Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Abbreviations

α-SMA:

α-smooth muscle actin

BMP:

Bone morphogenic protein

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EMT:

Epithelial-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

FAK:

Focal adhesion kinase

JNK:

c-Jun N-terminal kinase

MAP kinase:

Mitogen-activated protein kinase

MEC:

Mammary epithelial cell

mTOR:

Mammalian target of rapamycin

MET:

Mesenchymal-epithelial transition

MTA3:

Metastasis associated protein 3

NF-κB:

Nuclear factor-κB

PAI:

Plasminogen activator inhibitor

PDGF:

Platelet-derived growth factor

PI3K:

Phosphoinositide-3-kinase

TβR-I:

TGF-β type I receptor

TβR-II:

TGF-β type II receptor

TβR-III:

TGF-β type III receptor

TGF-β:

Transforming growth factor-β

uPA:

Urokinase plasminogen activator

uPAR:

uPA receptor

ZO-1:

Zonula occluden-1

References

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. 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.

    CAS  PubMed  Google Scholar 

  6. 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.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of the Schiemann Laboratory for critical comments and reading of the manuscript. W.P.S. was supported by grants from the National Institutes of Health (CA114039 and CA129359), the Komen Foundation (BCTR0706967), and the Department of Defense (BC084651), while M.A.T. was supported by the Department of Defense (BC093128).

Author information

Authors and Affiliations

  1. Case Comprehensive Cancer Center, Case Western Reserve University, Wolstein Research Building, Room 2131, 2103 Cornell Road, Cleveland, OH, 44106, USA

    Molly A. Taylor, Jenny G. Parvani & William P. Schiemann

Authors
  1. Molly A. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jenny G. Parvani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. William P. Schiemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William P. Schiemann.

Additional information

Financial Support

W.P.S. was supported by grants from the National Institutes of Health (CA114039 and CA129359), the Komen Foundation (BCTR0706967), and the Department of Defense (BC084651), while M.A.T. was supported by the Department of Defense (BC093128).

M. A. Taylor and J. G. Parvani were equal contributors to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taylor, M.A., Parvani, J.G. & Schiemann, W.P. The Pathophysiology of Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β in Normal and Malignant Mammary Epithelial Cells. J Mammary Gland Biol Neoplasia 15, 169–190 (2010). https://doi.org/10.1007/s10911-010-9181-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-010-9181-1

Keywords

Search

Navigation