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Special Focus Content: Epithelial-mesenchymal transition in tumor metastasis: a method to the madness - Review

Epithelial–mesenchymal transition in development and cancer

    Douglas S Micalizzi

    Program in Molecular Biology, Medical Scientist Training Program, University of Colorado School of Medicine, Aurora CO 80045, USA

    &
    Heide L Ford

    † Author for correspondence

    Departments of Obstetrics and Gynecology and Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora CO 80045, USA.

    Published Online:https://doi.org/10.2217/fon.09.94

    The epithelial–mesenchymal transition (EMT) is a critical developmental process from the earliest events of embryogenesis to later morphogenesis and organ formation. EMT contributes to the complex architecture of the embryo by permitting the progression of embryogenesis from a simple single-cell layer epithelium to a complex three-dimensional organism composed of both epithelial and mesenchymal cells. However, in most tissues EMT is a developmentally restricted process and fully differentiated epithelia typically maintain their epithelial phenotype. Recently, elements of EMT, specifically the loss of epithelial markers and the gain of mesenchymal markers, have been observed in pathological states, including epithelial cancers. Analysis of the molecular mechanisms of this oncogenic epithelial plasticity have implicated the inappropriate expression and activation of developmental EMT programs, suggesting that cancer cells may reinstitute properties of developmental EMT including enhanced migration and invasion. Thus, in the context of cancer, an EMT-like process may permit dissemination of tumor cells from the primary tumor into the surrounding stroma, setting the stage for metastatic spread. Consistent with this hypothesis, activation of these developmental EMT programs in human cancer correlates with advanced disease and poor prognosis. This review will focus on the current knowledge regarding developmental EMT pathways that have been implicated in cancer progression.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Solnica-Krezel L: Conserved patterns of cell movements during vertebrate gastrulation. Curr. Biol.15(6),R213–R228 (2005).
    • Mercado-Pimentel ME, Runyan RB: Multiple transforming growth factor-β isoforms and receptors function during epithelial–mesenchymal cell transformation in the embryonic heart. Cells Tissues Organs185(1–3),146–156 (2007).
    • Nawshad A, LaGamba D, Hay ED: Transforming growth factor β (TGFβ) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch. Oral Biol.49(9),675–689 (2004).
    • Tucker RP: Neural crest cells: a model for invasive behavior. Int. J. Biochem. Cell Biol.36(2),173–177 (2004).
    • Shook D, Keller R: Mechanisms, mechanics and function of epithelial–mesenchymal transitions in early development. Mech. Dev.120(11),1351–1383 (2003).
    • Kalluri R, Neilson EG: Epithelial–mesenchymal transition and its implications for fibrosis. J. Clin. Invest.112(12),1776–1784 (2003).
    • Thiery JP: Epithelial–mesenchymal transitions in tumor progression. Nat. Rev. Cancer2(6),442–454 (2002).
    • Olmeda D, Montes A, Moreno-Bueno G, Flores JM, Portillo F, Cano A: Snai1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines. Oncogene27(34),4690–4701 (2008).
    • Yang J, Mani SA, Donaher JL et al.: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell117(7),927–939 (2004).▪▪ Identified Twist from a screen designed to identify metastatic regulators, and demonstrated that Twist induces epithelial–mesenchymal transition (EMT), is necessary for metastasis and correlates with E-cadherin downregulation in human invasive lobular carcinoma.
    • 10  Micalizzi DS, Christensen KL, Jedlicka P et al.: The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial–mesenchymal transition and metastasis in mice through TGF-β signaling. J. Clin. Invest.119(9),2678–2690 (2009).▪▪ Establishes Six1 as an inducer of EMT and metastasis in mammary carcinoma cells dependent on TGF-β signaling. Also correlates Six1 with activated TGF-β signaling and poor prognosis in human breast cancer and identifies numerous cancer types where Six1 correlates with advanced disease.
    • 11  Self M, Lagutin OV, Bowling B et al.: Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. EMBO J.25(21),5214–5228 (2006).▪ Establishes Six2 as a critical regulator of the metanephric mesenchyme during kidney development.
    • 12  Jakowlew SB: Transforming growth factor-β in cancer and metastasis. Cancer Metastasis Rev.25(3),435–457 (2006).
    • 13  Brabletz T, Hlubek F, Spaderna S et al.: Invasion and metastasis in colorectal cancer: epithelial–mesenchymal transition, mesenchymal-epithelial transition, stem cells and β-catenin. Cells Tissues Organs179(1–2),56–65 (2005).
    • 14  Yang J, Weinberg RA: Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell14(6),818–829 (2008).
    • 15  Moustakas A, Heldin CH: Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci.98(10),1512–1520 (2007).
    • 16  Muller HA: Of mice, frogs and flies: generation of membrane asymmetries in early development. Dev. Growth Differ.43(4),327–342 (2001).
    • 17  Hay ED: The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev. Dyn.233(3),706–720 (2005).
    • 18  Nakaya Y, Sukowati EW, Wu Y, Sheng G: RhoA and microtubule dynamics control cell-basement membrane interaction in EMT during gastrulation. Nat. Cell Biol.10(7),765–775 (2008).
    • 19  Romano LA, Runyan RB: Slug is an essential target of TGFβ2 signaling in the developing chicken heart. Dev. Biol.223(1),91–102 (2000).
    • 20  Carver EA, Jiang R, Lan Y, Oram KF, Gridley T: The mouse snail gene encodes a key regulator of the epithelial–mesenchymal transition. Mol. Cell. Biol.21(23),8184–8188 (2001).
    • 21  Yu W, Kamara H, Svoboda KK: The role of twist during palate development. Dev. Dyn.237(10),2716–2725 (2008).
    • 22  Nawshad A, Hay ED: TGFβ3 signaling activates transcription of the LEF1 gene to induce epithelial mesenchymal transformation during mouse palate development. J. Cell Biol.163(6),1291–1301 (2003).▪ Defines the upregulation of LEF1 independent of β-catenin as a mechanism that mediates TGF-β-induced EMT during palatal development.
    • 23  Morkel M, Huelsken J, Wakamiya M et al.: β-catenin regulates Cripto- and Wnt3-dependent gene expression programs in mouse axis and mesoderm formation. Development130(25),6283–6294 (2003).
    • 24  Baum B, Settleman J, Quinlan MP: Transitions between epithelial and mesenchymal states in development and disease. Semin. Cell Dev. Biol.19(3),294–308 (2008).
    • 25  Martinez-Alvarez C, Blanco MJ, Perez R et al.: Snail family members and cell survival in physiological and pathological cleft palates. Dev. Biol.265(1),207–218 (2004).
    • 26  Azhar M, Schultz Jel J, Grupp I et al.: Transforming growth factor β in cardiovascular development and function. Cytokine Growth Factor Rev.14(5),391–407 (2003).
    • 27  Savagner P, Kusewitt DF, Carver EA et al.: Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J. Cell Physiol.202(3),858–866 (2005).
    • 28  Guarino M, Rubino B, Ballabio G: The role of epithelial–mesenchymal transition in cancer pathology. Pathology39(3),305–318 (2007).
    • 29  Gavert N, Ben-Ze’ev A: Epithelial–mesenchymal transition and the invasive potential of tumors. Trends Mol. Med.14(5),199–209 (2008).
    • 30  Trimboli AJ, Fukino K, de Bruin A et al.: Direct evidence for epithelial–mesenchymal transitions in breast cancer. Cancer Res.68(3),937–945 (2008).▪▪ Provides the first direct evidence of EMT in vivo in breast cancer using cell fate mapping in a Myc transgenic mouse tumor model.
    • 31  Massague J: TGFβ in cancer. Cell.134(2),215–230 (2008).
    • 32  Crawford SE, Stellmach V, Murphy-Ullrich JE et al.: Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell93(7),1159–1170 (1998).
    • 33  Massague J, Seoane J, Wotton D: Smad transcription factors. Genes Dev.19(23),2783–2810 (2005).
    • 34  Blobe GC, Schiemann WP, Lodish HF: Role of transforming growth factor β in human disease. N. Engl. J. Med.342(18),1350–1358 (2000).
    • 35  Ravitz MJ, Wenner CE: Cyclin-dependent kinase regulation during G1 phase and cell cycle regulation by TGF-β. Adv. Cancer Res.71165–207 (1997).
    • 36  Bartram U, Molin DG, Wisse LJ et al.: Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGF-β(2)-knockout mice. Circulation103(22),2745–2752 (2001).
    • 37  Sridurongrit S, Larsson J, Schwartz R, Ruiz-Lozano P, Kaartinen V: Signaling via the TGF-β type I receptor Alk5 in heart development. Dev. Biol.322(1),208–218 (2008).▪▪ Demonstrates that TGF-β signaling through Alk5 is necessary for EMT during cardiac cushion development through the development of tissue-specific knockout mice.
    • 38  Miettinen PJ, Ebner R, Lopez AR, Derynck R: TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J. Cell Biol.127(6 Pt 2),2021–2036 (1994).
    • 39  Oft M, Heider KH, Beug H: TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr. Biol.8(23),1243–1252 (1998).
    • 40  Zavadil J, Bottinger EP: TGF-β and epithelial-to-mesenchymal transitions. Oncogene24(37),5764–5774 (2005).
    • 41  Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL: Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science307(5715),1603–1609 (2005).▪ Establishes a mechanism through Par6 and Smurf1 for the dissolution of tight junctions during TGF-β-mediated EMT and identified an interaction between TβRI and Par6.
    • 42  Peinado H, Quintanilla M, Cano A: Transforming growth factor β-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J. Biol. Chem.278(23),21113–21123 (2003).
    • 43  Bhowmick NA, Ghiassi M, Bakin A et al.: Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell.12(1),27–36 (2001).
    • 44  Gregory PA, Bert AG, Paterson EL et al.: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol.10(5),593–601 (2008).▪ Provides a description of the recently discovered role of miRNAs in TGF-β induced EMT, identifies Zeb1 and Zeb2, repressors of E-cadherin, as targets of the miR-200 family and miR-205, and demonstrates the loss of miR-200 family expression in invasive breast cancer.
    • 45  Kong W, Yang H, He L et al.: MicroRNA-155 is regulated by the transforming growth factor β/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol. Cell. Biol.28(22),6773–6784 (2008).
    • 46  Stefani G, Slack FJ: Small noncoding RNAs in animal development. Nat. Rev. Mol. Cell Biol.9(3),219–230 (2008).
    • 47  Hannon GJ, Beach D: p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature371(6494),257–261 (1994).
    • 48  Reynisdottir I, Polyak K, Iavarone A, Massague J: Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-β. Genes Dev.9(15),1831–1845 (1995).
    • 49  Cui W, Fowlis DJ, Bryson S et al.: TGFβ1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell86(4),531–542 (1996).▪ Provides a description of the dual role of TGF-β signaling in tumorigenesis as both tumor suppressive and promotional.
    • 50  Chen CR, Kang Y, Massague J: Defective repression of c-myc in breast cancer cells: a loss at the core of the transforming growth factor β growth arrest program. Proc. Natl Acad. Sci. USA98(3),992–999 (2001).
    • 51  Baldwin RL, Tran H, Karlan BY: Loss of c-myc repression coincides with ovarian cancer resistance to transforming growth factor β growth arrest independent of transforming growth factor β/Smad signaling. Cancer Res.63(6),1413–1419 (2003).
    • 52  Janda E, Lehmann K, Killisch I et al.: Ras and TGF[β] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol.156(2),299–313 (2002).
    • 53  Rees JR, Onwuegbusi BA, Save VE, Alderson D, Fitzgerald RC: In vivo and in vitro evidence for transforming growth factor-β1-mediated epithelial to mesenchymal transition in esophageal adenocarcinoma. Cancer Res.66(19),9583–9590 (2006).
    • 54  Vasko V, Espinosa AV, Scouten W et al.: Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc. Natl Acad. Sci. USA104(8),2803–2808 (2007).
    • 55  Liu X: Inflammatory cytokines augments TGF-β1-induced epithelial–mesenchymal transition in A549 cells by up-regulating TβR-I. Cell Motil. Cytoskeleton65(12),935–944 (2008).
    • 56  Soufla G, Sifakis S, Baritaki S, Zafiropoulos A, Koumantakis E, Spandidos DA: VEGF, FGF2, TGFB1 and TGFBR1 mRNA expression levels correlate with the malignant transformation of the uterine cervix. Cancer Lett.221(1),105–118 (2005).
    • 57  Kjellman C, Olofsson SP, Hansson O et al.: Expression of TGF-β isoforms, TGF-β receptors, and SMAD molecules at different stages of human glioma. Int. J. Cancer89(3),251–258 (2000).
    • 58  Takanami I, Tanaka F, Hashizume T, Kodaira S: Roles of the transforming growth factor β 1 and its type I and II receptors in the development of a pulmonary adenocarcinoma: results of an immunohistochemical study. J. Surg. Oncol.64(4),262–267 (1997).
    • 59  Ghellal A, Li C, Hayes M, Byrne G, Bundred N, Kumar S: Prognostic significance of TGF β 1 and TGF β 3 in human breast carcinoma. Anticancer Res.20(6B),4413–4418 (2000).
    • 60  Mu L, Katsaros D, Lu L et al.: TGF-β1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival. Br. J. Cancer99(8),1357–1363 (2008).
    • 61  Langenskiold M, Holmdahl L, Falk P, Angenete E, Ivarsson ML: Increased TGF-β 1 protein expression in patients with advanced colorectal cancer. J. Surg. Oncol.97(5),409–415 (2008).
    • 62  Ivanovic V, Todorovic-Rakovic N, Demajo M et al.: Elevated plasma levels of transforming growth factor-β 1 (TGF-β 1) in patients with advanced breast cancer: association with disease progression. Eur. J. Cancer39(4),454–461 (2003).
    • 63  Muraoka RS, Dumont N, Ritter CA et al.: Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases. J. Clin. Invest.109(12),1551–1559 (2002).
    • 64  Muraoka-Cook RS, Shin I, Yi JY et al.: Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene25(24),3408–3423 (2006).
    • 65  Kemler R, Hierholzer A, Kanzler B et al.: Stabilization of β-catenin in the mouse zygote leads to premature epithelial–mesenchymal transition in the epiblast. Development131(23),5817–5824 (2004).
    • 66  Liebner S, Cattelino A, Gallini R et al.: β-catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. J. Cell Biol.166(3),359–367 (2004).
    • 67  Nelson WJ, Nusse R: Convergence of Wnt, β-catenin, and cadherin pathways. Science303(5663),1483–1487 (2004).
    • 68  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 β-catenin signaling, Slug, and MAPK. J. Cell Biol.163(4),847–857 (2003).
    • 69  Gilles C, Polette M, Mestdagt M et al.: Transactivation of vimentin by β-catenin in human breast cancer cells. Cancer Res.63(10),2658–2664 (2003).
    • 70  Gradl D, Kuhl M, Wedlich D: The Wnt/Wg signal transducer β-catenin controls fibronectin expression. Mol. Cell. Biol.19(8),5576–5587 (1999).
    • 71  Huber MA, Kraut N, Beug H: Molecular requirements for epithelial–mesenchymal transition during tumor progression. Curr. Opin. Cell Biol.17(5),548–558 (2005).
    • 72  Kim K, Lu Z, Hay ED: Direct evidence for a role of β-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol. Int.26(5),463–476 (2002).
    • 73  Yook JI, Li XY, Ota I et al.: A Wnt-Axin2-GSK3β cascade regulates Snail1 activity in breast cancer cells. Nat. Cell Biol.8(12),1398–1406 (2006).
    • 74  Wong SC, Lo ES, Lee KC, Chan JK, Hsiao WL: Prognostic and diagnostic significance of β-catenin nuclear immunostaining in colorectal cancer. Clin. Cancer Res.10(4),1401–1408 (2004).
    • 75  Cano A, Perez-Moreno MA, Rodrigo I et al.: The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol.2(2),76–83 (2000).▪▪ Demonstrates that Snail represses E-cadherin by binding directly to the E-boxes within the E-cadherin promoter, that SNAIL also induces EMT in epithelial cells, and that SNAIL is expressed in invasive human tumors.
    • 76  Taneyhill LA, Coles EG, Bronner-Fraser M: Snail2 directly represses cadherin6B during epithelial-to-mesenchymal transitions of the neural crest. Development134(8),1481–1490 (2007).
    • 77  Batlle E, Sancho E, Franci C et al.: The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumor cells. Nat. Cell Biol.2(2),84–89 (2000).▪▪ Demonstrates that Snail represses E-cadherin by binding directly to the E-cadherin promoter and is required for E-cadherin repression in human pancreatic cancer cells.
    • 78  Usami Y, Satake S, Nakayama F et al.: Snail-associated epithelial–mesenchymal transition promotes oesophageal squamous cell carcinoma motility and progression. J. Pathol.215(3),330–339 (2008).
    • 79  Dhasarathy A, Kajita M, Wade PA: The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-α. Mol. Endocrinol.21(12),2907–2918 (2007).
    • 80  Kurrey NK, K A, Bapat SA: Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level. Gynecol. Oncol.97(1),155–165 (2005).
    • 81  Moreno-Bueno G, Cubillo E, Sarrio D et al.: Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for Snail, Slug, and E47 factors in epithelial–mesenchymal transition. Cancer Res.66(19),9543–9556 (2006).
    • 82  Savagner P, Yamada KM, Thiery JP: The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial–mesenchymal transition. J. Cell Biol.137(6),1403–1419 (1997).
    • 83  Jorda M, Olmeda D, Vinyals A et al.: Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J. Cell Sci.118(Pt 15),3371–3385 (2005).
    • 84  de Boer TP, van Veen TA, Bierhuizen MF et al.: Connexin43 repression following epithelium-to-mesenchyme transition in embryonal carcinoma cells requires Snail1 transcription factor. Differentiation75(3),208–218 (2007).
    • 85  Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A: The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J. Cell Sci.116(Pt 3),499–511 (2003).
    • 86  Park SH, Cheung LW, Wong AS, Leung PC: Estrogen regulates Snail and Slug in the down-regulation of E-cadherin and induces metastatic potential of ovarian cancer cells through estrogen receptor α. Mol. Endocrinol.22(9),2085–2098 (2008).
    • 87  Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS, Wade PA: MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell113(2),207–219 (2003).
    • 88  Blanco MJ, Moreno-Bueno G, Sarrio D et al.: Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene21(20),3241–3246 (2002).
    • 89  Waldmann J, Feldmann G, Slater EP et al.: Expression of the zinc-finger transcription factor Snail in adrenocortical carcinoma is associated with decreased survival. Br. J. Cancer99(11),1900–1907 (2008).
    • 90  Castro Alves C, Rosivatz E, Schott C et al.: Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin. J. Pathol.211(5),507–515 (2007).
    • 91  Shioiri M, Shida T, Koda K et al.: Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Br. J. Cancer94(12),1816–1822 (2006).
    • 92  Olmeda D, Jorda M, Peinado H, Fabra A, Cano A: Snail silencing effectively suppresses tumor growth and invasiveness. Oncogene26(13),1862–1874 (2007).
    • 93  Moody SE, Perez D, Pan TC et al.: The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell8(3),197–209 (2005).▪ Describes a novel role for Snail, not only in tumor progression, but also in tumor recurrence.
    • 94  Vesuna F, van Diest P, Chen JH, Raman V: Twist is a transcriptional repressor of E-cadherin gene expression in breast cancer. Biochem. Biophys. Res. Commun.367(2),235–241 (2008).
    • 95  Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH: Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res.67(5),1979–1987 (2007).
    • 96  Lee YH, Albig AR, Maryann R, SchiemannBJ, Schiemann WP: Fibulin-5 initiates epithelial–mesenchymal transition (EMT) and enhances EMT induced by TGF-{β} in mammary epithelial cells via a MMP-dependent mechanism. Carcinogenesis29(12),2243–2251 (2008).
    • 97  Yang MH, Wu KJ: TWIST activation by hypoxia inducible factor-1 (HIF-1 ): implications in metastasis and development. Cell Cycle7(14),2090–2096 (2008).
    • 98  Yang MH, Wu MZ, Chiou SH et al.: Direct regulation of TWIST by HIF-1 α promotes metastasis. Nat. Cell Biol.10(3),295–305 (2008).▪ Identifies HIF-1 α as a novel regulator of Twist expression and links intratumoral hypoxia with EMT and metastasis.
    • 99  Lo HW, Hsu SC, Xia W et al.: Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial–mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res.67(19),9066–9076 (2007).
    • 100  Niu RF, Zhang L, Xi GM et al.: Upregulation of Twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma. J. Exp. Clin. Cancer Res.26(3),385–394 (2007).
    • 101  Yuen HF, Kwok WK, Chan KK et al.: TWIST modulates prostate cancer cell-mediated bone cell activity and is upregulated by osteogenic induction. Carcinogenesis29(8),1509–1518 (2008).
    • 102  Fondrevelle ME, Kantelip B, Reiter RE et al.: The expression of Twist has an impact on survival in human bladder cancer and is influenced by the smoking status. Urol. Oncol.27(3),268–276 (2008).
    • 103  Kyo S, Sakaguchi J, Ohno S et al.: High Twist expression is involved in infiltrative endometrial cancer and affects patient survival. Hum. Pathol.37(4),431–438 (2006).
    • 104  Li X, Oghi KA, Zhang J et al.: Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature426(6964),247–254 (2003).
    • 105  Oliver G, Wehr R, Jenkins NA et al.: Homeobox genes and connective tissue patterning. Development121(3),693–705 (1995).
    • 106  Laclef C, Hamard G, Demignon J, Souil E, Houbron C, Maire P: Altered myogenesis in Six1-deficient mice. Development130(10),2239–2252 (2003).
    • 107  Xu PX, Zheng W, Huang L, Maire P, Laclef C, Silvius D: Six1 is required for the early organogenesis of mammalian kidney. Development130(14),3085–3094 (2003).
    • 108  Birchmeier C, Brohmann H: Genes that control the development of migrating muscle precursor cells. Curr. Opin. Cell Biol.12(6),725–730 (2000).
    • 109  Ozaki H, Watanabe Y, Takahashi K et al.: Six4, a putative myogenin gene regulator, is not essential for mouse embryonal development. Mol. Cell. Biol.21(10),3343–3350 (2001).
    • 110  Grifone R, Demignon J, Houbron C et al.: Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo. Development132(9),2235–2249 (2005).▪▪ Describes the generation of Six1/Six4 knockout mice that show a more severe muscle developmental defect traced to a failure of muscle precursor to delaminate and migrate into the developing limb.
    • 111  McCoy EL, Jedlicka P, Abbey N et al.: Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial–mesenchymal transition. J. Clin. Invest.119(9) 2663–2677 (2009).▪▪ Demonstrates that Six1 expression in the mammary gland of transgenic mice induces increased stem/progenitor cell pools and aggressive tumor formation, many of which undergo EMT and have activated Wnt signaling. Reports that Six1 overexpression with the Wnt target Cyclin D1 more strongly predicts prognosis than Six1 alone.
    • 112  Ford HL, Kabingu EN, Bump EA, Mutter GL, Pardee AB: Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis. Proc. Natl Acad. Sci. USA95(21),12608–12613 (1998).
    • 113  Reichenberger KJ, Coletta RD, Schulte AP, Varella-Garcia M, Ford HL: Gene amplification is a mechanism of Six1 overexpression in breast cancer. Cancer Res.65(7),2668–2675 (2005).
    • 114  Behbakht K, Qamar L, Aldridge CS et al.: Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival. Cancer Res.67(7),3036–3042 (2007).
    • 115  Kloth JN, Fleuren GJ, Oosting J et al.: Substantial changes in gene expression of Wnt, MAPK and TNFα pathways induced by TGF-β1 in cervical cancer cell lines. Carcinogenesis26(9),1493–1502 (2005).