SPDEF

Gene Summary

Gene:SPDEF; SAM pointed domain containing ETS transcription factor
Aliases: PDEF, bA375E1.3
Location:6p21.3
Summary:The protein encoded by this gene belongs to the ETS family of transcription factors. It is highly expressed in the prostate epithelial cells, and functions as an androgen-independent transactivator of prostate-specific antigen (PSA) promoter. Higher expression of this protein has also been reported in brain, breast, lung and ovarian tumors, compared to the corresponding normal tissues, and it shows better tumor-association than other cancer-associated molecules, making it a more suitable target for developing specific cancer therapies. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:SAM pointed domain-containing Ets transcription factor
HPRD
Source:NCBIAccessed: 11 August, 2015

Ontology:

What does this gene/protein do?
Show (12)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 11 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Estrogen Receptors
  • Chromosome 6
  • MCF-7 Cells
  • Promoter Regions
  • Cell Proliferation
  • Proto-Oncogene Proteins c-ets
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • Signal Transduction
  • Androgen Receptors
  • Xenograft Models
  • Tumor Markers
  • beta Catenin
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Goblet Cells
  • Uteroglobin
  • RTPCR
  • Prostate Cancer
  • Adenocarcinoma
  • Colonic Neoplasms
  • Transfection
  • Prostate-Specific Antigen
  • Transcriptional Activation
  • Transcription
  • Breast Cancer
  • Colorectal Cancer
  • Apoptosis
  • Down-Regulation
  • Neoplasm Invasiveness
  • Urokinase-Type Plasminogen Activator
  • Neoplasm Metastasis
  • Cell Movement
  • Cancer RNA
  • Epithelial Cells
  • Tumor Suppressor Proteins
  • VEGFA
  • Lung Cancer
  • Prostate
  • Breast
  • Transcription Factors
Tag cloud generated 11 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SPDEF (cancer-related)

Naderi A
Coagulation factor VII is regulated by androgen receptor in breast cancer.
Exp Cell Res. 2015; 331(1):239-50 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Androgen receptor (AR) is widely expressed in breast cancer; however, there is limited information on the key molecular functions and gene targets of AR in this disease. In this study, gene expression data from a cohort of 52 breast cancer cell lines was analyzed to identify a network of AR co-expressed genes. A total of 300 genes, which were significantly enriched for cell cycle and metabolic functions, showed absolute correlation coefficients (|CC|) of more than 0.5 with AR expression across the dataset. In this network, a subset of 35 "AR-signature" genes were highly co-expressed with AR (|CC|>0.6) that included transcriptional regulators PATZ1, NFATC4, and SPDEF. Furthermore, gene encoding coagulation factor VII (F7) demonstrated the closest expression pattern with AR (CC=0.716) in the dataset and factor VII protein expression was significantly associated to that of AR in a cohort of 209 breast tumors. Moreover, functional studies demonstrated that AR activation results in the induction of factor VII expression at both transcript and protein levels and AR directly binds to a proximal region of F7 promoter in breast cancer cells. Importantly, AR activation in breast cancer cells induced endogenous factor VII activity to convert factor X to Xa in conjunction with tissue factor. In summary, F7 is a novel AR target gene and AR activation regulates the ectopic expression and activity of factor VII in breast cancer cells. These findings have functional implications in the pathobiology of thromboembolic events and regulation of factor VII/tissue factor signaling in breast cancer.

Scheiber MN, Watson PM, Rumboldt T, et al.
FLI1 expression is correlated with breast cancer cellular growth, migration, and invasion and altered gene expression.
Neoplasia. 2014; 16(10):801-13 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
ETS factors have been shown to be dysregulated in breast cancer. ETS factors control the expression of genes involved in many biological processes, such as cellular proliferation, differentiation, and apoptosis. FLI1 is an ETS protein aberrantly expressed in retrovirus-induced hematological tumors, but limited attention has been directed towards elucidating the role of FLI1 in epithelial-derived cancers. Using data mining, we show that loss of FLI1 expression is associated with shorter survival and more aggressive phenotypes of breast cancer. Gain and loss of function cellular studies indicate the inhibitory effect of FLI1 expression on cellular growth, migration, and invasion. Using Fli1 mutant mice and both a transgenic murine breast cancer model and an orthotopic injection of syngeneic tumor cells indicates that reduced Fli1 contributes to accelerated tumor growth. Global expression analysis and RNA-Seq data from an invasive human breast cancer cell line with over expression of either FLI1 and another ETS gene, PDEF, shows changes in several cellular pathways associated with cancer, such as the cytokine-cytokine receptor interaction and PI3K-Akt signaling pathways. This study demonstrates a novel role for FLI1 in epithelial cells. In addition, these results reveal that FLI1 down-regulation in breast cancer may promote tumor progression.

Cheng XH, Black M, Ustiyan V, et al.
SPDEF inhibits prostate carcinogenesis by disrupting a positive feedback loop in regulation of the Foxm1 oncogene.
PLoS Genet. 2014; 10(9):e1004656 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
SAM-pointed domain-containing ETS transcription factor (SPDEF) is expressed in normal prostate epithelium. While its expression changes during prostate carcinogenesis (PCa), the role of SPDEF in prostate cancer remains controversial due to the lack of genetic mouse models. In present study, we generated transgenic mice with the loss- or gain-of-function of SPDEF in prostate epithelium to demonstrate that SPDEF functions as tumor suppressor in prostate cancer. Loss of SPDEF increased cancer progression and tumor cell proliferation, whereas over-expression of SPDEF in prostate epithelium inhibited carcinogenesis and reduced tumor cell proliferation in vivo and in vitro. Transgenic over-expression of SPDEF inhibited mRNA and protein levels of Foxm1, a transcription factor critical for tumor cell proliferation, and reduced expression of Foxm1 target genes, including Cdc25b, Cyclin B1, Cyclin A2, Plk-1, AuroraB, CKS1 and Topo2alpha. Deletion of SPDEF in transgenic mice and cultures prostate tumor cells increased expression of Foxm1 and its target genes. Furthermore, an inverse correlation between SPDEF and Foxm1 levels was found in human prostate cancers. The two-gene signature of low SPDEF and high FoxM1 predicted poor survival in prostate cancer patients. Mechanistically, SPDEF bound to, and inhibited transcriptional activity of Foxm1 promoter by interfering with the ability of Foxm1 to activate its own promoter through auto-regulatory site located in the -745/-660 bp Foxm1 promoter region. Re-expression of Foxm1 restored cellular proliferation in the SPDEF-positive cancer cells and rescued progression of SPDEF-positive tumors in mouse prostates. Altogether, SPDEF inhibits prostate carcinogenesis by preventing Foxm1-regulated proliferation of prostate tumor cells. The present study identified novel crosstalk between SPDEF tumor suppressor and Foxm1 oncogene and demonstrated that this crosstalk is required for tumor cell proliferation during progression of prostate cancer in vivo.

Lo Sasso G, Ryu D, Mouchiroud L, et al.
Loss of Sirt1 function improves intestinal anti-bacterial defense and protects from colitis-induced colorectal cancer.
PLoS One. 2014; 9(7):e102495 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Dysfunction of Paneth and goblet cells in the intestine contributes to inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). Here, we report a role for the NAD+-dependent histone deacetylase SIRT1 in the control of anti-bacterial defense. Mice with an intestinal specific Sirt1 deficiency (Sirt1int-/-) have more Paneth and goblet cells with a consequent rearrangement of the gut microbiota. From a mechanistic point of view, the effects on mouse intestinal cell maturation are mediated by SIRT1-dependent changes in the acetylation status of SPDEF, a master regulator of Paneth and goblet cells. Our results suggest that targeting SIRT1 may be of interest in the management of IBD and CAC.

Correa RG, Krajewska M, Ware CF, et al.
The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling.
Oncotarget. 2014; 5(6):1666-82 [PubMed] Related Publications
Prostate cancer (PCa) is among the leading causes of cancer-related death in men. Androgen receptor (AR) signaling plays a seminal role in prostate development and homeostasis, and dysregulation of this pathway is intimately linked to prostate cancer pathogenesis and progression. Here, we identify the cytosolic NLR-related protein NWD1 as a novel modulator of AR signaling. We determined that expression of NWD1 becomes elevated during prostate cancer progression, based on analysis of primary tumor specimens. Experiments with cultured cells showed that NWD1 expression is up-regulated by the sex-determining region Y (SRY) family proteins. Gene silencing procedures, in conjunction with transcriptional profiling, showed that NWD1 is required for expression of PDEF (prostate-derived Ets factor), which is known to bind and co-regulate AR. Of note, NWD1 modulates AR protein levels. Depleting NWD1 in PCa cell lines reduces AR levels and suppresses activity of androgen-driven reporter genes. NWD1 knockdown potently suppressed growth of androgen-dependent LNCaP prostate cancer cells, thus showing its functional importance in an AR-dependent tumor cell model. Proteomic analysis suggested that NWD1 associates with various molecular chaperones commonly related to AR complexes. Altogether, these data suggest a role for tumor-associated over-expression of NWD1 in dysregulation of AR signaling in PCa.

He W, Zhang MG, Wang XJ, et al.
KAT5 and KAT6B are in positive regulation on cell proliferation of prostate cancer through PI3K-AKT signaling.
Int J Clin Exp Pathol. 2013; 6(12):2864-71 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Histone modifications play important roles in the tumorigenesis and progression of prostate cancer (PCa) and genes involved in histone modifications are seemed as ideal targets for treatment of PCa patients. However, clinical trials have shown that those existing drugs exert the minimal antitumor activity and excess adverse effects on PCa patients. Therefore, it is of great interest to figure out novel specific biomarkers to guide the development of new drugs. In present study, an RNAi screening with 44 genes involved in histone modifications was applied to a PCa cell line, Du145. The results showed that nine genes were in positive regulation of Du145 cell growth. Then four selected genes (KAT2B, KAT5, KAT6B and HDAC1) were found to exert this effect by a gene-specific manner when silenced. And then KAT5 or KAT6B silenced cells were subjected to DNA microarray analysis. The common differentially expressed genes were analyzed by Ingenuity Pathway Analysis (IPA) and found that PDEF signaling, EIF2 signaling and PI3K signaling was suppressed following by KAT5 or KAT6B silencing. Subsequent immunoblotting assay showed that AKT signaling was inhibited, which suggested that KAT5 or KAT6B regulates cancer cell growth through PI3K-AKT signaling. Together with our published data [31] that AURKA inhibitoin increased drug sensitivity of DU145, our work demonstrated the underlying mechanism that how the acetylation enzyme regulates cancer cells survial and might provide potential therapeutic targets for prostate cancer patients in future epigenetic drug development.

Fletcher MN, Castro MA, Wang X, et al.
Master regulators of FGFR2 signalling and breast cancer risk.
Nat Commun. 2013; 4:2464 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The fibroblast growth factor receptor 2 (FGFR2) locus has been consistently identified as a breast cancer risk locus in independent genome-wide association studies. However, the molecular mechanisms underlying FGFR2-mediated risk are still unknown. Using model systems we show that FGFR2-regulated genes are preferentially linked to breast cancer risk loci in expression quantitative trait loci analysis, supporting the concept that risk genes cluster in pathways. Using a network derived from 2,000 transcriptional profiles we identify SPDEF, ERα, FOXA1, GATA3 and PTTG1 as master regulators of fibroblast growth factor receptor 2 signalling, and show that ERα occupancy responds to fibroblast growth factor receptor 2 signalling. Our results indicate that ERα, FOXA1 and GATA3 contribute to the regulation of breast cancer susceptibility genes, which is consistent with the effects of anti-oestrogen treatment in breast cancer prevention, and suggest that fibroblast growth factor receptor 2 signalling has an important role in mediating breast cancer risk.

Sabherwal Y, Mahajan N, Zhang M
Epigenetic modifications of prostate-derived Ets transcription factor in breast cancer cells.
Oncol Rep. 2013; 30(4):1985-8 [PubMed] Related Publications
The importance of epigenetic alterations such as DNA methylation, histone modification and nucleosome remodeling in breast cancer is well established. Epigenetic alterations are reversible, and much research has been focused on understanding these alterations with the aim of developing effective therapies. Prostate-derived Ets factor (PDEF) is a member of the Ets family of transcription factors and has long been under investigation for its key role in tumor development and progression. To date, no studies have been conducted to elucidate the epigenetic modifications of PDEF in cancer progression. Using breast and prostate cancer cells, we investigated the effect of the methylation inhibitor 5' azacytidine (AZA) on the expression of PDEF in these cells. The inhibition of methylation observed was specific to breast cancer cells as experiments with prostate cells did not exhibit any significant change. Notably, the expression of p21, a cyclin-dependent kinase (CDK) inhibitor 1 and also a target gene of PDEF, was found to be positively correlated with PDEF expression following 5'AZA treatment. Inhibition of methylation led to a decrease in the proliferation rate of MDA-MB-468 cells as revealed by MTT proliferation assay. Other epigenetic alterations such as histone modifications were not observed in these breast cancer cells following treatment with specific HDAC inhibitors. Our data suggest the possibility of epigenetic modification of PDEF due to DNA methylation and involvement of the cell cycle inhibitor p21. Future studies on the epigenetic alterations of PDEF in correlation with p21 or other targets may facilitate the development of effective therapies for the treatment of breast cancer.

Buchwalter G, Hickey MM, Cromer A, et al.
PDEF promotes luminal differentiation and acts as a survival factor for ER-positive breast cancer cells.
Cancer Cell. 2013; 23(6):753-67 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Breast cancer is a heterogeneous disease and can be classified based on gene expression profiles that reflect distinct epithelial subtypes. We identify prostate-derived ETS factor (PDEF) as a mediator of mammary luminal epithelial lineage-specific gene expression and as a factor required for tumorigenesis in a subset of breast cancers. PDEF levels strongly correlate with estrogen receptor (ER)-positive luminal breast cancer, and PDEF transcription is inversely regulated by ER and GATA3. Furthermore, PDEF is essential for luminal breast cancer cell survival and is required in models of endocrine resistance. These results offer insights into the function of this ETS factor that are clinically relevant and may be of therapeutic value for patients with breast cancer treated with endocrine therapy.

Mukhopadhyay A, Khoury T, Stein L, et al.
Prostate derived Ets transcription factor and Carcinoembryonic antigen related cell adhesion molecule 6 constitute a highly active oncogenic axis in breast cancer.
Oncotarget. 2013; 4(4):610-21 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
We previously reported overexpression of Prostate derived Ets transcription factor (PDEF) in breast cancer and its role in breast cancer progression, supporting PDEF as an attractive target in this cancer. The goal of this research was to identify specific PDEF induced molecules that, like PDEF, show overexpression in breast tumors and a role in breast tumor progression. PDEF expression was down regulated by shRNA in MCF-7 human breast tumor cell line, and probes from PDEF down-regulated and control MCF-7 cells were used to screen the HG-U133A human gene chips. These analyses identified 1318 genes that were induced two-fold or higher by PDEF in MCF-7 cells. Further analysis of three of these genes, namely CEACAM6, S100A7 and B7-H4, in relation to PDEF in primary breast tumors showed that in 82% of ER+, 67% of Her2 overexpressing and 24% of triple-negative breast tumors both PDEF and CEACAM6 expression was elevated 10-fold or higher in comparison to normal breast tissue. Overall, 72% (94 of 131) of the primary breast tumors showed 10-fold or higher expression of both PDEF and CEACAM6. In contrast, S100A7 and B7-H4 failed to show concordant elevated expression with PDEF in primary tumors. To determine the significance of elevated PDEF and CEACAM6 expression to tumor phenotype, their expression was down regulated by specific siRNAs in human breast tumor cell lines. This resulted in the loss of viability of tumor cells in vitro, supporting an oncogenic role for both PDEF and CEACAM6 in breast cancer. Together, these findings show that PDEF-CEACAM6 is a highly active oncogenic axis in breast cancer and suggest that targeting of these molecules should provide novel treatments for most breast cancer patients.

Pal M, Koul S, Koul HK
The transcription factor sterile alpha motif (SAM) pointed domain-containing ETS transcription factor (SPDEF) is required for E-cadherin expression in prostate cancer cells.
J Biol Chem. 2013; 288(17):12222-31 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Loss of E-cadherin is one of the key steps in tumor progression. Our previous studies demonstrate that SAM pointed domain-containing ETS transcription factor (SPDEF) inhibited prostate cancer metastasis in vitro and in vivo. In the present study, we evaluated the relationship between SPDEF and E-cadherin expression in an effort to better understand the mechanism of action of SPDEF in prostate tumor cell invasion and metastasis. The results presented here demonstrate a direct correlation between expression of E-cadherin and SPDEF in prostate cancer cells. Additional data demonstrate that modulation of E-cadherin and SPDEF had similar effects on cell migration/invasion. In addition, siRNA-mediated knockdown of E-cadherin was sufficient to block the effects of SPDEF on cell migration and invasion. We also show that stable forced expression of SPDEF results in increased expression of E-cadherin, whereas down-regulation of SPDEF decreased E-cadherin expression. In addition, we demonstrate that SPDEF expression is not regulated by E-cadherin. Moreover, our chromatin immunoprecipitation and luciferase reporter assay revealed that SPDEF occupies E-cadherin promoter site and acts as a direct transcriptional inducer of E-cadherin in prostate cancer cells. Taken together, to the best of our knowledge, these studies are the first demonstrating requirement of SPDEF for expression of E-cadherin, an essential epithelial cell junction protein. Given that loss of E-cadherin is a central tenant in tumor metastasis, the results of our studies, by providing a new mechanism for regulation of E-cadherin expression, could have far reaching impact.

Noah TK, Lo YH, Price A, et al.
SPDEF functions as a colorectal tumor suppressor by inhibiting β-catenin activity.
Gastroenterology. 2013; 144(5):1012-1023.e6 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND & AIMS: Expression of the SAM pointed domain containing ETS transcription factor (SPDEF or prostate-derived ETS factor) is regulated by Atoh1 and is required for the differentiation of goblet and Paneth cells. SPDEF has been reported to suppress the development of breast, prostate, and colon tumors. We analyzed levels of SPDEF in colorectal tumor samples from patients and its tumor-suppressive functions in mouse models of colorectal cancer (CRC).
METHODS: We analyzed levels of SPDEF messenger RNA and protein in more than 500 human CRC samples and more than 80 nontumor controls. Spdef(-/-)and wild-type mice (controls) were either bred with Apc(Min/+) mice, or given azoxymethane (AOM) and dextran sodium sulfate (DSS), or 1,2-dimethylhydrazine and DSS, to induce colorectal tumors. Expression of Spdef also was induced transiently by administration of tetracycline to Spdef(dox-intestine) mice with established tumors, induced by the combination of AOM and DSS or by breeding with Apc(Min/+) mice. Colon tissues were collected and analyzed for tumor number, size, grade, and for cell proliferation and apoptosis. We also analyzed the effects of SPDEF expression in HCT116 and SW480 human CRC cells.
RESULTS: In colorectal tumors from patients, loss of SPDEF was observed in approximately 85% of tumors and correlated with progression from normal tissue, to adenoma, to adenocarcinoma. Spdef(-/-); Apc(Min/+) mice developed approximately 3-fold more colon tumors than Spdef(+/+); Apc(Min/+) mice. Likewise, Spdef(-/-) mice developed approximately 3-fold more colon tumors than Spdef(+/+) mice after administration of AOM and DSS. After administration of 1,2-dimethylhydrazine and DSS, invasive carcinomas were observed exclusively in Spdef(-/-) mice. Conversely, expression of SPDEF was sufficient to promote cell-cycle exit in cells of established adenomas from Spdef(dox-intestine); Apc(Min/+) mice and in Spdef(dox-intestine) mice after administration of AOM + DSS. SPDEF inhibited the expression of β-catenin-target genes in mouse colon tumors, and interacted with β-catenin to block its transcriptional activity in CRC cell lines, resulting in lower levels of cyclin D1 and c-MYC.
CONCLUSIONS: SPDEF is a colon tumor suppressor and a candidate therapeutic target for colon adenomas and adenocarcinoma.

Stavnes HT, Nymoen DA, Langerød A, et al.
AZGP1 and SPDEF mRNA expression differentiates breast carcinoma from ovarian serous carcinoma.
Virchows Arch. 2013; 462(2):163-73 [PubMed] Related Publications
The ANPEP, AZGP1, and SPDEF genes were previously found to be overexpressed in breast compared to ovarian carcinoma effusions. The present study validated this finding in a larger cohort consisting of both primary and metastatic tumors. ANPEP, AZGP1, and SPDEF mRNA expression was investigated in 83 breast carcinomas (57 primary carcinomas and 26 effusions) and 40 ovarian carcinomas (20 primary carcinomas and 20 effusions) using qPCR. ANPEP protein expression was immunohistochemically analyzed in 53 breast carcinoma effusions and patient-matched primary carcinomas (n = 25) and lymph node metastases (n = 16). mRNA and protein levels were studied for association with tumor type and anatomic site, and for clinical role in breast carcinoma. AZGP1 and SPDEF mRNA was overexpressed in breast compared to ovarian carcinoma (both p < 0.001). AZGP1 mRNA was overexpressed in primary breast carcinoma compared to effusions (p < 0.001), with opposite findings for ANPEP (p = 0.044). AZGP1 mRNA expression correlated with positive ER status (p = 0.032) and grade 1 histology (p = 0.011), whereas SPDEF mRNA levels were associated with positive ER (p = 0.002) and PR (p = 0.013) status and tamoxifen treatment (p = 0.004). ANPEP protein expression was higher in breast carcinoma effusions compared to primary tumors and lymph node metastases (both p = 0.001). ANPEP, AZGP1, and SPDEF levels were unrelated to disease-free or overall survival. This is the first study documenting ANPEP, AZGP1, and SPDEF expression in breast carcinoma effusions. AZGP1 and SPDEF may be novel molecular markers for the differentiation of breast from ovarian carcinoma. ANPEP may be involved in breast carcinoma progression in view of its overexpression in effusions compared to solid specimens.

Maeda Y, Tsuchiya T, Hao H, et al.
Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung.
J Clin Invest. 2012; 122(12):4388-400 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Mucinous adenocarcinoma of the lung is a subtype of highly invasive pulmonary tumors and is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1). Here, we show that haploinsufficiency of Nkx2-1 in combination with oncogenic Kras(G12D), but not with oncogenic EGFR(L858R), caused pulmonary tumors in transgenic mice that were phenotypically similar to human mucinous adenocarcinomas. Gene expression patterns distinguished tumor goblet (mucous) cells from nontumorigenic airway and intestinal goblet cells. Expression of NKX2-1 inhibited urethane and oncogenic Kras(G12D)-induced tumorigenesis in vivo. Haploinsufficiency of Nkx2-1 enhanced Kras(G12D)-mediated tumor progression, but reduced EGFR(L858R)-mediated progression. Genome-wide analysis of gene expression demonstrated that a set of genes induced in mucinous tumors was shared with genes induced in a nontumorigenic chronic lung disease, while a distinct subset of genes was specific to mucinous tumors. ChIP with massively parallel DNA sequencing identified a direct association of NKX2-1 with the genes induced in mucinous tumors. NKX2-1 associated with the AP-1 binding element as well as the canonical NKX2-1 binding element. NKX2-1 inhibited both AP-1 activity and tumor colony formation in vitro. These data demonstrate that NKX2-1 functions in a context-dependent manner in lung tumorigenesis and inhibits Kras(G12D)-driven mucinous pulmonary adenocarcinoma.

Steffan JJ, Koul S, Meacham RB, Koul HK
The transcription factor SPDEF suppresses prostate tumor metastasis.
J Biol Chem. 2012; 287(35):29968-78 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Emerging evidence suggests that the SAM pointed domain containing ETS transcription factor (SPDEF) plays a significant role in tumorigenesis in prostate, breast, colon, and ovarian cancer. However, there are no in vivo studies with respect to the role of SPDEF in tumor metastasis. The present study examined the effects of SPDEF on tumor cell metastasis using prostate tumor cells as a model. Utilizing two experimental metastasis models, we demonstrate that SPDEF inhibits cell migration and invasion in vitro and acts a tumor metastasis suppressor in vivo. Using stable expression of SPDEF in PC3-Luc cells and shRNA-mediated knockdown of SPDEF in LNCaP-Luc cells, we demonstrate for the first time that SPDEF diminished the ability of disseminated tumors cells to survive at secondary sites and establish micrometastases. These effects on tumor metastasis were not a result of the effect of SPDEF on cell growth as SPDEF expression had no effect on cell growth in vitro or subcutaneous tumor xenograft-growth in vivo. Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. Further analysis indicated that forced MMP9 or MMP13 expression rescued the invasive phenotype in SPDEF expressing PC3 cells in vitro, suggesting that the effects of SPDEF on tumor invasion are mediated, in part, through the suppression of MMP9 and MMP13 expression. These results demonstrate for the first time, in any system, that SPDEF functions as a tumor metastasis suppressor in vivo.

Sabherwal Y, Mahajan N, Helseth DL, et al.
PDEF downregulates stathmin expression in prostate cancer.
Int J Oncol. 2012; 40(6):1889-99 [PubMed] Related Publications
The Ets proteins are a family of transcription factors characterized by an evolutionarily conserved DNA binding domain that controls key cellular processes. Prostate-derived Ets transcription factor (PDEF), a member of the Ets family, is reported to be present in tissues with high epithelial content, notably breast and prostate. However, the role of PDEF in cancer development is not fully understood. To gain insight into the molecular mechanisms associated with prostate cancer progression, we employed iTRAQ labeling followed by mass spectrometric (MS) analysis to identify candidate proteins that are differentially expressed in prostate cancer cells with or without PDEF. To this end, we overexpressed PDEF in PC3 human prostate cells using a tetracycline inducible system (Tet-On). Many differentially expressed proteins which play important roles in various cellular and biological processes were identified. Among them, stathmin (STMN), which is a microtubule (MT)-destabilizing protein, was found to be downregulated in multiple analyses. We demonstrated that re-expression of STMN reversed the antitumor properties of PDEF in PDEF-overexpressing PC3 cells. Using in vitro functional assays, we showed that STMN overexpression counteracted PDEF's effects against cell proliferation, colony formation and tumor migration. Similar results were further confirmed with the prostate cancer cell line CWR22rv1. In conclusion, many differentially expressed proteins were identified and STMN was found to be downregulated by PDEF. These results suggest that PDEF may inhibit prostate cancer progression by transcriptional downregulation of oncogenic STMN expression. Analyzing the association among differentially expressed proteins may provide a basis to better understand the molecular mechanisms underlying the process of cancer progression and development and further aid in designing therapeutics in the future.

Davidson B, Stavnes HT, Risberg B, et al.
Gene expression signatures differentiate adenocarcinoma of lung and breast origin in effusions.
Hum Pathol. 2012; 43(5):684-94 [PubMed] Related Publications
Lung and breast adenocarcinoma at advanced stages commonly involve the serosal cavities, giving rise to malignant effusions. The aim of the present study was to compare the global gene expression patterns of metastases from these 2 malignancies, to expand and improve the diagnostic panel of biomarkers currently available for their differential diagnosis, as well as to define type-specific biological targets. Gene expression profiles of 7 breast and 4 lung adenocarcinoma effusions were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time polymerase chain reaction and immunohistochemistry. Unsupervised hierarchical clustering using all 54,675 genes in the array separated lung from breast adenocarcinoma samples. We identified 289 unique probes that were significantly differentially expressed in the 2 cancers by greater than 2-fold using moderated t statistics, of which 65 and 224 were overexpressed in breast and lung adenocarcinoma, respectively. Genes overexpressed in breast adenocarcinoma included TFF1, TFF3, FOXA1, CA12, PITX1, RARRES1, CITED4, MYC, TFAP2A, EFHD1, TOB1, SPDEF, FASN, and TH. Genes overexpressed in lung adenocarcinoma included TITF1, SFTPG, MMP7, EVA1, GPR116, HOP, SCGB3A2, and MET. The differential expression of 15 genes was validated by quantitative real-time PCR, and differences in 8 gene products were confirmed by immunohistochemistry. Expression profiling distinguishes breast adenocarcinoma from lung adenocarcinoma and identifies genes that are differentially expressed in these 2 tumor types. The molecular signatures unique to these cancers may facilitate their differential diagnosis and may provide a molecular basis for therapeutic target discovery.

Tsui KH, Chung LC, Feng TH, et al.
Upregulation of prostate-derived Ets factor by luteolin causes inhibition of cell proliferation and cell invasion in prostate carcinoma cells.
Int J Cancer. 2012; 130(12):2812-23 [PubMed] Related Publications
Luteolin is a polyphenolic flavone and has antitumor activity for many cancers. The prostate-derived Ets factor (PDEF), a novel epithelium-specific Ets transcription factor, acts as an androgen-independent transcriptional activator of the prostate-specific antigen (PSA) promoter. We determined the antitumor function of luteolin via upregulation of PDEF gene expression in human prostate carcinoma LNCaP cells. Results from flow cytometry and (3) H-thymidine incorporation assays revealed that luteolin treatments attenuated cell proliferation and arrested the cell cycle at the G1/S phase. High concentration of luteolin (30 μM) induced cell apoptosis. Immunoblot assays and enzyme linked immunosorbent assay revealed that luteolin treatment upregulated PDEF but downregulated androgen receptor (AR) gene expression, which decreased PSA gene expression in LNCaP cells. Results of immunoblot and transient gene expression assays revealed that luteolin treatments at proapoptosis dosage, enhanced gene expression of PDEF, B-cell translocation gene 2 (BTG2), N-myc downstream regulated gene 1 (NDRG1) and Maspin. Transient gene expression assays indicated that cotransfection of the PDEF expression vector enhanced the promoter activities of the BTG2, NDRG1 and Maspin genes. Stable overexpression of PDEF significantly induced BTG2, NDRG1 and Maspin gene expression, which markedly attenuated in vitro cell proliferation and invasion of LNCaP cells. The modulatory effect of luteolin on BTG2, NDRG1 and Maspin gene expression were attenuated when PDEF was knocked-down. These results suggest that luteolin blocks PSA gene expression by downregulation of AR expression. The enhancement of PDEF expression, which induced BTG2, NDRG1 and Maspin gene expression, could account for the function of luteolin for antiproliferation and anti-invasion in LNCaP cells.

Steffan JJ, Koul HK
Prostate derived ETS factor (PDEF): a putative tumor metastasis suppressor.
Cancer Lett. 2011; 310(1):109-17 [PubMed] Related Publications
The prostate-derived ETS factor (PDEF) is the latest family member of the ETS transcription factor family, although it is unique in many aspects. PDEF was first described as an mRNA transcript highly expressed in prostate tumor cells where it regulates prostate-specific antigen gene expression and is an androgen receptor co-regulator. PDEF expression is highly restricted to epithelial cells and has only been found in prostate, breast, colon, ovary, gastric, and airway epithelium. Strong preclinical evidence is emerging that PDEF is a negative regulator of tumor progression and metastasis. PDEF expression is often lost in late-stage, advanced tumors. The induction of tumor aggressiveness in response to the loss of PDEF is thought to be due to the plethora of PDEF-regulated gene targets, many of which are known players in tumor progression including tumor cell invasion and metastasis. These data have lead to the hypothesis that PDEF may function as a tumor metastasis suppressor. In this review, we summarize what is known about PDEF since its discovery over a decade ago and give a detailed overview of PDEF-regulated gene products and the expression profiles of PDEF in clinical tumor samples.

Turner DP, Findlay VJ, Moussa O, et al.
Mechanisms and functional consequences of PDEF protein expression loss during prostate cancer progression.
Prostate. 2011; 71(16):1723-35 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Ets is a large family of transcriptional regulators with functions in most biological processes. While the Ets family gene, prostate-derived epithelial factor (PDEF), is expressed in epithelial tissues, PDEF protein expression has been found to be reduced or lost during cancer progression. The goal of this study was to examine the mechanism for and biologic impact of altered PDEF expression in prostate cancer.
METHODS: PDEF protein expression of prostate specimens was examined by immunohistochemistry. RNA and protein expression in cell lines were measured by q-PCR and Western blot, respectively. Cellular growth was determined by quantifying viable and apoptotic cells over time. Cell cycle was measured by flow cytometry. Migration and invasion were determined by transwell assays. PDEF promoter occupancy was determined by chromatin immunoprecipitation (ChIP).
RESULTS: While normal prostate epithelium expresses PDEF mRNA and protein, tumors show no or decreased PDEF protein expression. Re-expression of PDEF in prostate cancer cells inhibits cell growth. PDEF expression is inversely correlated with survivin, urokinase plasminogen activator (uPA) and slug expression and ChIP studies identify survivin and uPA as direct transcriptional targets of PDEF. This study also shows that PDEF expression is regulated via a functional microRNA-204 (miR-204) binding site within the 3'UTR. Furthermore, we demonstrate the biologic significance of miR-204 expression and that miR-204 is over-expressed in human prostate cancer specimens.
CONCLUSIONS: Collectively, the reported studies demonstrate that PDEF is a negative regulator of tumor progression and that the miR-204-PDEF regulatory axis contributes to PDEF protein loss and resultant cancer progression.

Deves C, Renck D, Garicochea B, et al.
Analysis of select members of the E26 (ETS) transcription factors family in colorectal cancer.
Virchows Arch. 2011; 458(4):421-30 [PubMed] Related Publications
The E-twenty-six (ETS) family of transcription factors is known to act as positive or negative regulators of the expression of genes that are involved in diverse biological processes, including those that control cellular proliferation, differentiation, hematopoiesis, apoptosis, metastasis, tissue remodeling, and angiogenesis. Identification of target gene promoters of normal and oncogenic transcription factors provides new insights into the regulation of genes that are involved in the control of normal cell growth and differentiation. The aim of the present investigation was to analyze the differential expression of 11 ETS (ELF-3, ESE3, ETS1, ETV3, ETV4, ETV6, NERF, PDEF, PU1, Spi-B, and Spi-C) as potential markers for prognostic of colorectal cancer. A series of paired tissue biopsies consisting of a tumor and a non-affected control sample were harvested from 28 individuals suffering from diagnosed colorectal lesions. Total RNA was isolated from the samples, and after reverse transcription, differential expression of the select ETS was carried out through real-time polymerase chain reaction. Tumor staging as determined by histopathology was carried out to correlate the degree of tumor invasiveness with the expression of the ETS genes. The results demonstrated a different quantitative profile of expression in tumors and normal tissues. ETV4 was significantly upregulated with further increase in the event of lymph node involvement. PDEF and Spi-B presented downregulation, which was more significant when lymph node involvement was present. These findings were supported by immunohistochemistry of tumoral tissues. The results suggest that select ETS may serve as potential markers of colorectal cancer invasiveness and metastasis.

Juang HH, Lin YF, Chang PL, Tsui KH
Cardiac glycosides decrease prostate specific antigen expression by down-regulation of prostate derived Ets factor.
J Urol. 2010; 184(5):2158-64 [PubMed] Related Publications
PURPOSE: While cardiac glycosides are the mainstay of congestive heart failure treatment, early studies showed that pharmacological doses of cardiac glycosides inhibited prostate cancer cell line proliferation. We evaluated the mechanisms of cardiac glycosides, including digoxin, digitoxin and ouabain (Sigma®), on prostate specific antigen gene expression in vitro.
MATERIALS AND METHODS: We cultured LNCaP cells (ATCC®) and used them to determine the effect of cardiac glycosides on prostate derived Ets factor and prostate specific antigen expression. We determined prostate derived Ets factor and prostate specific antigen expression by reverse transcription-polymerase chain reaction, immunoblot, transient gene expression assay or enzyme-linked immunosorbent assay.
RESULTS: Noncytotoxic doses (100 nM) of cardiac glycosides for 24 hours inhibited prostate specific antigen secretion by LNCaP cells. Reverse transcriptase-polymerase chain reaction and immunoblot revealed that cardiac glycosides significantly down-regulated prostate specific antigen and prostate derived Ets factor expression. Transient gene expression assays showed that prostate derived Ets factor over expression enhanced prostate specific antigen promoter activity. However, prostate specific antigen and prostate derived Ets factor gene promoter activity was attenuated when LNCaP cells were treated with 100 nM cardiac glycosides. When LNCaP cells were treated with 25 nM digitoxin or digoxin for 60 hours, prostate specific antigen secretion decreased by 30%.
CONCLUSIONS: Results suggest that cardiac glycoside inhibition of prostate specific antigen gene expression may be caused by the down-regulation of prostate derived Ets factor gene expression. When cells were chronically treated with digoxin or digitoxin at concentrations close to or at therapeutic plasma levels, prostate specific antigen secretion decreased. This phenomenon merits further study to determine whether it occurs in men on cardiac glycoside therapy.

Matuschek C, Bölke E, Lammering G, et al.
Methylated APC and GSTP1 genes in serum DNA correlate with the presence of circulating blood tumor cells and are associated with a more aggressive and advanced breast cancer disease.
Eur J Med Res. 2010; 15:277-86 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Tumor-related methylated DNA and circulating tumor cells (CTC) in the peripheral blood might be of prognostic importance in breast cancer. Thus, the aim of our study was to examine free methylated DNA and CTC in the blood from breast cancer patients and to correlate it with clinicopathological features known to influence prognosis.
MATERIALS AND METHODS: We prospectively obtained serum samples from 85 patients with breast cancer and 22 healthy volunteers. Sera were analysed by methylation specific PCR (MethyLight PCR) for five genes: adenomatous polyposis coli (APC), ras association domain family protein 1A (RASSF1A), estrogen receptor 1 (ESR1), CDKN2A (p16) and glutathione s-transferase pi 1 (GSTP1). Beta actin (ACTB) served as control. In parallel matched peripheral blood of 63 patients was used to assay for circulating tumor cells in the peripheral blood by a modified immunomagnetic AdnaTest BreastCancerSelect with PCR detection for EPCAM, MUC1, MGB1 and SPDEF.
RESULTS: A hypermethylation in the APC gene in 29% (25/85), in RASSF1A in 26% (22/85), in GSTP1 in 18% (14/76) and in ESR1 in 38% (32/85) of all breast cancer patients was detected. No hypermethylation of CDKN2A was found (0/25). Blood samples of patients were defined CTC positive by detecting the EPCAM 13% (8/63), MUC1 16% (10/63), MGB 9% (5/55), SPDEF 12% (7/58) and in 27% detecting one or more genes (15/55). A significant difference was seen in methylated APC DNA between cancer patients and healthy volunteers. Moreover, methylated APC, RASSF1 and CTC were significantly different in metastatic versus non-metastatic disease. In addition, the presence of methylated APC, RASSF1A and CTC correlated significantly with AJCC-staging (p = 0.001, p = 0.031 and 0.002, respectively). High incidences of methylations were found for the genes RASSF1 and ESR1 in healthy individuals (both 23% 5/22). Methylated GSTP1 was predominantly found in the serum of patients with large primaries (p = 0.023) and was highly significantly correlated with positive Her2/neu status (p = 0.003). Elevated serum CA15.3 was strongly correlated with methylated APC and CTC detection (both p = 0.000). Methylated ESR1 failed to exhibit significant correlations with any of the above mentioned parameters. The presence of CTC in peripheral blood was significantly associated with methylated APC (p = 0.012) and methylated GSTP1 (p = 0.001).
CONCLUSION: The detection of methylated APC and GSTP1 DNA in serum correlated with the presence of CTC in the blood of breast cancer patients. Both methylated DNA and CTC correlated with a more aggressive tumor biology and advanced disease.

Frietsch JJ, Grunewald TG, Jasper S, et al.
Nuclear localisation of LASP-1 correlates with poor long-term survival in female breast cancer.
Br J Cancer. 2010; 102(11):1645-53 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: LIM and SH3 protein 1 (LASP-1) is a nucleo-cytoplasmatic signalling protein involved in cell proliferation and migration and is upregulated in breast cancer in vitro studies have shown that LASP-1 might be regulated by prostate-derived ETS factor (PDEF), p53 and/or LASP1 gene amplification. This current study analysed the prognostic significance of LASP-1 on overall survival (OS) in 177 breast cancer patients and addressed the suggested mechanisms of LASP-1-regulation.
METHODS: Nucleo-cytoplasmatic LASP-1-positivity of breast carcinoma samples was correlated with long-term survival, clinicopathological parameters, Ki67-positivity and PDEF expression. Rate of LASP1 amplification was determined in micro-dissected primary breast cancer cells using quantitative RT-PCR. Cell-phase dependency of nuclear LASP-1-localisation was studied in synchronised cells. In addition, LASP-1, PDEF and p53 expression was compared in cell lines of different tumour entities to define principles for LASP-1-regulation.
RESULTS: We showed that LASP-1 overexpression is not due to LASP1 gene amplification. Moreover, no correlation between p53-mutations or PDEF-expression and LASP-1-status was observed. However, nuclear LASP-1-localisation in breast carcinomas is increased during proliferation with peak in G2/M-phase and correlated significantly with Ki67-positivity and poor OS.
CONCLUSION: Our results provide evidence that nuclear LASP-1-positivity may serve as a negative prognostic indicator for long-term survival of breast cancer patients.

Schaefer JS, Sabherwal Y, Shi HY, et al.
Transcriptional regulation of p21/CIP1 cell cycle inhibitor by PDEF controls cell proliferation and mammary tumor progression.
J Biol Chem. 2010; 285(15):11258-69 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The Ets family of transcription factors control a myriad of cellular processes and contribute to the underlying genetic loss of cellular homeostasis resulting in cancer. PDEF (prostate-derived Ets factor) has been under investigation for its role in tumor development and progression. However, the role of PDEF in cancer development has been controversial. Some reports link PDEF to tumor promoter, and others show tumor-suppressing functions in various systems under different conditions. So far, there has been no conclusive evidence from in vivo experiments to prove the role of PDEF. We have used both in vitro and in vivo systems to provide a conclusive role of PDEF in the progression process. PDEF-expressing cells block the cell growth rate, and this retardation was reversible when PDEF expression was silenced with PDEF-specific small interfering RNA. When these PDEF-expressing cells were orthotopically implanted into the mouse mammary gland, tumor incidence and growth rate were significantly retarded. Cell cycle analysis revealed that PDEF expression partially blocked cell cycle progression at G(1)/S without an effect on apoptosis. PDEF overexpression resulted in an increase in p21/CIP1 at both the mRNA and protein levels, resulting in decreased Cdk2 activity. Promoter deletion analysis, electrophoresis mobility shift assays, and chromatin immunoprecipitation studies identified the functional Ets DNA binding site at -2118 bp of the p21/CIP1 gene promoter. This site is capable of binding and responding to PDEF. Furthermore, we silenced p21/CIP1 expression in PDEF-overexpressing cells by small interfering RNA. p21-silenced PDEF cells exhibited significantly increased cell growth in vitro and in vivo, demonstrating the p21 regulation by PDEF as a key player. These experiments identified PDEF as a new transcription factor that directly regulates p21/CIP1 expression under non-stressed conditions. This study conclusively proves that PDEF is a breast tumor suppressor for the first time using both in vitro and in vivo systems. PDEF can be further developed as a target for designing therapeutic intervention of breast cancer.

Sun Y, Wang L, Jiang M, et al.
Secreted phosphoprotein 1 upstream invasive network construction and analysis of lung adenocarcinoma compared with human normal adjacent tissues by integrative biocomputation.
Cell Biochem Biophys. 2010; 56(2-3):59-71 [PubMed] Related Publications
The aim of this study is to set up single molecular secreted phosphoprotein 1 (SPP1) upstream invasive network of lung adenocarcinoma. This paper proposed an integrated method based on linear programming and a decomposition procedure with integrated analysis of the significant function cluster using Kappa statistics and fuzzy heuristic clustering. Our study proved that only modules appearing in lung adenocarcinoma include cytokine module (CXCL13, GREM1_2 inhibition), cell adhesion module (COL11A1_2 activation; CDH3 inhibition), and receptor binding module (NMU activation; CXCL13, GREM1_2 inhibition), which increase the invasion of cancer cell. We compared skeletal development, signal, biological regulation, sequence variant modules between human normal adjacent tissues and lung adenocarcinoma. SPP1 skeletal development module appears in human normal adjacent tissues (COL11A1_1 activation; COL10A1 inhibition), whereas in lung adenocarcinoma (COL11A1_2, COL1A2 activation); signal module appears in human normal adjacent tissues (COL11A1_1, CXCL13, MMP11, SPINK1 activation; COL10A1, COL3A1 inhibition), whereas in lung adenocarcinoma (COL11A1_2, COL1A2, MMP12 activation; CDH3, CXCL13, GREM1_2, MMP11, SPINK1 inhibition); biological regulation module appears in human normal adjacent tissues (CXCL13, MKI67, PYCR1 activation; NEK2, SPDEF, TOP2A_2, TOX3_1 inhibition), whereas in lung adenocarcinoma (HMGB3, MKI67, NMU, PYCR1, TOX3_2 activation; CXCL13, SPDEF, TOP2A_2 inhibition); sequence variant module appears in human normal adjacent tissues (COL11A1_1, MKI67, MMP11 activation; ASPM, COL10A1, COL3A1, NEK2, TMPRSS4, TOP2A_2 inhibition), whereas in lung adenocarcinoma (COL11A1_2, COL1A2, HMMR, MKI67, MMP12 activation; ABCC3, ASPM, CDH3, MMP11, TOP2A_2 inhibition). It can be deduced that modules above in human normal adjacent tissues reflect the invasive inhibition of normal cells, whereas in lung adenocarcinoma increase the invasion of cancer cell. Our study of SPP1 upstream invasive network may be useful to identify novel and potentially targets for prognosis and therapy of lung adenocarcinoma.

Moussa O, Turner DP, Feldman RJ, et al.
PDEF is a negative regulator of colon cancer cell growth and migration.
J Cell Biochem. 2009; 108(6):1389-98 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
ETS is a family of transcriptional regulators with functions in most biological processes. Dysregulated ETS factor function leads to altered expression of multiple genes that play critical roles in many of the processes required for cancer progression. While the Ets family gene, prostate-derived ETS factor (PDEF), is expressed in epithelial tissues including prostate, breast, and colon, PDEF protein expression has been found to be reduced or lost during prostate and breast cancer progression. The goal of this study was to examine the expression and biologic impact of altered PDEF expression in colon cancer. PDEF mRNA and protein are not detectable in several colon-cancer-derived cell lines. Re-expression of PDEF in colon cancer cells inhibits growth and migration. Growth affects are due to altered cellular proliferation, indicated by increased altered cell population in G(1) and S phases of the cell cycle, as well as increased apoptosis. Relevant to its modulation of growth and migration phenotypes, PDEF expression resulted in altered expression of genes with established roles in cell cycle, motility, and invasion. Furthermore, chromatin immunoprecipitation studies show that p21 and urokinase plasminogen activator (uPA) are direct PDEF transcriptional targets. While non-tumor colon epithelium expresses PDEF mRNA and protein, the majority of tumors showed decreased mRNA and/or protein expression. In human tumor tissue samples, PDEF expression was inversely correlated with the expression levels of uPA. Collectively, the data support the model that PDEF is a negative regulator of tumor progression by modulating the expression of growth and migration promoting genes.

Noah TK, Kazanjian A, Whitsett J, Shroyer NF
SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells.
Exp Cell Res. 2010; 316(3):452-65 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND AND AIMS: SPDEF (also termed PDEF or PSE) is an ETS family transcription factor that regulates gene expression in the prostate and goblet cell hyperplasia in the lung. Spdef has been reported to be expressed in the intestine. In this paper, we identify an important role for Spdef in regulating intestinal epithelial cell homeostasis and differentiation.
METHODS: SPDEF expression was inhibited in colon cancer cells to determine its ability to control goblet cell gene activation. The effects of transgenic expression of Spdef on intestinal differentiation and homeostasis were determined.
RESULTS: In LS174T colon cancer cells treated with Notch/gamma-secretase inhibitor to activate goblet cell gene expression, shRNAs that inhibited SPDEF also repressed expression of goblet cell genes AGR2, MUC2, RETLNB, and SPINK4. Transgenic expression of Spdef caused the expansion of intestinal goblet cells and corresponding reduction in Paneth, enteroendocrine, and absorptive enterocytes. Spdef inhibited proliferation of intestinal crypt cells without induction of apoptosis. Prolonged expression of the Spdef transgene caused a progressive reduction in the number of crypts that expressed Spdef, consistent with its inhibitory effects on cell proliferation.
CONCLUSIONS: Spdef was sufficient to inhibit proliferation of intestinal progenitors and induce differentiation into goblet cells; SPDEF was required for activation of goblet cell associated genes in vitro. These data support a model in which Spdef promotes terminal differentiation into goblet cells of a common goblet/Paneth progenitor.

Bölke E, Orth K, Gerber PA, et al.
Gene expression of circulating tumour cells in breast cancer patients.
Eur J Med Res. 2009; 14(10):426-32 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: The diagnostic tools to predict the prognosis in patients suffering from breast cancer (BC) need further improvements. New technological achievements like the gene profiling of circulating tumour cells (CTC) could help identify new prognostic markers in the clinical setting. Furthermore, gene expression patterns of CTC might provide important informations on the mechanisms of tumour cell metastasation.
MATERIALS AND METHODS: We performed realtime-PCR and multiplex-PCR analyses following immunomagnetic separation of CTC. Peripheral blood (PB) samples of 63 patients with breast cancer of various stages were analyzed and compared to a control group of 14 healthy individuals. After reverse-transcription, we performed multiplex PCR using primers for the genes ga733.3, muc-1 and c-erbB2. Mammaglobin1, spdef and c-erbB2 were analyzed applying realtime-PCR.
RESULTS: ga733.2 overexpression was found in 12.7% of breast cancer cases, muc-1 in 15.9%, mgb1 in 9.1% and spdef in 12.1%. In this study, c-erbB2 did not show any significant correlation to BC, possibly due to a highly ambient expression. Besides single gene analyses, gene profiles were additionally evaluated. Highly significant correlations to BC were found in single gene analyses of ga733.2 and muc-1 and in gene profile analyses of ga733.3*muc-1 and GA7 ga733.3*muc-1*mgb1*spdef.
CONCLUSION: Our study reveals that the single genes ga733.3, muc-1 and the gene profiles ga733.3*muc-1 and ga733.3*3muc-1*mgb1*spdef can serve as markers for the detection of CTC in BC. The multigene analyses found highly positive levels in BC patients. Our study indicates that not single gene analyses but subtle patterns of multiple genes lead to rising accuracy and low loss of specificity in detection of breast cancer cases.

Bölke E, Orth K, Gerber PA, et al.
Gene expression of circulating tumour cells and its correlation with tumour stage in breast cancer patients.
Eur J Med Res. 2009; 14(8):359-63 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Breast cancer (BC) represents one of the leading causes of cancer related deaths worldwide. New tools for diagnostic staging and therapeutic monitoring are needed to improve individualized therapies and improve clinical outcome. The analyses of circulating tumour cells may provide important prognostic information in the clinical setting.
MATERIALS AND METHODS: Circulating tumour cells (CTC) of 63 BC patients were isolated from peripheral blood (PB) through immunomagnetic separation. Subsequently, RT-PCR or mPCR for the genes ga733.2, muc-1, c-erbB2, mgb-1, spdef and c-erbB2 were performed. Subsequently, expression data were correlated with the tumour stages. Fourteen healthy individuals served as controls.
RESULTS: Significant correlations with tumour stages were found in single gene analyses of ga733.2, muc-1 and in multi-gene analyses of ga733.2/muc-1/mgb1/ spdef. Furthermore, a significant correlation of Ca 15-3 and all studied genes was also observed.
CONCLUSION: Herein, we demonstrated a positive correlation of a gene signature consisting of ga733.2, muc-1, mgb1 and spdef and advanced stages of BC. Moreover, all studied genes and gene patterns revealed a significant correlation with Ca 15-3 positive cases.

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