche M, Canny GO.
Fertil Steril. 2012 Nov;98(5):1200-8. doi: 10.1016/j.fertnstert.2012.06.056. Epub 2012 Aug 11.
PMID 22884659
GREB1 is a novel androgen-regulated gene required for prostate cancer growth.
Rae JM, Johnson MD, Cordero KE, Scheys JO, Larios JM, Gottardis MM, Pienta KJ, Lippman ME.
Prostate. 2006 Jun 1;66(8):886-94.
PMID 16496412
Long-range activation of GREB1 by estrogen receptor via three distal consensus estrogen-responsive elements in breast cancer cells.
Sun J, Nawaz Z, Slingerland JM.
Mol Endocrinol. 2007 Nov;21(11):2651-62. Epub 2007 Jul 31.
PMID 17666587
Effects of oestrogen on gene expression in epithelium and stroma of normal human breast tissue.
Wilson CL, Sims AH, Howell A, Miller CJ, Clarke RB.
Endocr Relat Cancer. 2006 Jun;13(2):617-28.
PMID 16728587
Identification of primary gene targets of TFAP2C in hormone responsive breast carcinoma cells.
Woodfield GW, Chen Y, Bair TB, Domann FE, Weigel RJ.
Genes Chromosomes Cancer. 2010 Oct;49(10):948-62. doi: 10.1002/gcc.20807.
PMID 20629094
Development of transcriptomic biomarker signature in human saliva to detect lung cancer.
Zhang L, Xiao H, Zhou H, Santiago S, Lee JM, Garon EB, Yang J, Brinkmann O, Yan X, Akin D, Chia D, Elashoff D, Park NH, Wong DT.
Cell Mol Life Sci. 2012 Oct;69(19):3341-50. doi: 10.1007/s00018-012-1027-0. Epub 2012 Jun 12.
PMID 22689099


This paper should be referenced as such :
Knower, KC ; Magne, Nde CB ; Lazarus, K ; To, SQ ; Zhao, Z ; Chand, AL ; Clyne, CD
GREB1 (growth regulation by estrogen in breast cancer 1)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(3):155-158.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(2;2)(p25;p25) GREB1::E2F6

External links


HGNC (Hugo)GREB1   24885
Entrez_Gene (NCBI)GREB1    growth regulating estrogen receptor binding 1
GeneCards (Weizmann)GREB1
Ensembl hg19 (Hinxton)ENSG00000196208 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000196208 [Gene_View]  ENSG00000196208 [Sequence]  chr2:11539819-11588229 [Contig_View]  GREB1 [Vega]
ICGC DataPortalENSG00000196208
TCGA cBioPortalGREB1
Genatlas (Paris)GREB1
SOURCE (Princeton)GREB1
Genetics Home Reference (NIH)GREB1
Genomic and cartography
GoldenPath hg38 (UCSC)GREB1  -     chr2:11539819-11588229 +  2p25.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)GREB1  -     2p25.1   [Description]    (hg19-Feb_2009)
GoldenPathGREB1 - 2p25.1 [CytoView hg19]  GREB1 - 2p25.1 [CytoView hg38]
Genome Data Viewer NCBIGREB1 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB011147 AF245388 AF245389 AF245390 AK056886
RefSeq transcript (Entrez)NM_014668 NM_033090 NM_148903
Consensus coding sequences : CCDS (NCBI)GREB1
Gene ExpressionGREB1 [ NCBI-GEO ]   GREB1 [ EBI - ARRAY_EXPRESS ]   GREB1 [ SEEK ]   GREB1 [ MEM ]
Gene Expression Viewer (FireBrowse)GREB1 [ Firebrowse - Broad ]
GenevisibleExpression of GREB1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9687
GTEX Portal (Tissue expression)GREB1
Human Protein AtlasENSG00000196208-GREB1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ4ZG55   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ4ZG55  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ4ZG55
Domains : Interpro (EBI)GREB1   
Domain families : Pfam (Sanger)GREB1 (PF15782)   
Domain families : Pfam (NCBI)pfam15782   
Conserved Domain (NCBI)GREB1
AlphaFold pdb e-kbQ4ZG55   
Human Protein Atlas [tissue]ENSG00000196208-GREB1 [tissue]
Protein Interaction databases
IntAct (EBI)Q4ZG55
Ontologies - Pathways
Ontology : AmiGOnucleoplasm  multicellular organism development  integral component of membrane  extracellular exosome  
Ontology : EGO-EBInucleoplasm  multicellular organism development  integral component of membrane  extracellular exosome  
Pathways : BIOCARTADownregulated of MTA-3 in ER-negative Breast Tumors [Genes]   
REACTOMEQ4ZG55 [protein]
REACTOME PathwaysR-HSA-9018519 [pathway]   
NDEx NetworkGREB1
Atlas of Cancer Signalling NetworkGREB1
Wikipedia pathwaysGREB1
Orthology - Evolution
GeneTree (enSembl)ENSG00000196208
Phylogenetic Trees/Animal Genes : TreeFamGREB1
Homologs : HomoloGeneGREB1
Homology/Alignments : Family Browser (UCSC)GREB1
Gene fusions - Rearrangements
Fusion : MitelmanGREB1::E2F6 [2p25.1/2p25.1]  
Fusion : MitelmanGREB1::PDE1A [2p25.1/2q32.1]  
Fusion : QuiverGREB1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGREB1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GREB1
Exome Variant ServerGREB1
GNOMAD BrowserENSG00000196208
Varsome BrowserGREB1
ACMGGREB1 variants
Genomic Variants (DGV)GREB1 [DGVbeta]
DECIPHERGREB1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisGREB1 
ICGC Data PortalGREB1 
TCGA Data PortalGREB1 
Broad Tumor PortalGREB1
OASIS PortalGREB1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGREB1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DGREB1
Mutations and Diseases : HGMDGREB1
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)GREB1
DoCM (Curated mutations)GREB1
CIViC (Clinical Interpretations of Variants in Cancer)GREB1
NCG (London)GREB1
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry GREB1
NextProtQ4ZG55 [Medical]
Target ValidationGREB1
Huge Navigator GREB1 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDGREB1
Pharm GKB GenePA164747489
Clinical trialGREB1
DataMed IndexGREB1
PubMed50 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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