The 5-year survival rate is very low when breast cancer becomes metastatic. The metastatic process is governed by a network of molecules of which SLUG is known to play a major role as a regulator of epithelial-to-mesenchymal transition (EMT). Prostate-derived ETS factor (PDEF) has been proposed as a tumor suppressor, possibly through inhibition of invasion and metastasis; therefore, understanding the mechanism of PDEF regulation may help to better understand its role in breast cancer progression. This study shows for the first time that the transcription factor SLUG is a direct target of PDEF in breast cancer. We show that the expression of PDEF is able to suppress/dampen EMT through the negative regulation of SLUG. In addition, we show that PDEF is also able to regulate downstream targets of SLUG, namely E-cadherin, in both SLUG-dependent and -independent manners, suggesting a critical role for PDEF in regulating EMT.
Seth A,Watson DK.ETS transcription factors and their emerging roles in human cancer.Eur J Cancer. 2005;41 (16): 2462-78
2.
Watson DK,Turner DP,Scheiber MN,Findlay VJ,Watson PM.ETS transcription factor expression and conversion during prostate and breast cancer progression.Open Cancer J. 2010;3:24-39
3.
Ghadersohi A,Sood AK.Prostate epithelium-derived Ets transcription factor mRNA is overexpressed in human breast tumors and is a candidate breast tumor marker and a breast tumor antigen.Clin Cancer Res. 2001;7 (9): 2731-8
4.
Thompson HG,Harris JW,Wold BJ,Lin F,Brody JP.p62 overexpression in breast tumors and regulation by prostate-derived Ets factor in breast cancer cells.Oncogene. 2003;22 (15): 2322-33
5.
Feldman RJ,Sementchenko VI,Gayed M,Fraig MM,Watson DK.Pdef expression in human breast cancer is correlated with invasive potential and altered gene expression.Cancer Res. 2003;63 (15): 4626-31
6.
Ghadersohi A,Pan D,Fayazi Z,Hicks DG,Winston JS,Li F.Prostate-derived Ets transcription factor (PDEF) downregulates survivin expression and inhibits breast cancer cell growth in vitro and xenograft tumor formation in vivo.Breast Cancer Res Treat. 2007;102 (1): 19-30
7.
Gu X,Zerbini LF,Otu HH, et al.Reduced PDEF expression increases invasion and expression of mesenchymal genes in prostate cancer cells.Cancer Res. 2007;67 (9): 4219-26
8.
Turner DP,Moussa O,Sauane M,Fisher PB,Watson DK.Prostate-derived ETS factor is a mediator of metastatic potential through the inhibition of migration and invasion in breast cancer.Cancer Res. 2007;67 (4): 1618-25
9.
Ghadersohi A,Odunsi K,Zhang S, et al.Prostate-derived Ets transcription factor as a favorable prognostic marker in ovarian cancer patients.Int J Cancer. 2008;123 (6): 1376-84
10.
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
11.
Johnson TR,Koul S,Kumar B, et al.Loss of PDEF, a prostate-derived Ets factor is associated with aggressive phenotype of prostate cancer: regulation of MMP 9 by PDEF.Mol Cancer. 2010;9:148
12.
Gunawardane RN,Sgroi DC,Wrobel CN,Koh E,Daley GQ,Brugge JS.Novel role for PDEF in epithelial cell migration and invasion.Cancer Res. 2005;65 (24): 11572-80
Storci G,Sansone P,Trere D, et al.The basal-like breast carcinoma phenotype is regulated by SLUG gene expression.J Pathol. 2008;214 (1): 25-37
20.
Jethwa P,Naqvi M,Hardy RG, et al.Overexpression of Slug is associated with malignant progression of esophageal adenocarcinoma.World J Gastroenterol. 2008;14 (7): 1044-52
21.
Sarrio D,Rodriguez-Pinilla SM,Hardisson D,Cano A,Moreno-Bueno G,Palacios J.Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype.Cancer Res. 2008;68 (4): 989-97
22.
Bhowmick NA,Ghiassi M,Bakin A, et al.Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism.Mol Biol Cell. 2001;12 (1): 27-36
23.
Lindley LE,Briegel KJ.Molecular characterization of TGFbeta-induced epithelial-mesenchymal transition in normal finite lifespan human mammary epithelial cells.Biochem Biophys Res Commun. 2010;399 (4): 659-64
24.
Maeda M,Johnson KR,Wheelock MJ.Cadherin switching: essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition.J Cell Sci. 2005;118 (Pt 5): 873-87
25.
Nguyen DX,Bos PD,Massague J.Metastasis: from dissemination to organ-specific colonization.Nat Rev Cancer. 2009;9 (4): 274-84
26.
Talmadge JE,Fidler IJ.AACR Centennial Series. The biology of cancer metastasis: historical perspective.Cancer Res. 2010;70 (14): 5649-69
27.
Feldman RJ,Sementchenko VI,Watson DK.The epithelial-specific Ets factors occupy a unique position in defining epithelial proliferation, differentiation and carcinogenesis.Anticancer Res. 2003;23 (3A): 2125-31
28.
Oka H,Shiozaki H,Kobayashi K, et al.Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis.Cancer Res. 1993;53 (7): 1696-701
29.
Umbas R,Isaacs WB,Bringuier PP, et al.Decreased E-cadherin expression is associated with poor prognosis in patients with prostate cancer.Cancer Res. 1994;54 (14): 3929-33
30.
Onder TT,Gupta PB,Mani SA,Yang J,Lander ES,Weinberg RA.Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways.Cancer Res. 2008;68 (10): 3645-54
31.
Conacci-Sorrell M,Simcha I,Ben-Yedidia T,Blechman J,Savagner P,Ben-Ze’ev A.Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK.J Cell Biol. 2003;163 (4): 847-57
32.
Alves CC,Carneiro F,Hoefler H,Becker KF.Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers.Front Biosci. 2009;14:3035-50
33.
Feng XH.The changing faces of cancer cells.Nat Rev Mol Cell Biol. 2010;11 (7): 466
34.
Radisky DC,LaBarge MA.Epithelial-mesenchymal transition and the stem cell phenotype.Cell Stem Cell. 2008;2 (6): 511-2
35.
Mani SA,Guo W,Liao MJ, et al.The epithelial-mesenchymal transition generates cells with properties of stem cells.Cell. 2008;133 (4): 704-15
36.
Blick T,Hugo H,Widodo E, et al.Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer.J Mammary Gland Biol Neoplasia. 2010;15 (2): 235-52
37.
Nowak DE,Tian B,Brasier AR.Two-step cross-linking method for identification of NF-kappaB gene network by chromatin immunoprecipitation.Biotechniques. 2005;39 (5): 715-25
38.
Deveaux S,Filipe A,Lemarchandel V,Ghysdael J,Romeo PH,Mignotte V.Analysis of the thrombopoietin receptor (MPL) promoter implicates GATA and Ets proteins in the coregulation of megakaryocyte-specific genes.Blood. 1996;87 (11): 4678-85
39.
Mignotte V,Vigon I,Boucher de Crevecoeur E,Romeo PH,Lemarchandel V,Chretien S.Structure and transcription of the human c-mpl gene (MPL).Genomics. 1994;20 (1): 5-12
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