nach oben

Journal of Mammary Gland Biology and Neoplasia

Erschienen in:

01.06.2010

The Pathophysiology of Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β in Normal and Malignant Mammary Epithelial Cells

verfasst von: Molly A. Taylor, Jenny G. Parvani, William P. Schiemann

Erschienen in: Journal of Mammary Gland Biology and Neoplasia | Ausgabe 2/2010

Einloggen, um Zugang zu erhalten

Abstract

Epithelial-mesenchymal transition (EMT) is an essential process that drives polarized, immotile mammary epithelial cells (MECs) to acquire apolar, highly migratory fibroblastoid-like features. EMT is an indispensable process that is associated with normal tissue development and organogenesis, as well as with tissue remodeling and wound healing. In stark contrast, inappropriate reactivation of EMT readily contributes to the development of a variety of human pathologies, particularly those associated with tissue fibrosis and cancer cell invasion and metastasis, including that by breast cancer cells. Although metastasis is unequivocally the most lethal aspect of breast cancer and the most prominent feature associated with disease recurrence, the molecular mechanisms whereby EMT mediates the initiation and resolution of breast cancer metastasis remains poorly understood. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is intimately involved in regulating numerous physiological processes, including cellular differentiation, homeostasis, and EMT. In addition, TGF-β also functions as a powerful tumor suppressor in MECs, whose neoplastic development ultimately converts TGF-β into an oncogenic cytokine in aggressive late-stage mammary tumors. Recent findings have implicated the process of EMT in mediating the functional conversion of TGF-β during breast cancer progression, suggesting that the chemotherapeutic targeting of EMT induced by TGF-β may offer new inroads in ameliorating metastatic disease in breast cancer patients. Here we review the molecular, cellular, and microenvironmental factors that contribute to the pathophysiological activities of TGF-β during its regulation of EMT in normal and malignant MECs.

Wendt MK, Allington TM, Schiemann WP. Mechanisms of the epithelial-mesenchymal transition by TGF-β. Future Oncol. 2009;5(8):1145–68.PubMed

Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.PubMed

Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.PubMed

Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14(6):818–29.PubMed

Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, et al. Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213(2):374–83.PubMed

Wells A, Yates C, Shepard CR. E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis. 2008;25(6):621–8.PubMed

Barcellos-Hoff MH, Akhurst RJ. TGF-β in breast cancer: too much, too late. Breast Cancer Res. 2009;11(1):202.PubMed

Buck MB, Knabbe C. TGF-β signaling in breast cancer. Ann NY Acad Sci. 2006;1089:119–26.PubMed

Serra R, Crowley MR. Mouse models of TGF-β impact in breast development and cancer. Endocr Relat Cancer. 2005;12(4):749–60.PubMed

10.

Schiemann WP. Targeted TGF-β chemotherapies: friend or foe in treating human malignancies? Expert Rev Anticancer Ther. 2007;7(5):609–11.PubMed

11.

Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006;439(7072):84–8.PubMed

12.

Stingl J, Raouf A, Eirew P, Eaves CJ. Deciphering the mammary epithelial cell hierarchy. Cell Cycle. 2006;5(14):1519–22.PubMed

13.

Villadsen R, Fridriksdottir AJ, Ronnov-Jessen L, Gudjonsson T, Rank F, LaBarge MA, et al. Evidence for a stem cell hierarchy in the adult human breast. J Cell Biol. 2007;177(1):87–101.PubMed

14.

Heldin CH, Landstrom M, Moustakas A. Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr Opin Cell Biol. 2009;21(2):166–76.PubMed

15.

Zavadil J, Bottinger EP. TGF-β and epithelial-to-mesenchymal transitions. Oncogene. 2005;24(37):5764–74.PubMed

16.

Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15.PubMed

17.

Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS ONE. 2008;3(8):e2888.PubMed

18.

Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 2008;40(5):499–507.PubMed

19.

Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11(3):259–73.PubMed

20.

Xu J, Lamouille S, Derynck R. TGF-β-induced epithelial to mesenchymal transition. Cell Res. 2009;19(2):156–72.PubMed

21.

Chang H, Brown CW, Matzuk MM. Genetic analysis of the mammalian TGF-β superfamily. Endocr Rev. 2002;23(6):787–823.PubMed

22.

Massague J, Seoane J, Wotton D. Smad transcription factors. Genes Dev. 2005;19(23):2783–810.PubMed

23.

Galliher AJ, Neil JR, Schiemann WP. Role of TGF-β in cancer progression. Future Oncol. 2006;2(6):743–63.PubMed

24.

Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL. SARA, a FYVE domain protein that recruits Smad2 to the TGF-β receptor. Cell. 1998;95(6):779–91.PubMed

25.

Miura S, Takeshita T, Asao H, Kimura Y, Murata K, Sasaki Y, et al. Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA. Mol Cell Biol. 2000;20(24):9346–55.PubMed

26.

Hocevar BA, Smine A, Xu XX, Howe PH. The adaptor molecule Disabled-2 links the TGF-β receptors to the Smad pathway. EMBO J. 2001;20(11):2789–801.PubMed

27.

Mok SC, Wong KK, Chan RK, Lau CC, Tsao SW, Knapp RC, et al. Molecular cloning of differentially expressed genes in human epithelial ovarian cancer. Gynecol Oncol. 1994;52(2):247–52.PubMed

28.

Xu XX, Yang W, Jackowski S, Rock CO. Cloning of a novel phosphoprotein regulated by colony-stimulating factor 1 shares a domain with the Drosophila disabled gene product. J Biol Chem. 1995;270(23):14184–91.PubMed

29.

Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, et al. The MAD-related protein Smad7 associates with the TGF-β receptor and functions as an antagonist of TGF-β signaling. Cell. 1997;89:1165–73.PubMed

30.

Nakao A, Afrakht M, Moren A, Nakayama T, Christian JL, Heuchel R, et al. Identification of Smad7, a TGF-β-inducible antagonist of TGF-β signalling. Nature. 1997;389:631–5.PubMed

31.

Souchelnytskyi S, Nakayama T, Nakao A, Moren A, Heldin CH, Christian JL, et al. Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and TGF-β receptors. J Biol Chem. 1998;273:25364–70.PubMed

32.

Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, et al. Smurf1 interacts with TGF-β type I receptor through Smad7 and induces receptor degradation. J Biol Chem. 2001;276(16):12477–80.PubMed

33.

Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF-β receptor for degradation. Mol Cell. 2000;6(6):1365–75.PubMed

34.

Datta PK, Moses HL. STRAP and Smad7 synergize in the inhibition of TGF-β signaling. Mol Cell Biol. 2000;20(9):3157–67.PubMed

35.

Ibarrola N, Kratchmarova I, Nakajima D, Schiemann WP, Moustakas A, Pandey A, et al. Cloning of a novel signaling molecule, AMSH-2, that potentiates TGF-β signaling. BMC Cell Biol. 2004;5:2.PubMed

36.

Koinuma D, Shinozaki M, Komuro A, Goto K, Saitoh M, Hanyu A, et al. Arkadia amplifies TGF-β superfamily signalling through degradation of Smad7. EMBO J. 2003;22(24):6458–70.PubMed

37.

Liu FY, Li XZ, Peng YM, Liu H, Liu YH. Arkadia-Smad7-mediated positive regulation of TGF-β signaling in a rat model of tubulointerstitial fibrosis. Am J Nephrol. 2007;27(2):176–83.PubMed

38.

Liu W, Rui H, Wang J, Lin S, He Y, Chen M, et al. Axin is a scaffold protein in TGF-β signaling that promotes degradation of Smad7 by Arkadia. EMBO J. 2006;25(8):1646–58.PubMed

39.

Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL. p38 mitogen-activated protein kinase is required for TGF-β-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci. 2002;115((Pt) 15):3193–206.PubMed

40.

Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for TGF-β-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275(47):36803–10.PubMed

41.

Bhowmick NA, Ghiassi M, Bakin A, Aakre M, Lundquist CA, Engel ME, et al. TGF-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell. 2001;12(1):27–36.PubMed

42.

Lamouille S, Derynck R. Cell size and invasion in TGF-β-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol. 2007;178(3):437–51.PubMed

43.

Perlman R, Schiemann WP, Brooks MW, Lodish HF, Weinberg RA. TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol. 2001;3(8):708–14.PubMed

44.

Zavadil J, Bitzer M, Liang D, Yang YC, Massimi A, Kneitz S, et al. Genetic programs of epithelial cell plasticity directed by TGF-β. Proc Natl Acad Sci USA. 2001;98(12):6686–91.PubMed

45.

Galliher AJ, Schiemann WP. β3 integrin and Src facilitate TGF-β mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res. 2006;8(4):R42.PubMed

46.

Galliher-Beckley AJ, Schiemann WP. Grb2 binding to Tyr284 in TβR-II is essential for mammary tumor growth and metastasis stimulated by TGF-β. Carcinogenesis. 2008;29(2):244–51.PubMed

47.

Arsura M, Panta GR, Bilyeu JD, Cavin LG, Sovak MA, Oliver AA, et al. Transient activation of NF-κB through a TAK1/IKK kinase pathway by TGF-β1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene. 2003;22(3):412–25.PubMed

48.

Park J-I, Lee M-G, Cho K, Park B-J, Chae K-S, Byun D-S, et al. TGF-β1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-κB, JNK, and Ras signaling pathways. Oncogene. 2003;22:4314–32.PubMed

49.

Neil JR, Schiemann WP. Altered TAB1:IκB kinase interaction promotes TGF-β-mediated NF-κB activation during breast cancer progression. Cancer Res. 2008;68(5):1462–70.PubMed

50.

Neil JR, Johnson KM, Nemenoff RA, Schiemann WP. Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-β through a PGE2-dependent mechanisms. Carcinogenesis. 2008;29(11):2227–35.PubMed

51.

Tian M, Schiemann WP. PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-β signaling during mammary tumorigenesis. FASEB J. 2010;24(4):1105–16.PubMed

52.

Dong M, How T, Kirkbride KC, Gordon KJ, Lee JD, Hempel N, et al. The type III TGF-β receptor suppresses breast cancer progression. J Clin Invest. 2007;117(1):206–17.PubMed

53.

Sun L, Chen C. Expression of TGF-β type III receptor suppresses tumorigenicity of human breast cancer MDA-MB-231 cells. J Biol Chem. 1997;272(40):25367–72.PubMed

54.

Gordon KJ, Blobe GC. Role of TGF-β superfamily signaling pathways in human disease. Biochim Biophys Acta. 2008;1782(4):197–228.PubMed

55.

Gordon KJ, Dong M, Chislock EM, Fields TA, Blobe GC. Loss of type III TGF-β receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. Carcinogenesis. 2008;29(2):252–62.PubMed

56.

Galliher AJ, Schiemann WP. Src phosphorylates Tyr284 in TGF-β type II receptor and regulates TGF-β stimulation of p38 MAPK during breast cancer cell proliferation and invasion. Cancer Res. 2007;67(8):3752–8.PubMed

57.

Park SS, Eom YW, Kim EH, Lee JH, Min DS, Kim S, et al. Involvement of c-Src kinase in the regulation of TGF-β1-induced apoptosis. Oncogene. 2004;23(37):6272–81.PubMed

58.

Horowitz JC, Rogers DS, Sharma V, Vittal R, White ES, Cui Z, et al. Combinatorial activation of FAK and AKT by TGF-β1 confers an anoikis-resistant phenotype to myofibroblasts. Cell Signal. 2007;19(4):761–71.PubMed

59.

Thannickal VJ, Lee DY, White ES, Cui Z, Larios JM, Chacon R, et al. Myofibroblast differentiation by TGF-β1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem. 2003;278(14):12384–9.PubMed

60.

Allington TM, Galliher-Beckley AJ, Schiemann WP. Activated Abl kinase inhibits oncogenic TGF-β signaling and tumorigenesis in mammary tumors. FASEB J. 2009;23(12):4231–43.PubMed

61.

Micalizzi DS, Ford HL. Epithelial-mesenchymal transition in development and cancer. Future Oncol. 2009;5(8):1129–43.PubMed

62.

Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest. 2009;119(6):1438–49.PubMed

63.

Skromne I, Stern CD. Interactions between Wnt and Vg1 signalling pathways initiate primitive streak formation in the chick embryo. Development. 2001;128(15):2915–27.PubMed

64.

Popperl H, Schmidt C, Wilson V, Hume CR, Dodd J, Krumlauf R, et al. Misexpression of Cwnt8C in the mouse induces an ectopic embryonic axis and causes a truncation of the anterior neuroectoderm. Development. 1997;124(15):2997–3005.PubMed

65.

Liu P, Wakamiya M, Shea MJ, Albrecht U, Behringer RR, Bradley A. Requirement for Wnt3 in vertebrate axis formation. Nat Genet. 1999;22(4):361–5.PubMed

66.

Chea HK, Wright CV, Swalla BJ. Nodal signaling and the evolution of deuterostome gastrulation. Dev Dyn. 2005;234(2):269–78.PubMed

67.

Zhou X, Sasaki H, Lowe L, Hogan BL, Kuehn MR. Nodal is a novel TGF-β-like gene expressed in the mouse node during gastrulation. Nature. 1993;361(6412):543–7.PubMed

68.

Conlon FL, Lyons KM, Takaesu N, Barth KS, Kispert A, Herrmann B, et al. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development. 1994;120(7):1919–28.PubMed

69.

Birsoy B, Kofron M, Schaible K, Wylie C, Heasman J. Vg1 is an essential signaling molecule in Xenopus development. Development. 2006;133(1):15–20.PubMed

70.

Shah SB SI, Hume CR, Kessler DS, Lee KJ, Stern CD, Dodd J. Misexpression of chick Vg1 in the marginal zone induces primitive streak formation. Development. 1997;125(24):5127–38.

71.

Sauka-Spengler T, Bronner-Fraser M. A gene regulatory network orchestrates neural crest formation. Nat Rev Mol Cell Biol. 2008;9(7):557–68.PubMed

72.

Raible DW. Development of the neural crest: achieving specificity in regulatory pathways. Curr Opin Cell Biol. 2006;18(6):698–703.PubMed

73.

Correia AC, Costa M, Moraes F, Bom J, Novoa A, Mallo M. BMP2 is required for migration but not for induction of neural crest cells in the mouse. Dev Dyn. 2007;236(9):2493–501.PubMed

74.

Wu MY, Hill CS. TGF-β superfamily signaling in embryonic development and homeostasis. Dev Cell. 2009;16(3):329–43.PubMed

75.

Boyer AS, Ayerinskas II, Vincent EB, McKinney LA, Weeks DL, Runyan RB. TGF-β2 and TGF-β3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev Biol. 1999;208(2):530–45.PubMed

76.

Mercado-Pimentel ME, Hubbard AD, Runyan RB. Endoglin and Alk5 regulate epithelial-mesenchymal transformation during cardiac valve formation. Dev Biol. 2007;304(1):420–32.PubMed

77.

Mercado-Pimentel ME, Runyan RB. Multiple TGF-β isoforms and receptors function during epithelial-mesenchymal cell transformation in the embryonic heart. Cells Tissues Organs. 2007;185(1–3):146–56.PubMed

78.

Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N, et al. Abnormal lung development and cleft palate in mice lacking TGF-β3 indicates defects of epithelial-mesenchymal interaction. Nat Genet. 1995;11(4):415–21.PubMed

79.

Ahmed S, Liu CC, Nawshad A. Mechanisms of palatal epithelial seam disintegration by TGF-β3. Dev Biol. 2007;309(2):193–207.PubMed

80.

Brown CB, Boyer AS, Runyan RB, Barnett JV. Requirement of type III TGF-β receptor for endocardial cell transformation in the heart. Science. 1999;283(5410):2080–2.PubMed

81.

Nakajima A, Ito Y, Asano M, Maeno M, Iwata K, Mitsui N, et al. Functional role of TGF-β type III receptor during palatal fusion. Dev Dyn. 2007;236(3):791–801.PubMed

82.

Nelson CM, Vanduijn MM, Inman JL, Fletcher DA, Bissell MJ. Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science. 2006;314(5797):298–300.PubMed

83.

Ewald AJ, Brenot A, Duong M, Chan BS, Werb Z. Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis. Dev Cell. 2008;14(4):570–81.PubMed

84.

McCoy EL, Iwanaga R, Jedlicka P, Abbey NS, Chodosh LA, Heichman KA, et al. Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition. J Clin Invest. 2009;119(9):2663–77.PubMed

85.

Micalizzi DS, Christensen KL, Jedlicka P, Coletta RD, Baron AE, Harrell JC, et al. The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-β signaling. J Clin Invest. 2009;119(9):2678–90.PubMed

86.

Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210.PubMed

87.

Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117(3):524–9.PubMed

88.

Radisky DC, Przybylo JA. Matrix metalloproteinase-induced fibrosis and malignancy in breast and lung. Proc Am Thorac Soc. 2008;5(3):316–22.PubMed

89.

Pohlers D, Brenmoehl J, Loffler I, Muller CK, Leipner C, Schultze-Mosgau S, et al. TGF-β and fibrosis in different organs—molecular pathway imprints. Biochim Biophys Acta. 2009;1792(8):746–56.PubMed

90.

Hay ED. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn. 2005;233(3):706–20.PubMed

91.

Vaughan MB, Howard EW, Tomasek JJ. TGF-β1 promotes the morphological and functional differentiation of the myofibroblast. Exp Cell Res. 2000;257(1):180–9.PubMed

92.

Wallace K, Burt AD, Wright MC. Liver fibrosis. Biochem J. 2008;411(1):1–18.PubMed

93.

Grande MT, Lopez-Novoa JM. Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat Rev Nephrol. 2009;5(6):319–28.PubMed

94.

Guarino M, Tosoni A, Nebuloni M. Direct contribution of epithelium to organ fibrosis: epithelial-mesenchymal transition. Hum Pathol. 2009;40(10):1365–76.PubMed

95.

Yazhou C, Wenlv S, Weidong Z, Licun W. Clinicopathological significance of stromal myofibroblasts in invasive ductal carcinoma of the breast. Tumour Biol. 2004;25(5–6):290–5.PubMed

96.

Masszi A, Di Ciano C, Sirokmany G, Arthur WT, Rotstein OD, Wang J, et al. Central role for Rho in TGF-β1-induced α-smooth muscle actin expression during epithelial-mesenchymal transition. Am J Physiol Renal Physiol. 2003;284(5):F911–24.PubMed

97.

Akhmetshina A, Dees C, Pileckyte M, Szucs G, Spriewald BM, Zwerina J, et al. Rho-associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts. Arthritis Rheum. 2008;58(8):2553–64.PubMed

98.

Vardouli L, Vasilaki E, Papadimitriou E, Kardassis D, Stournaras C. A novel mechanism of TGF-β-induced actin reorganization mediated by Smad proteins and Rho GTPases. FEBS J. 2008;275(16):4074–87.PubMed

99.

Vasilaki E, Papadimitriou E, Tajadura V, Ridley AJ, Stournaras C, Kardassis D. Transcriptional regulation of the small GTPase RhoB gene by TGF-β-induced signaling pathways. FASEN J. 2010;24(3):891–905.

100.

Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, et al. Epithelial cell α3β1 integrin links β-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest. 2009;119(1):213–24.PubMed

101.

Kim Y, Kugler MC, Wei Y, Kim KK, Li X, Brumwell AN, et al. Integrin α3β1-dependent β-catenin phosphorylation links epithelial Smad signaling to cell contacts. J Cell Biol. 2009;184(2):309–22.PubMed

102.

White LR, Blanchette JB, Ren L, Awn A, Trpkov K, Muruve DA. The characterization of α5-integrin expression on tubular epithelium during renal injury. Am J Physiol Renal Physiol. 2007;292(2):F567–76.PubMed

103.

Boyd NF, Dite GS, Stone J, Gunasekara A, English DR, McCredie MR, et al. Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med. 2002;347(12):886–94.PubMed

104.

Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ, et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol. 2005;6(10):798–808.PubMed

105.

Choi YW, Munden RF, Erasmus JJ, Park KJ, Chung WK, Jeon SC, et al. Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis. Radiographics. 2004;24(4):985–97.PubMed

106.

Andarawewa KL, Erickson AC, Chou WS, Costes SV, Gascard P, Mott JD, et al. Ionizing radiation predisposes nonmalignant human mammary epithelial cells to undergo TGF-β induced epithelial to mesenchymal transition. Cancer Res. 2007;67(18):8662–70.PubMed

107.

Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression. Nat Rev Cancer. 2009;9(2):108–22.PubMed

108.

Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8(3):241–54.PubMed

109.

Turley EA, Veiseh M, Radisky DC, Bissell MJ. Mechanisms of disease: epithelial-mesenchymal transition—does cellular plasticity fuel neoplastic progression? Nat Clin Pract Oncol. 2008;5(5):280–90.PubMed

110.

Tian M, Schiemann WP. The TGF-β paradox in human cancer: an update. Future Oncol. 2009;5(2):259–71.PubMed

111.

Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139(5):891–906.PubMed

112.

Frank NY, Schatton T, Frank MH. The therapeutic promise of the cancer stem cell concept. J Clin Invest. 2010;120(1):41–50.PubMed

113.

Brown KA, Pietenpol JA, Moses HL. A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-β signaling. J Cell Biochem. 2007;101(1):9–33.PubMed

114.

Hoot KE, Lighthall J, Han G, Lu SL, Li A, Ju W, et al. Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression. J Clin Invest. 2008;118(8):2722–32.PubMed

115.

Ju W, Ogawa A, Heyer J, Nierhof D, Yu L, Kucherlapati R, et al. Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol Cell Biol. 2006;26(2):654–67.PubMed

116.

Oft M, Akhurst RJ, Balmain A. Metastasis is driven by sequential elevation of H-Ras and Smad2 levels. Nat Cell Biol. 2002;4(7):487–94.PubMed

117.

Runyan CE, Hayashida T, Hubchak S, Curley JF, Schnaper HW. Role of SARA (SMAD anchor for receptor activation) in maintenance of epithelial cell phenotype. J Biol Chem. 2009;284(37):25181–9.PubMed

118.

Saika S, Kono-Saika S, Ohnishi Y, Sato M, Muragaki Y, Ooshima A, et al. Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury. Am J Pathol. 2004;164(2):651–63.PubMed

119.

Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A. Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest. 2003;112(10):1486–94.PubMed

120.

Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol. 1999;1(5):260–6.PubMed

121.

Davies M, Robinson M, Smith E, Huntley S, Prime S, Paterson I. Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-β1 involves MAPK, Smad and AP-1 signalling pathways. J Cell Biochem. 2005;95(5):918–31.PubMed

122.

Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006;20(22):3130–46.PubMed

123.

Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A. TGF-β and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell. 2005;16(4):1987–2002.PubMed

124.

Dooley S, Hamzavi J, Ciuclan L, Godoy P, Ilkavets I, Ehnert S, et al. Hepatocyte-specific Smad7 expression attenuates TGF-β-mediated fibrogenesis and protects against liver damage. Gastroenterology. 2008;135(2):642–59.PubMed

125.

Saika S, Ikeda K, Yamanaka O, Sato M, Muragaki Y, Ohnishi Y, et al. Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial-mesenchymal transition of lens epithelium in mice. Lab Invest. 2004;84(10):1259–70.PubMed

126.

Gal A, Sjoblom T, Fedorova L, Imreh S, Beug H, Moustakas A. Sustained TGF-β exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene. 2008;27(9):1218–30.PubMed

127.

Deckers M, van Dinther M, Buijs J, Que I, Lowik C, van der Pluijm G, et al. The tumor suppressor Smad4 is required for TGF-β-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res. 2006;66(4):2202–9.PubMed

128.

Zhao BM, Hoffmann FM. Inhibition of TGF-β1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-SARA. Mol Biol Cell. 2006;17(9):3819–31.PubMed

129.

Papageorgis P, Lambert AW, Ozturk S, Gao F, Pan H, Manne U, et al. Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res. 2010;70(3):968–78.PubMed

130.

Liu IM, Schilling SH, Knouse KA, Choy L, Derynck R, Wang XF. TGF-β-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGF-β switch. EMBO J. 2009;28(2):88–98.PubMed

131.

Hall A. Rho GTPases and the control of cell behaviour. Biochem Soc Trans. 2005;33(Pt 5):891–5.PubMed

132.

Hall A, Nobes CD. Rho GTPases: molecular switches that control the organization and dynamics of the actin cytoskeleton. Philos Trans R Soc Lond B Biol Sci. 2000;355(1399):965–70.PubMed

133.

Takaishi K, Sasaki T, Kotani H, Nishioka H, Takai Y. Regulation of cell–cell adhesion by Rac and Rho small G proteins in MDCK cells. J Cell Biol. 1997;139(4):1047–59.PubMed

134.

Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JG. Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol. 1999;147(5):1009–22.PubMed

135.

Mythreye K, Blobe GC. The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42. Proc Natl Acad Sci USA. 2009;106(20):8221–6.PubMed

136.

Simpson KJ, Dugan AS, Mercurio AM. Functional analysis of the contribution of RhoA and RhoC GTPases to invasive breast carcinoma. Cancer Res. 2004;64(23):8694–701.PubMed

137.

Sequeira L, Dubyk CW, Riesenberger TA, Cooper CR, van Golen KL. Rho GTPases in PC-3 prostate cancer cell morphology, invasion and tumor cell diapedesis. Clin Exp Metastasis. 2008;25(5):569–79.PubMed

138.

Bellovin DI, Simpson KJ, Danilov T, Maynard E, Rimm DL, Oettgen P, et al. Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma. Oncogene. 2006;25(52):6959–67.PubMed

139.

Hutchison N, Hendry BM, Sharpe CC. Rho isoforms have distinct and specific functions in the process of epithelial to mesenchymal transition in renal proximal tubular cells. Cell Signal. 2009;21(10):1522–31.PubMed

140.

Viloria-Petit AM, David L, Jia JY, Erdemir T, Bane AL, Pinnaduwage D, et al. A role for the TGF-β-Par6 polarity pathway in breast cancer progression. Proc Natl Acad Sci USA. 2009;106(33):14028–33.PubMed

141.

Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGF-β receptors controls epithelial cell plasticity. Science. 2005;307(5715):1603–9.PubMed

142.

Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS, et al. MicroRNA-155 is regulated by the TGF-β/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol. 2008;28(22):6773–84.PubMed

143.

Valastyan S, Benaich N, Chang A, Reinhardt F, Weinberg RA. Concomitant suppression of three target genes can explain the impact of a microRNA on metastasis. Genes Dev. 2009;23(22):2592–7.PubMed

144.

Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szasz AM, Wang ZC, et al. A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell. 2009;137(6):1032–46.PubMed

145.

Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9(8):550–62.PubMed

146.

Murillo MM, del Castillo G, Sanchez A, Fernandez M, Fabregat I. Involvement of EGF receptor and c-Src in the survival signals induced by TGF-β1 in hepatocytes. Oncogene. 2005;24(28):4580–7.PubMed

147.

Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, et al. Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest. 2006;116(6):1561–70.PubMed

148.

Uttamsingh S, Bao X, Nguyen KT, Bhanot M, Gong J, Chan JL, et al. Synergistic effect between EGF and TGF-β1 in inducing oncogenic properties of intestinal epithelial cells. Oncogene. 2008;27(18):2626–34.PubMed

149.

Karin M. NF-κB in cancer development and progression. Nature. 2006;441(7092):431–6.PubMed

150.

Sovak MA, Arsura M, Zanieski G, Kavanagh KT, Sonenshein GE. The inhibitory effects of TGF-β1 on breast cancer cell proliferation are mediated through regulation of aberrant NF-κB/Rel expression. Cell Growth Differ. 1999;10(8):537–44.PubMed

151.

Arsura M, Wu M, Sonenshein GE. TGF-β1 inhibits NF-κB/Rel activity inducing apoptosis of B cells: transcriptional activation of IκBα. Immunity. 1996;5(1):31–40.PubMed

152.

You HJ, How T, Blobe GC. The type III TGF-β receptor negatively regulates NF-κB signaling through its interaction with β-arrestin2. Carcinogenesis. 2009;30(8):1281–7.PubMed

153.

Neil JR, Tian M, Schiemann WP. xIAP and its E3 ligase activity promote TGF-β-mediated NF-κB activation during breast cancer progression. J Biol Chem. 2009;284(32):21209–17.PubMed

154.

Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H. NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene. 2007;26(5):711–24.PubMed

155.

Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, et al. NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004;114(4):569–81.PubMed

156.

Bertran E, Caja L, Navarro E, Sancho P, Mainez J, Murillo MM, et al. Role of CXCR4/SDF-1α in the migratory phenotype of hepatoma cells that have undergone epithelial-mesenchymal transition in response to the TGF-β. Cell Signal. 2009;21(11):1595–606.PubMed

157.

Bhowmick NA, Zent R, Ghiassi M, McDonnell M, Moses HL. Integrin β1 signaling is necessary for TGF-β activation of p38MAPK and epithelial plasticity. J Biol Chem. 2001;276(50):46707–13.PubMed

158.

Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL. Activation of the Erk pathway is required for TGF-β1-induced EMT in vitro. Neoplasia. 2004;6(5):603–10.PubMed

159.

Atfi A, Djelloul S, Chastre E, Davis R, Gespach C. Evidence for a role of Rho-like GTPases and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in TGF-β-mediated signaling. J Biol Chem. 1997;272(3):1429–32.PubMed

160.

Hocevar BA, Prunier C, Howe PH. Disabled-2 (Dab2) mediates TGF-β-stimulated fibronectin synthesis through TGF-β-activated kinase 1 and activation of the JNK pathway. J Biol Chem. 2005;280(27):25920–7.PubMed

161.

Santibanez JF. JNK mediates TGF-β1-induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes. FEBS Lett. 2006;580(22):5385–91.PubMed

162.

Shintani Y, Wheelock MJ, Johnson KR. Phosphoinositide-3 kinase-Rac1-c-Jun NH2-terminal kinase signaling mediates collagen I-induced cell scattering and up-regulation of N-cadherin expression in mouse mammary epithelial cells. Mol Biol Cell. 2006;17(7):2963–75.PubMed

163.

Shintani Y, Hollingsworth MA, Wheelock MJ, Johnson KR. Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH(2)-terminal kinase 1 and up-regulating N-cadherin expression. Cancer Res. 2006;66(24):11745–53.PubMed

164.

Zuo W, Chen YG. Specific activation of mitogen-activated protein kinase by TGF-β receptors in lipid rafts is required for epithelial cell plasticity. Mol Biol Cell. 2009;20(3):1020–9.PubMed

165.

Dedhar S, Williams B, Hannigan G. Integrin-linked kinase (ILK): a regulator of integrin and growth-factor signalling. Trends Cell Biol. 1999;9(8):319–23.PubMed

166.

Hannigan G, Troussard AA, Dedhar S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer. 2005;5(1):51–63.PubMed

167.

Hehlgans S, Haase M, Cordes N. Signalling via integrins: implications for cell survival and anticancer strategies. Biochim Biophys Acta. 2007;1775(1):163–80.PubMed

168.

Somasiri A, Howarth A, Goswami D, Dedhar S, Roskelley CD. Overexpression of the integrin-linked kinase mesenchymally transforms mammary epithelial cells. J Cell Sci. 2001;114(Pt 6):1125–36.PubMed

169.

White DE, Cardiff RD, Dedhar S, Muller WJ. Mammary epithelial-specific expression of the integrin-linked kinase (ILK) results in the induction of mammary gland hyperplasias and tumors in transgenic mice. Oncogene. 2001;20(48):7064–72.PubMed

170.

Lin SW, Ke FC, Hsiao PW, Lee PP, Lee MT, Hwang JJ. Critical involvement of ILK in TGFbeta1-stimulated invasion/migration of human ovarian cancer cells is associated with urokinase plasminogen activator system. Exp Cell Res. 2007;313(3):602–13.PubMed

171.

Li Y, Dai C, Wu C, Liu Y. PINCH-1 promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase. J Am Soc Nephrol. 2007;18(9):2534–43.PubMed

172.

Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer. 2002;2(2):91–100.PubMed

173.

Mizejewski GJ. Role of integrins in cancer: survey of expression patterns. Proc Soc Exp Biol Med. 1999;222(2):124–38.PubMed

174.

Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10(1):9–22.PubMed

175.

Legate KR, Wickstrom SA, Fassler R. Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev. 2009;23(4):397–418.PubMed

176.

Hauck CR, Sieg DJ, Hsia DA, Loftus JC, Gaarde WA, Monia BP, et al. Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. Cancer Res. 2001;61(19):7079–90.PubMed

177.

Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, et al. FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol. 2000;2(5):249–56.PubMed

178.

Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, et al. The integrin αvβ6 binds and activates latent TGF-β1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999;96(3):319–28.PubMed

179.

Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, et al. The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1. J Cell Biol. 2002;157(3):493–507.PubMed

180.

Wendt MK, Schiemann WP. Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-β signaling and metastasis. Breast Cancer Res. 2009;11(5):R68.PubMed

181.

Bandyopadhyay A, Agyin JK, Wang L, Tang Y, Lei X, Story BM, et al. Inhibition of pulmonary and skeletal metastasis by a TGF-β type I receptor kinase inhibitor. Cancer Res. 2006;66(13):6714–21.PubMed

182.

Sloan EK, Pouliot N, Stanley KL, Chia J, Moseley JM, Hards DK, et al. Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Res. 2006;8(2):R20.PubMed

183.

Cicchini C, Laudadio I, Citarella F, Corazzari M, Steindler C, Conigliaro A, et al. TGF-β-induced EMT requires focal adhesion kinase (FAK) signaling. Exp Cell Res. 2008;314(1):143–52.PubMed

184.

Liu S, Xu SW, Kennedy L, Pala D, Chen Y, Eastwood M, et al. FAK is required for TGF-β-induced JNK phosphorylation in fibroblasts: implications for acquisition of a matrix-remodeling phenotype. Mol Biol Cell. 2007;18(6):2169–78.PubMed

185.

Kim W, Seok Kang Y, Soo Kim J, Shin NY, Hanks SK, Song WK. The integrin-coupled signaling adaptor p130Cas suppresses Smad3 function in TGF-β signaling. Mol Biol Cell. 2008;19(5):2135–46.PubMed

186.

van der Flier S, Chan CM, Brinkman A, Smid M, Johnston SR, Dorssers LC, et al. BCAR1/p130Cas expression in untreated and acquired tamoxifen-resistant human breast carcinomas. Int J Cancer. 2000;89(5):465–8.PubMed

187.

Ta HQ, Thomas KS, Schrecengost RS, Bouton AH. A novel association between p130Cas and resistance to the chemotherapeutic drug adriamycin in human breast cancer cells. Cancer Res. 2008;68(21):8796–804.PubMed

188.

Cabodi S, Tinnirello A, Di Stefano P, Bisaro B, Ambrosino E, Castellano I, et al. p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis. Cancer Res. 2006;66(9):4672–80.PubMed

189.

Wendt MK, Smith JA, Schiemann WP. p130Cas is required for mammary tumor growth and TGF-β-mediated metastasis through regulation of Smad2/3 activity. J Biol Chem. 2009;284(49):34145–56.PubMed

190.

Tumbarello DA, Brown MC, Hetey SE, Turner CE. Regulation of paxillin family members during epithelial-mesenchymal transformation: a putative role for paxillin delta. J Cell Sci. 2005;118(Pt 20):4849–63.PubMed

191.

Fujimoto N, Yeh S, Kang HY, Inui S, Chang HC, Mizokami A, et al. Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate. J Biol Chem. 1999;274(12):8316–21.PubMed

192.

Tumbarello DA, Turner CE. Hic-5 contributes to epithelial-mesenchymal transformation through a RhoA/ROCK-dependent pathway. J Cell Physiol. 2007;211(3):736–47.PubMed

193.

Wang H, Song K, Krebs TL, Yang J, Danielpour D. Smad7 is inactivated through a direct physical interaction with the LIM protein Hic-5/ARA55. Oncogene. 2008;27(54):6791–805.PubMed

194.

Wang H, Song K, Sponseller TL, Danielpour D. Novel function of androgen receptor-associated protein 55/Hic-5 as a negative regulator of Smad3 signaling. J Biol Chem. 2005;280(7):5154–62.PubMed

195.

Prunier C, Hocevar BA, Howe PH. Wnt signaling: physiology and pathology. Growth Factors. 2004;22(3):141–50.PubMed

196.

Prunier C, Howe PH. Disabled-2 (Dab2) is required for TGF-β-induced epithelial to mesenchymal transition (EMT). J Biol Chem. 2005;280(17):17540–8.PubMed

197.

Chaudhury A, Hussey GS, Ray PS, Jin G, Fox PL, Howe PH. TGF-β-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol. 2010;12(3):286–93.PubMed

198.

Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene. 2008;27(55):6958–69.PubMed

199.

Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415–28.PubMed

200.

Ikenouchi J, Matsuda M, Furuse M, Tsukita S. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci. 2003;116(Pt 10):1959–67.PubMed

201.

Vincent T, Neve EP, Johnson JR, Kukalev A, Rojo F, Albanell J, et al. A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition. Nat Cell Biol. 2009;11(8):943–50.PubMed

202.

Smith AP, Verrecchia A, Faga G, Doni M, Perna D, Martinato F, et al. A positive role for Myc in TGF-β-induced Snail transcription and epithelial-to-mesenchymal transition. Oncogene. 2009;28(3):422–30.PubMed

203.

Lee YH, Albig AR, Regner M, Schiemann BJ, 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. Carcinogenesis. 2008;29(12):2243–51.PubMed

204.

Araki S, Eitel JA, Batuello CN, Bijangi-Vishehsaraei K, Xie XJ, Danielpour D, et al. TGF-β1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer. J Clin Invest. 2010;120(1):290–302.PubMed

205.

Thuault S, Valcourt U, Petersen M, Manfioletti G, Heldin CH, Moustakas A. TGF-β employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol. 2006;174(2):175–83.PubMed

206.

Yu M, Smolen GA, Zhang J, Wittner B, Schott BJ, Brachtel E, et al. A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression. Genes Dev. 2009;23(15):1737–42.PubMed

207.

Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002;2(2):101–12.PubMed

208.

Dhasarathy A, Kajita M, Wade PA. The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-alpha. Mol Endocrinol. 2007;21(12):2907–18.PubMed

209.

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. Cell. 2003;113(2):207–19.PubMed

210.

Matsuda T, Yamamoto T, Muraguchi A, Saatcioglu F. Cross-talk between TGF-β and estrogen receptor signaling through Smad3. J Biol Chem. 2001;276(46):42908–14.PubMed

211.

Radaelli E, Arnold A, Papanikolaou A, Garcia-Fernandez RA, Mattiello S, Scanziani E, et al. Mammary tumor phenotypes in wild-type aging female FVB/N mice with pituitary prolactinomas. Vet Pathol. 2009;46(4):736–45.PubMed

212.

Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65(16):7065–70.PubMed

213.

Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6(11):857–66.PubMed

214.

Silveri L, Tilly G, Vilotte JL, Le Provost F. MicroRNA involvement in mammary gland development and breast cancer. Reprod Nutr Dev. 2006;46(5):549–56.PubMed

215.

Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22(7):894–907.PubMed

216.

Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10(5):593–601.PubMed

217.

Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 2008;283(22):14910–4.PubMed

218.

Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008;9(6):582–9.PubMed

219.

Zavadil J, Narasimhan M, Blumenberg M, Schneider RJ. TGF-β and microRNA:mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs. 2007;185(1–3):157–61.PubMed

220.

Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 2007;282(19):14328–36.PubMed

221.

Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 2008;18(3):350–9.PubMed

222.

Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J, et al. E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br J Cancer. 2006;94(5):661–71.PubMed

223.

Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T, Hirohashi S. Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci USA. 1995;92(16):7416–9.PubMed

224.

Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349(21):2042–54.PubMed

225.

Vrba L, Jensen TJ, Garbe JC, Heimark RL, Cress AE, Dickinson S, et al. Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS One. 2010;5(1):e8697.PubMed

226.

Dumont N, Wilson MB, Crawford YG, Reynolds PA, Sigaroudinia M, Tlsty TD. Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc Natl Acad Sci. 2008;105(39):14867–72.PubMed

227.

Bierie B, Moses HL. Tumour microenvironment: TGF-β: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006;6(7):506–20.PubMed

228.

Bissell MJ, Labarge MA. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell. 2005;7(1):17–23.PubMed

229.

Radisky DC, Bissell MJ. Cancer. Respect thy neighbor! Science. 2004;303(5659):775–7.PubMed

230.

Massague J. TGFbeta in Cancer. Cell. 2008;134(2):215–30.PubMed

231.

Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 2004;4(2):118–32.PubMed

232.

Agiostratidou G, Hulit J, Phillips GR, Hazan RB. Differential cadherin expression: potential markers for epithelial to mesenchymal transformation during tumor progression. J Mammary Gland Biol Neoplasia. 2007;12(2–3):127–33.PubMed

233.

Christofori G. Changing neighbours, changing behaviour: cell adhesion molecule-mediated signalling during tumour progression. EMBO J. 2003;22(10):2318–23.PubMed

234.

Graff JR, Greenberg VE, Herman JG, Westra WH, Boghaert ER, Ain KB, et al. Distinct patterns of E-cadherin CpG island methylation in papillary, follicular, Hurthle’s cell, and poorly differentiated human thyroid carcinoma. Cancer Res. 1998;58(10):2063–6.PubMed

235.

Makrilia N, Kollias A, Manolopoulos L, Syrigos K. Cell adhesion molecules: role and clinical significance in cancer. Cancer Invest. 2009;27(10):1023–37.PubMed

236.

Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA. A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res. 2007;13(23):7003–11.PubMed

237.

Tomita K, van Bokhoven A, van Leenders GJ, Ruijter ET, Jansen CF, Bussemakers MJ, et al. Cadherin switching in human prostate cancer progression. Cancer Res. 2000;60(13):3650–4.PubMed

238.

Pyo SW, Hashimoto M, Kim YS, Kim CH, Lee SH, Johnson KR, et al. Expression of E-cadherin, P-cadherin and N-cadherin in oral squamous cell carcinoma: correlation with the clinicopathologic features and patient outcome. J Craniomaxillofac Surg. 2007;35(1):1–9.PubMed

239.

Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol. 2000;148(4):779–90.PubMed

240.

Cavallaro U, Niedermeyer J, Fuxa M, Christofori G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol. 2001;3(7):650–7.PubMed

241.

Lehembre F, Yilmaz M, Wicki A, Schomber T, Strittmatter K, Ziegler D, et al. NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin. EMBO J. 2008;27(19):2603–15.PubMed

242.

Illman SA, Lehti K, Keski-Oja J, Lohi J. Epilysin (MMP-28) induces TGF-β mediated epithelial to mesenchymal transition in lung carcinoma cells. J Cell Sci. 2006;119(Pt 18):3856–65.PubMed

243.

Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161–74.PubMed

244.

Mott JD, Werb Z. Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol. 2004;16(5):558–64.PubMed

245.

Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14(2):163–76.PubMed

246.

Dangelo M, Sarment DP, Billings PC, Pacifici M. Activation of TGF-β in chondrocytes undergoing endochondral ossification. J Bone Miner Res. 2001;16(12):2339–47.PubMed

247.

Noe V, Fingleton B, Jacobs K, Crawford HC, Vermeulen S, Steelant W, et al. Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci. 2001;114(Pt 1):111–8.PubMed

248.

Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436(7047):123–7.PubMed

249.

Stuelten CH, DaCosta Byfield S, Arany PR, Karpova TS, Stetler-Stevenson WG, Roberts AB. Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-α and TGF-β. J Cell Sci. 2005;118(Pt 10):2143–53.PubMed

250.

Duivenvoorden WC, Hirte HW, Singh G. TGF-β1 acts as an inducer of matrix metalloproteinase expression and activity in human bone-metastasizing cancer cells. Clin Exp Metastasis. 1999;17(1):27–34.PubMed

251.

Kim ES, Sohn YW, Moon A. TGF-β-induced transcriptional activation of MMP-2 is mediated by activating transcription factor (ATF)2 in human breast epithelial cells. Cancer Lett. 2007;252(1):147–56.PubMed

252.

Kim ES, Kim MS, Moon A. TGF-β in conjunction with H-Ras activation promotes malignant progression of MCF10A breast epithelial cells. Cytokine. 2005;29(2):84–91.PubMed

253.

Harbeck N, Kates RE, Gauger K, Willems A, Kiechle M, Magdolen V, et al. Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer. Thromb Haemost. 2004;91(3):450–6.PubMed

254.

Duffy MJ, Duggan C. The urokinase plasminogen activator system: a rich source of tumour markers for the individualised management of patients with cancer. Clin Biochem. 2004;37(7):541–8.PubMed

255.

Mitra SK, Lim ST, Chi A, Schlaepfer DD. Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model. Oncogene. 2006;25(32):4429–40.PubMed

256.

Lester RD, Jo M, Montel V, Takimoto S, Gonias SL. uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J Cell Biol. 2007;178(3):425–36.PubMed

257.

Ge R, Rajeev V, Ray P, Lattime E, Rittling S, Medicherla S, et al. Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of TGF-β type I receptor kinase in vivo. Clin Cancer Res. 2006;12(14 Pt 1):4315–30.PubMed

258.

Nam JS, Terabe M, Mamura M, Kang MJ, Chae H, Stuelten C, et al. An anti-TGF-β antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res. 2008;68(10):3835–43.PubMed

259.

Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, et al. Abrogation of TGF-β signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell. 2008;13(1):23–35.PubMed

260.

Zhang F, Tom CC, Kugler MC, Ching TT, Kreidberg JA, Wei Y, et al. Distinct ligand binding sites in integrin α3β1 regulate matrix adhesion and cell–cell contact. J Cell Biol. 2003;163(1):177–88.PubMed

261.

Whitley BR, Palmieri D, Twerdi CD, Church FC. Expression of active plasminogen activator inhibitor-1 reduces cell migration and invasion in breast and gynecological cancer cells. Exp Cell Res. 2004;296(2):151–62.PubMed

262.

Descotes F, Riche B, Saez S, De Laroche G, Datchary J, Roy P, et al. Plasminogen activator inhibitor type 1 is the most significant of the usual tissue prognostic factors in node-negative breast ductal adenocarcinoma independent of urokinase-type plasminogen activator. Clin Breast Cancer. 2008;8(2):168–77.PubMed

263.

Samarakoon R, Higgins CE, Higgins SP, Higgins PJ. Differential requirement for MEK/ERK and SMAD signaling in PAI-1 and CTGF expression in response to microtubule disruption. Cell Signal. 2009;21(6):986–95.PubMed

264.

Ignotz RA, Massague J. TGF-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986;261(9):4337–45.PubMed

265.

Wienke D, Davies GC, Johnson DA, Sturge J, Lambros MB, Savage K, et al. The collagen receptor Endo180 (CD280) Is expressed on basal-like breast tumor cells and promotes tumor growth in vivo. Cancer Res. 2007;67(21):10230–40.PubMed

266.

Garamszegi N, Garamszegi SP, Samavarchi-Tehrani P, Walford E, Schneiderbauer MM, Wrana JL, et al. Extracellular matrix-induced TGF-β receptor signaling dynamics. Oncogene 2010; PMID: 20101206.

267.

Xie L, Law BK, Aakre ME, Edgerton M, Shyr Y, Bhowmick NA, et al. TGF-β-regulated gene expression in a mouse mammary gland epithelial cell line. Breast Cancer Res. 2003;5(6):R187–98.PubMed

268.

Maschler S, Wirl G, Spring H, Bredow DV, Sordat I, Beug H, et al. Tumor cell invasiveness correlates with changes in integrin expression and localization. Oncogene. 2005;24(12):2032–41.PubMed

269.

Camara J, Jarai G. Epithelial-mesenchymal transition in primary human bronchial epithelial cells is Smad-dependent and enhanced by fibronectin and TNF-α. Fibrogenesis Tissue Repair. 2010;3(1):2.PubMed

270.

Wels J, Kaplan RN, Rafii S, Lyden D. Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev. 2008;22(5):559–74.PubMed

271.

Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell. 2009;15(1):35–44.PubMed

272.

Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645–59.PubMed

Titel: The Pathophysiology of Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β in Normal and Malignant Mammary Epithelial Cells
verfasst von: Molly A. Taylor
Jenny G. Parvani
William P. Schiemann
Publikationsdatum: 01.06.2010
Verlag: Springer US
Erschienen in: Journal of Mammary Gland Biology and Neoplasia / Ausgabe 2/2010
Print ISSN: 1083-3021
Elektronische ISSN: 1573-7039
DOI: https://doi.org/10.1007/s10911-010-9181-1

Neu im Fachgebiet Onkologie

24.04.2024 | DGIM 2024 | Nachrichten

Springer Medizin

The Pathophysiology of Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β in Normal and Malignant Mammary Epithelial Cells

Abstract

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2010

Snail Family Regulation and Epithelial Mesenchymal Transitions in Breast Cancer Progression

Epithelial-Mesenchymal Transition (EMT) in Tumor-Initiating Cells and Its Clinical Implications in Breast Cancer

The Pathology of EMT in Mouse Mammary Tumorigenesis

Epithelial Mesenchymal Transition Traits in Human Breast Cancer Cell Lines Parallel the CD44hi/CD24lo/- Stem Cell Phenotype in Human Breast Cancer

Cell Polarity in Motion: Redefining Mammary Tissue Organization Through EMT and Cell Polarity Transitions

Matrix Metalloproteinase-Induced Epithelial-Mesenchymal Transition in Breast Cancer

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie