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Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer?

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Abstract

In most human breast cancers, lowering of TGFβ receptor- or Smad gene expression combined with increased levels of TGFβs in the tumor microenvironment is sufficient to abrogate TGFβs tumor suppressive effects and to induce a mesenchymal, motile and invasive phenotype. In genetic mouse models, TGFβ signaling suppresses de novo mammary cancer formation but promotes metastasis of tumors that have broken through TGFβ tumor suppression. In mouse models of “triple-negative” or basal-like breast cancer, treatment with TGFβ neutralizing antibodies or receptor kinase inhibitors strongly inhibits development of lung- and bone metastases. These TGFβ antagonists do not significantly affect tumor cell proliferation or apoptosis. Rather, they de-repress anti-tumor immunity, inhibit angiogenesis and reverse the mesenchymal, motile, invasive phenotype characteristic of basal-like and HER2-positive breast cancer cells. Patterns of TGFβ target genes upregulation in human breast cancers suggest that TGFβ may drive tumor progression in estrogen-independent cancer, while it mediates a suppressive host cell response in estrogen-dependent luminal cancers. In addition, TGFβ appears to play a key role in maintaining the mammary epithelial (cancer) stem cell pool, in part by inducing a mesenchymal phenotype, while differentiated, estrogen receptor-positive, luminal cells are unresponsive to TGFβ because the TGFBR2 receptor gene is transcriptionally silent. These same cells respond to estrogen by downregulating TGFβ, while antiestrogens act by upregulating TGFβ. This model predicts that inhibiting TGFβ signaling should drive the differentiation of mammary stem cells into ductal cells. Consequently, TGFβ antagonists may convert basal-like or HER2-positive cancers to a more epithelioid, non-proliferating (and, perhaps, non-metastatic) phenotype. Conversely, these agents might antagonize the therapeutic effects of anti-estrogens in estrogen-dependent luminal cancers. These predictions need to be addressed prospectively in clinical trials and should inform the selection of patient populations most likely to benefit from this novel anti-metastatic therapeutic approach.

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Abbreviations

4-OH-T:

4-Hydroxy-tamoxifen

ATM:

Ataxia teleangiectasia mutated protein

CIC:

Cancer initiating cells

DC:

Dendritic cells

DMBA:

7,12-Dimethylbenz[α]anthracene

DNTβRII:

Dominant negative TGFβ type II receptor

EMT:

Epithelial to mesenchymal transition

ER:

Estrogen receptor

EST:

Expressed sequence tag

Fc:TβRII:

Fc-soluble TGFβ type II receptor fusion protein

HMEC:

Human mammary epithelial cells

IHC:

Immunohistochemistry

MMTV:

Mouse mammary tumor virus

NK:

Natural killer cells

PBMC:

Peripheral blood mononuclear cells

PR:

Progesterone receptor

PyVmT:

Polyoma virus middle T antigen

TBRS:

TGFβ response gene signature

TGFBR1 :

TGFβ type I receptor gene

TGFBR2 :

TGFβ type II receptor gene

TGFα:

Transforming growth factor-α

TGFβ:

Transforming growth factor-β

TPA:

12-Tetradecanoyl-phorbol-13-acetate

TβR:

TGFβ receptor

WAP:

Whey acidic protein

References

  1. Roberts AB, Sporn MB (1993) Physiological actions and clinical applications of transforming growth factor-beta (TGF-beta). Growth Factors 8(1):1–9

    CAS  PubMed  Google Scholar 

  2. Wakefield LM, Smith DM, Flanders KC, Sporn MB (1988) Latent transforming growth factor-beta from human platelets. A high molecular weight complex containing precursor sequences. J Biol Chem 263:7646–7654

    CAS  PubMed  Google Scholar 

  3. Wakefield LM, Smith DM, Masui T, Harris CC, Sporn MB (1987) Distribution and modulation of the cellular receptor for transforming growth factor-beta. J Cell Biol 105(2):965–975. doi:10.1083/jcb.105.2.965

    Article  CAS  PubMed  Google Scholar 

  4. Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 116(Pt 2):217–224. doi:10.1242/jcs.00229

    Article  CAS  PubMed  Google Scholar 

  5. Massague J, Chen YG (2000) Controlling TGF-beta signaling. Genes Dev 14(6):627–644

    CAS  PubMed  Google Scholar 

  6. Bharathy S, Xie W, Yingling JM, Reiss M (2008) Cancer-associated transforming growth factor beta type II receptor gene mutant causes activation of bone morphogenic protein-Smads and invasive phenotype. Cancer Res 68(6):1656–1666. doi:10.1158/0008-5472.CAN-07-5089

    Article  CAS  PubMed  Google Scholar 

  7. Konig HG, Kogel D, Rami A, Prehn JH (2005) TGF-{beta}1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling. J Cell Biol 168(7):1077–1086. doi:10.1083/jcb.200407027

    Article  PubMed  CAS  Google Scholar 

  8. Lebrin F, Deckers M, Bertolino P, Ten Dijke P (2005) TGF-beta receptor function in the endothelium. Cardiovasc Res 65(3):599–608. doi:10.1016/j.cardiores.2004.10.036

    Article  CAS  PubMed  Google Scholar 

  9. Daly AC, Randall RA, Hill CS (2008) TGF-β-induced Smad1/5 phosphorylation in epithelial cells is mediated by novel receptor complexes and is essential for anchorage-independent growth. Mol Cell Biol. doi:10.1128/MCB.01192-08

    Google Scholar 

  10. Massague J, Chen Y-G (2000) Controlling TGF-β signaling. Genes Dev 14:627–644

    CAS  PubMed  Google Scholar 

  11. Cui W, Fowlis DJ, Cousins FM, Duffie E, Bryson S, Balmain A et al (1995) Concerted action of TGF-beta 1 and its type II receptor in control of epidermal homeostasis in transgenic mice. Genes Dev 9(8):945–955. doi:10.1101/gad.9.8.945

    Article  CAS  PubMed  Google Scholar 

  12. Glick AB, Kulkarni AB, Tennenbaum T, Hennings H, Flanders KC, O’Reilly M et al (1993) Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc Natl Acad Sci USA 90(13):6076–6080. doi:10.1073/pnas.90.13.6076

    Article  CAS  PubMed  Google Scholar 

  13. Glick AB, Weinberg WC, Wu IH, Quan W, Yuspa SH (1996) Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. Cancer Res 56(16):3645–3650 Published erratum appears in Cancer Res 1997 May 15;57(10):2079

    CAS  PubMed  Google Scholar 

  14. Ge R, Rajeev V, Subramanian G, Reiss KA, Liu D, Higgins L et al (2004) Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling. Biochem Pharmacol 68(1):41–50. doi:10.1016/j.bcp.2004.03.011

    Article  CAS  PubMed  Google Scholar 

  15. Xie W, Mertens JC, Reiss DJ, Rimm DL, Camp RL, Haffty BG et al (2002) Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. Cancer Res 62(2):497–505

    CAS  PubMed  Google Scholar 

  16. Xie W, Kim D, Haffty BG, Rimm DL, Reiss M (2003) Frequent alterations of Smad signaling in human head-&-neck squamous cell carcinomas-a tissue microarray analysis. Oncol Res 14:61–73

    CAS  PubMed  Google Scholar 

  17. Xie W, Rimm DL, Lin Y, Shih WJ, Reiss M (2003) Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis. Cancer J 9(4):302–312. doi:10.1097/00130404-200307000-00013

    Article  CAS  PubMed  Google Scholar 

  18. Sterner-Kock A, Thorey IS, Koli K, Wempe F, Otte J, Bangsow T et al (2002) Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. Genes Dev 16(17):2264–2273. doi:10.1101/gad.229102

    Article  CAS  PubMed  Google Scholar 

  19. Faure E, Heisterkamp N, Groffen J, Kaartinen V (2000) Differential expression of TGF-beta isoforms during postlactational mammary gland involution. Cell Tissue Res 300(1):89–95

    CAS  PubMed  Google Scholar 

  20. D’Cruz CM, Moody SE, Master SR, Hartman JL, Keiper EA, Imielinski MB (2002) Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol Endocrinol (Baltimore, MD) 16(9):2034–2051

    Article  CAS  Google Scholar 

  21. Yang YA, Tang B, Robinson G, Hennighausen L, Brodie SG, Deng CX et al (2002) Smad3 in the mammary epithelium has a nonredundant role in the induction of apoptosis, but not in the regulation of proliferation or differentiation by transforming growth factor-beta. Cell Growth Differ 13(3):123–130

    CAS  PubMed  Google Scholar 

  22. Kirshner J, Jobling MF, Pajares MJ, Ravani SA, Glick AB, Lavin MJ et al (2006) Inhibition of transforming growth factor-beta1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress. Cancer Res 66(22):10861–10869. doi:10.1158/0008-5472.CAN-06-2565

    Article  CAS  PubMed  Google Scholar 

  23. Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL et al (2007) Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest 117(5):1305–1313. doi:10.1172/JCI30740

    Article  CAS  PubMed  Google Scholar 

  24. Ewan KB, Henshall-Powell RL, Ravani SA, Pajares MJ, Arteaga C, Warters R et al (2002) Transforming growth factor-beta1 mediates cellular response to DNA damage in situ. Cancer Res 62(20):5627–5631

    CAS  PubMed  Google Scholar 

  25. Andarawewa KL, Paupert J, Pal A, Barcellos-Hoff MH (2007) New rationales for using TGFbeta inhibitors in radiotherapy. Int J Radiat Biol 83(11–12):803–811. doi:10.1080/09553000701711063

    Article  CAS  PubMed  Google Scholar 

  26. Li MO, Flavell RA (2008) TGF-beta: a master of all T cell trades. Cell 134(3):392–404. doi:10.1016/j.cell.2008.07.025

    Article  CAS  PubMed  Google Scholar 

  27. Li MO, Sanjabi S, Flavell RA (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25(3):455–471. doi:10.1016/j.immuni.2006.07.011

    Article  CAS  PubMed  Google Scholar 

  28. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146. doi:10.1146/annurev.immunol.24.021605.090737

    Article  CAS  PubMed  Google Scholar 

  29. Li MO, Flavell RA (2008) Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity 28(4):468–476. doi:10.1016/j.immuni.2008.03.003

    Article  PubMed  CAS  Google Scholar 

  30. Wan YY, Flavell RA (2007) ‘Yin-Yang’ functions of transforming growth factor-beta and T regulatory cells in immune regulation. Immunol Rev 220(1):199–213. doi:10.1111/j.1600-065X.2007.00565.x

    Article  CAS  PubMed  Google Scholar 

  31. Wrzesinski SH, Wan YY, Flavell RA (2007) Transforming growth factor-{beta} and the immune response: implications for anticancer therapy. Clin Cancer Res 13(18):5262–5270. doi:10.1158/1078-0432.CCR-07-1157

    Article  CAS  PubMed  Google Scholar 

  32. Maharaj AS, Walshe TE, Saint-Geniez M, Venkatesha S, Maldonado AE, Himes NC et al (2008) VEGF and TGF-beta are required for the maintenance of the choroid plexus and ependyma. J Exp Med 205(2):491–501. doi:10.1084/jem.20072041

    Article  CAS  PubMed  Google Scholar 

  33. Stuhrmann M, El-Harith el-HA (2007) Hereditary hemorrhagic telangiectasia. genetics, pathogenesis, clinical manifestation and management. Saudi Med J 28(1):11–21

    PubMed  Google Scholar 

  34. Fernandez LA, Sanz-Rodriguez F, Blanco FJ, Bernabeu C, Botella LM (2006) Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway. Clin Med Res 4(1):66–78

    Article  Google Scholar 

  35. Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H et al (2006) Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 355(8):788–798. doi:10.1056/NEJMoa055695

    Article  CAS  PubMed  Google Scholar 

  36. Goumans MJ, Lebrin F, Valdimarsdottir G (2003) Controlling the angiogenic switch: a balance between two distinct TGF-b receptor signaling pathways. Trends Cardiovasc Med 13(7):301–307. doi:10.1016/S1050-1738(03)00142-7

    Article  CAS  PubMed  Google Scholar 

  37. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70. doi:10.1016/S0092-8674(00)81683-9

    Article  CAS  PubMed  Google Scholar 

  38. Roberts AB, Piek E, Bottinger EP, Ashcroft G, Mitchell JB, Flanders KC (2001) Is Smad3 a major player in signal transduction pathways leading to fibrogenesis? Chest 120(Suppl 1):43S–47S. doi:10.1378/chest.120.1_suppl.S43-a

    Article  CAS  PubMed  Google Scholar 

  39. Barcellos-Hoff MH (1998) How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues. Radiat Res 150(Suppl 5):S109–S120. doi:10.2307/3579813

    Article  CAS  PubMed  Google Scholar 

  40. Border WA, Noble NA (1994) Transforming growth factor β in tissue fibrosis. N Engl J Med 331:1286–1292. doi:10.1056/NEJM199411103311907

    Article  CAS  PubMed  Google Scholar 

  41. Branton MH, Kopp JB (1999) TGF-beta and fibrosis. Microbes Infect 1(15):1349–1365. doi:10.1016/S1286-4579(99)00250-6

    Article  CAS  PubMed  Google Scholar 

  42. Massague J (2008) TGFbeta in cancer. Cell 134(2):215–230. doi:10.1016/j.cell.2008.07.001

    Article  CAS  PubMed  Google Scholar 

  43. Tang B, Bottinger EP, Jakowlew SB, Bagnall KM, Mariano J, Anver MR et al (1998) Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat Med 4(7):802–807. doi:10.1038/nm0798-802

    Article  CAS  PubMed  Google Scholar 

  44. Ewan KB, Shyamala G, Ravani SA, Tang Y, Akhurst R, Wakefield L et al (2002) Latent transforming growth factor-beta activation in mammary gland: regulation by ovarian hormones affects ductal and alveolar proliferation. Am J Pathol 160(6):2081–2093

    CAS  PubMed  Google Scholar 

  45. Yang YA, Dukhanina O, Tang B, Mamura M, Letterio JJ, MacGregor J et al (2002) Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest 109(12):1607–1615

    CAS  PubMed  Google Scholar 

  46. Gorska AE, Joseph H, Derynck R, Moses HL, Serra R (1998) Dominant-negative interference of the transforming growth factor beta type II receptor in mammary gland epithelium results in alveolar hyperplasia and differentiation in virgin mice. Cell Growth Differ 9(3):229–238

    CAS  PubMed  Google Scholar 

  47. Lenferink AE, Magoon J, Pepin MC, Guimond A, O’Connor-McCourt MD (2003) Expression of TGF-beta type II receptor antisense RNA impairs TGF-beta signaling in vitro and promotes mammary gland differentiation in vivo. Int J Cancer 107(6):919–928. doi:10.1002/ijc.11494

    Article  CAS  PubMed  Google Scholar 

  48. Gorska AE, Jensen RA, Shyr Y, Aakre ME, Bhowmick NA, Moses HL (2003) Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. Am J Pathol 163(4):1539–1549

    CAS  PubMed  Google Scholar 

  49. Forrester E, Chytil A, Bierie B, Aakre M, Gorska AE, Sharif-Afshar AR et al (2005) Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res 65(6):2296–2302. doi:10.1158/0008-5472.CAN-04-3272

    Article  CAS  PubMed  Google Scholar 

  50. Reiss M (1999) TGF-beta and cancer. Microbes Infect 1(15):1327–1347. doi:10.1016/S1286-4579(99)00251-8

    Article  CAS  PubMed  Google Scholar 

  51. Gold LI (1999) The role for transforming growth factor-beta (TGF-beta) in human cancer. Crit Rev Oncog 10(4):303–360 (In Process Citation)

    CAS  PubMed  Google Scholar 

  52. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S et al (2004) TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303(5659):848–851. doi:10.1126/science.1090922

    Article  CAS  PubMed  Google Scholar 

  53. Bierie B, Stover DG, Abel TW, Chytil A, Gorska AE, Aakre M et al (2008) Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. Cancer Res 68(6):1809–1819. doi:10.1158/0008-5472.CAN-07-5597

    Article  CAS  PubMed  Google Scholar 

  54. Minn AJ, Gupta GP, Padua D, Bos P, Nguyen DX, Nuyten D et al (2007) Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci USA 104(16):6740–6745. doi:10.1073/pnas.0701138104

    Article  CAS  PubMed  Google Scholar 

  55. Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M et al (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13(1):23–35. doi:10.1016/j.ccr.2007.12.004

    Article  CAS  PubMed  Google Scholar 

  56. Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z et al (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8(5):R76. doi:10.1186/gb-2007-8-5-r76

    Article  PubMed  CAS  Google Scholar 

  57. Sahai E (2007) Illuminating the metastatic process. Nat Rev Cancer 7(10):737–749. doi:10.1038/nrc2229

    Article  CAS  PubMed  Google Scholar 

  58. Welch DR, Fabra A, Nakajima M (1990) Transforming growth factor β stimulates mammary adenocarcinoma cell invasion and metastatic potential. Proc Natl Acad Sci USA 87:7678–7682. doi:10.1073/pnas.87.19.7678

    Article  CAS  PubMed  Google Scholar 

  59. Lichtner RB, Julian JA, North SM, Glasser SR, Nicolson GL (1991) Coexpression of cytokeratins characteristic for myoepithelial and luminal cell lineages in rat 13762NF mammary adenocarcinoma tumors and their spontaneous metastases. Cancer Res 51(21):5943–5950

    CAS  PubMed  Google Scholar 

  60. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715. doi:10.1016/j.cell.2008.03.027

    Article  CAS  PubMed  Google Scholar 

  61. Pierce DF Jr, Johnson MD, Matsui Y, Robinson SD, Gold LI, Purchio AF et al (1993) Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1. Genes Dev 7(12A):2308–2317. doi:10.1101/gad.7.12a.2308

    Article  CAS  PubMed  Google Scholar 

  62. Pierce DF Jr, Gorska AE, Chytil A, Meise KS, Page DL, Coffey RJ Jr et al (1995) Mammary tumor suppression by transforming growth factor beta 1 transgene expression. Proc Natl Acad Sci USA 92(10):4254–4258. doi:10.1073/pnas.92.10.4254

    Article  CAS  PubMed  Google Scholar 

  63. Booth BW, Jhappan C, Merlino G, Smith GH (2007) TGFbeta1 and TGFalpha contrarily affect alveolar survival and tumorigenesis in mouse mammary epithelium. Int J Cancer 120(3):493–499. doi:10.1002/ijc.22310

    Article  CAS  PubMed  Google Scholar 

  64. Muraoka RS, Koh Y, Roebuck LR, Sanders ME, Brantley-Sieders D, Gorska AE et al (2003) Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor beta1. Mol Cell Biol 23(23):8691–8703. doi:10.1128/MCB.23.23.8691-8703.2003

    Article  CAS  PubMed  Google Scholar 

  65. Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J (2003) Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci USA 100(14):8430–8435. doi:10.1073/pnas.0932636100

    Article  CAS  PubMed  Google Scholar 

  66. Muraoka-Cook RS, Shin I, Yi JY, Easterly E, Barcellos-Hoff MH, Yingling JM et al (2006) Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene 25(24):3408–3423. doi:10.1038/sj.onc.1208964

    Article  CAS  PubMed  Google Scholar 

  67. Kareddula A, Zachariah E, Notterman D, Reiss M (2008) Transforming growth factor-β signaling strength determines target gene expression profile in human keratinocytes. J Epithel Biol Pharmacol 1:40–94

    Article  CAS  Google Scholar 

  68. Piek E, Roberts AB (2001) Suppressor and oncogenic roles of transforming growth factor-beta and its signaling pathways in tumorigenesis. Adv Cancer Res 83:1–54. doi:10.1016/S0065-230X(01)83001-3

    Article  CAS  PubMed  Google Scholar 

  69. Oft M, Heider KH, Beug H (1998) TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 8(23):1243–1252. doi:10.1016/S0960-9822(07)00533-7

    Article  CAS  PubMed  Google Scholar 

  70. Yin JJ, Selander K, Chirgwin JM, Dallas M, Grubbs BG, Wieser R et al (1999) TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 103(2):197–206. doi:10.1172/JCI3523

    Article  CAS  PubMed  Google Scholar 

  71. Dumont N, Arteaga CL (2000) Transforming growth factor-beta and breast cancer: tumor promoting effects of transforming growth factor-beta. Breast Cancer Res 2(2):125–132. doi:10.1186/bcr44

    Article  CAS  PubMed  Google Scholar 

  72. Fynan TM, Reiss M (1993) Resistance to inhibition of cell growth by transforming growth factor-β and its role in oncogenesis. Crit Rev Oncog 4:493–540

    CAS  PubMed  Google Scholar 

  73. Valverius EM, Walker-Jones D, Bates SE, Stampfer MR, Clark R, McCormick F et al (1989) Production of and responsiveness to transforming growth factor-beta in normal and oncogene-transformed human mammary epithelial cells. Cancer Res 49(22):6269–6274

    CAS  PubMed  Google Scholar 

  74. Zugmaier G, Paik S, Wilding G, Knabbe C, Bano M, Lupu R et al (1991) Transforming growth factor β1 induces cachexia and systemic fibrosis without an antitumor effect in nude mice. Cancer Res 51:3590–3594

    CAS  PubMed  Google Scholar 

  75. Arteaga CL, Tandon AK, Von Hoff DD, Osborne CK (1988) Transforming growth factor beta: potential autocrine growth inhibitor of estrogen receptor-negative human breast cancer cells. Cancer Res 48(14):3898–3904

    CAS  PubMed  Google Scholar 

  76. Knabbe C, Lippman ME, Wakefield LM, Flanders KC, Kasid A, Derynck R et al (1987) Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells. Cell 48(3):417–428. doi:10.1016/0092-8674(87)90193-0

    Article  CAS  PubMed  Google Scholar 

  77. Zugmaier G, Ennis BW, Deschauer B, Katz D, Knabbe C, Wilding G et al (1989) Transforming growth factor type β1 and β2 are equipotent growth inhibitors of human breast cancer cell lines. J Cell Physiol 141:353–361. doi:10.1002/jcp.1041410217

    Article  CAS  PubMed  Google Scholar 

  78. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J et al (2007) Molecular definition of breast tumor heterogeneity. Cancer Cell 11(3):259–273. doi:10.1016/j.ccr.2007.01.013

    Article  CAS  PubMed  Google Scholar 

  79. Herman ME, Katzenellenbogen BS (1994) Alterations in transforming growth factor-alpha and -beta production and cell responsiveness during the progression of MCF-7 human breast cancer cells to estrogen-autonomous growth. Cancer Res 54(22):5867–5874

    CAS  PubMed  Google Scholar 

  80. Jeng MH, Jordan VC (1991) Growth stimulation and differential regulation of transforming growth factor-beta 1 (TGF beta 1), TGF beta 2, and TGF beta 3 messenger RNA levels by norethindrone in MCF-7 human breast cancer cells. Mol Endocrinol (Baltimore, MD) 5(8):1120–1128

    Article  CAS  Google Scholar 

  81. Jeng MH, ten Dijke P, Iwata KK, Jordan VC (1993) Regulation of the levels of three transforming growth factor beta mRNAs by estrogen and their effects on the proliferation of human breast cancer cells. Mol Cell Endocrinol 97(1–2):115–123. doi:10.1016/0303-7207(93)90217-8

    Article  CAS  PubMed  Google Scholar 

  82. Manni A, Wright C, Buck H (1991) Growth factor involvement in the multihormonal regulation of MCF-7 breast cancer cell growth in soft agar. Breast Cancer Res Treat 20(1):43–52. doi:10.1007/BF01833356

    Article  CAS  PubMed  Google Scholar 

  83. Ge R, Rajeev V, Ray P, Lattime E, Rittling S, Medicherla S et al (2006) Inhibition of growth and metastasis of mouse mammary carcinoma by selective inhibitor of transforming growth factor-beta type I receptor kinase in vivo. Clin Cancer Res 12(14 Pt 1):4315–4330. doi:10.1158/1078-0432.CCR-06-0162

    Article  CAS  PubMed  Google Scholar 

  84. Miettinen PJ, Ebner R, Lopez AR, Derynck R (1994) TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 127(6 Pt 2):2021–2036. doi:10.1083/jcb.127.6.2021

    Article  CAS  PubMed  Google Scholar 

  85. Piek E, Moustakas A, Kurisaki A, Heldin CH, ten Dijke P (1999) TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci 112(Pt 24):4557–4568

    CAS  PubMed  Google Scholar 

  86. Buck M, Der Fecht JV, Knabbe C (2002) Antiestrogenic regulation of transforming growth factor beta receptors I and II in human breast cancer cells. Ann N Y Acad Sci 963:140–143

    CAS  PubMed  Google Scholar 

  87. Knabbe C, Kopp A, Hilgers W, Lang D, Muller V, Zugmaier G et al (1996) Regulation and role of TGF beta production in breast cancer. Ann N Y Acad Sci 784:263–276. doi:10.1111/j.1749-6632.1996.tb16241.x

    Article  CAS  PubMed  Google Scholar 

  88. Pink JJ, Bilimoria MM, Assikis J, Jordan VC (1996) Irreversible loss of the oestrogen receptor in T47D breast cancer cells following prolonged oestrogen deprivation. Br J Cancer 74(8):1227–1236

    CAS  PubMed  Google Scholar 

  89. Knabbe C, Zugmaier G, Schmahl M, Dietel M, Lippman ME, Dickson RB (1991) Induction of transforming growth factor beta by the antiestrogens droloxifene, tamoxifen, and toremifene in MCF-7 cells. Am J Clin Oncol 14(Suppl 2):S15–S20. doi:10.1097/00000421-199112002-00005

    Article  PubMed  Google Scholar 

  90. Muller V, Jensen EV, Knabbe C (1998) Partial antagonism between steroidal and nonsteroidal antiestrogens in human breast cancer cell lines. Cancer Res 58(2):263–267

    CAS  PubMed  Google Scholar 

  91. Buck MB, Coller JK, Murdter TE, Eichelbaum M, Knabbe C (2008) TGFbeta2 and TbetaRII are valid molecular biomarkers for the antiproliferative effects of tamoxifen and tamoxifen metabolites in breast cancer cells. Breast Cancer Res Treat 107(1):15–24. doi:10.1007/s10549-007-9526-7

    Article  CAS  PubMed  Google Scholar 

  92. Kopp A, Jonat W, Schmahl M, Knabbe C (1995) Transforming growth factor beta 2 (TGF-beta 2) levels in plasma of patients with metastatic breast cancer treated with tamoxifen. Cancer Res 55(20):4512–4515

    CAS  PubMed  Google Scholar 

  93. MacCallum J, Keen JC, Bartlett JM, Thompson AM, Dixon JM, Miller WR (1996) Changes in expression of transforming growth factor beta mRNA isoforms in patients undergoing tamoxifen therapy. Br J Cancer 74(3):474–478

    CAS  PubMed  Google Scholar 

  94. Butta A, MacLennan K, Flanders KC, Sacks NP, Smith I, McKinna A et al (1992) Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res 52(15):4261–4264

    CAS  PubMed  Google Scholar 

  95. Morena AM, Oshima CT, Gebrim LH, Egami MI, Silva MR, Segreto RA et al (2004) Early nuclear alterations and immunohistochemical expression of Ki-67, Erb-B2, vascular endothelial growth factor (VEGF), transforming growth factor (TGF-beta1) and integrine-linked kinase (ILK) two days after tamoxifen in breast carcinoma. Neoplasma 51(6):481–486

    CAS  PubMed  Google Scholar 

  96. Colletta AA, Wakefield LM, Howell FV, van Roozendaal KE, Danielpour D, Ebbs SR et al (1990) Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts. Br J Cancer 62(3):405–409

    CAS  PubMed  Google Scholar 

  97. Colletta AA, Benson JR, Baum M (1994) Alternative mechanisms of action of anti-oestrogens. Breast Cancer Res Treat 31(1):5–9. doi:10.1007/BF00689672

    Article  CAS  PubMed  Google Scholar 

  98. van Roozendaal CE, Klijn JG, van Ooijen B, Claassen C, Eggermont AM, Henzen-Logmans SC et al (1995) Transforming growth factor beta secretion from primary breast cancer fibroblasts. Mol Cell Endocrinol 111(1):1–6. doi:10.1016/0303-7207(95)03539-J

    Article  PubMed  Google Scholar 

  99. Thompson AM, Kerr DJ, Steel CM (1991) Transforming growth factor beta 1 is implicated in the failure of tamoxifen therapy in human breast cancer. Br J Cancer 63(4):609–614

    CAS  PubMed  Google Scholar 

  100. Arteaga CL, Koli KM, Dugger TC, Clarke R (1999) Reversal of tamoxifen resistance of human breast carcinomas in vivo by neutralizing antibodies to transforming growth factor-beta. J Natl Cancer Inst 91(1):46–53. doi:10.1093/jnci/91.1.46

    Article  CAS  PubMed  Google Scholar 

  101. McEarchern JA, Kobie JJ, Mack V, Wu RS, Meade-Tollin L, Arteaga CL et al (2001) Invasion and metastasis of a mammary tumor involves TGF-beta signaling. Int J Cancer 91(1):76–82. doi:10.1002/1097-0215(20010101)91:1<76::AID-IJC1012>3.0.CO;2-8

    Article  CAS  PubMed  Google Scholar 

  102. Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR et al (2003) TGF-{beta} switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest 112(7):1116–1124

    CAS  PubMed  Google Scholar 

  103. Kang Y, He W, Tulley S, Gupta GP, Serganova I, Chen CR et al (2005) Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci USA 102(39):13909–13914. doi:10.1073/pnas.0506517102

    Article  CAS  PubMed  Google Scholar 

  104. Deckers M, van Dinther M, Buijs J, Que I, Lowik C, van der Pluijm G et al (2006) The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res 66(4):2202–2209. doi:10.1158/0008-5472.CAN-05-3560

    Article  CAS  PubMed  Google Scholar 

  105. Kakonen SM, Selander KS, Chirgwin JM, Yin JJ, Burns S, Rankin WA et al (2002) Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. J Biol Chem 277(27):24571–24578. doi:10.1074/jbc.M202561200

    Article  CAS  PubMed  Google Scholar 

  106. Tian F, DaCosta Byfield S, Parks WT, Yoo S, Felici A, Tang B et al (2003) Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res 63(23):8284–8292

    CAS  PubMed  Google Scholar 

  107. Kang Y (2006) New tricks against an old foe: molecular dissection of metastasis tissue tropism in breast cancer. Breast Dis 26:129–138

    CAS  PubMed  Google Scholar 

  108. Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3(6):537–549. doi:10.1016/S1535-6108(03)00132-6

    Article  CAS  PubMed  Google Scholar 

  109. Kang Y (2004) Breast cancer bone metastasis: molecular basis of tissue tropism. J Musculoskelet Neuronal Interact 4(4):379–380

    CAS  PubMed  Google Scholar 

  110. Guise TA (2000) Molecular mechanisms of osteolytic bone metastases. Cancer 88(S12):2892–2898. doi:10.1002/1097-0142(20000615)88:12+<2892::AID-CNCR2>3.0.CO;2-Y

    Article  CAS  PubMed  Google Scholar 

  111. van der Pluijm G, Sijmons B, Vloedgraven H, Deckers M, Papapoulos S, Lowik C (2001) Monitoring metastatic behavior of human tumor cells in mice with species-specific polymerase chain reaction: elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. J Bone Miner Res 16(6):1077–1091. doi:10.1359/jbmr.2001.16.6.1077

    Article  PubMed  Google Scholar 

  112. Carano R, Li Y, Bao M, Li J, Berry L, Ross J et al (2004) Effect of anti-TGF-beta antibodies in syngeneic mouse models of metastasis. J Musculoskelet Neuronal Interact 4(4):377–378

    CAS  PubMed  Google Scholar 

  113. Hiraga T, Myoui A, Choi ME, Yoshikawa H, Yoneda T (2006) Stimulation of cyclooxygenase-2 expression by bone-derived transforming growth factor-beta enhances bone metastases in breast cancer. Cancer Res 66(4):2067–2073. doi:10.1158/0008-5472.CAN-05-2012

    Article  CAS  PubMed  Google Scholar 

  114. Yin JJ, Mohammad KS, Kakonen SM, Harris S, Wu-Wong JR, Wessale JL et al (2003) A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases. Proc Natl Acad Sci USA 100(19):10954–10959. doi:10.1073/pnas.1830978100

    Article  CAS  PubMed  Google Scholar 

  115. Guise TA, Yin JJ, Mohammad KS (2003) Role of endothelin-1 in osteoblastic bone metastases. Cancer 97(Suppl 3):779–784. doi:10.1002/cncr.11129

    Article  PubMed  Google Scholar 

  116. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM (2005) Molecular mechanisms of breast cancer metastases to bone. Clin Breast Cancer 5(Suppl 2):S46–S53

    Article  CAS  PubMed  Google Scholar 

  117. Lee SD, Lee DS, Chun YG, Paik SH, Kim WS, Kim DS et al (2000) Transforming growth factor-beta1 induces endothelin-1 in a bovine pulmonary artery endothelial cell line and rat lungs via cAMP. Pulm Pharmacol Ther 13(6):257–265. doi:10.1006/pupt.2000.0252

    Article  CAS  PubMed  Google Scholar 

  118. Trompezinski S, Pernet I, Mayoux C, Schmitt D, Viac J (2000) Transforming growth factor-beta1 and ultraviolet A1 radiation increase production of vascular endothelial growth factor but not endothelin-1 in human dermal fibroblasts. Br J Dermatol 143(3):539–545. doi:10.1111/j.1365-2133.2000.03707.x

    Article  CAS  PubMed  Google Scholar 

  119. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436(7050):518–524. doi:10.1038/nature03799

    Article  CAS  PubMed  Google Scholar 

  120. Gupta GP, Nguyen DX, Chiang AC, Bos PD, Kim JY, Nadal C et al (2007) Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446(7137):765–770. doi:10.1038/nature05760

    Article  CAS  PubMed  Google Scholar 

  121. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J et al (2002) Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156(2):299–313. doi:10.1083/jcb.200109037

    Article  CAS  PubMed  Google Scholar 

  122. Seton-Rogers SE, Brugge JS (2004) ErbB2 and TGF-beta: a cooperative role in mammary tumor progression? Cell Cycle 3(5):597–600

    CAS  PubMed  Google Scholar 

  123. Seton-Rogers SE, Lu Y, Hines LM, Koundinya M, LaBaer J, Muthuswamy SK et al (2004) Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci USA 101(5):1257–1262. doi:10.1073/pnas.0308090100

    Article  CAS  PubMed  Google Scholar 

  124. Ueda Y, Wang S, Dumont N, Yi JY, Koh Y, Arteaga CL (2004) Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. J Biol Chem 279(23):24505–24513. doi:10.1074/jbc.M400081200

    Article  CAS  PubMed  Google Scholar 

  125. Northey JJ, Chmielecki J, Ngan E, Russo C, Annis MG, Muller WJ et al (2008) Signaling through ShcA is required for transforming growth factor beta- and Neu/ErbB-2-induced breast cancer cell motility and invasion. Mol Cell Biol 28(10):3162–3176. doi:10.1128/MCB.01734-07

    Article  CAS  PubMed  Google Scholar 

  126. Reiss M (2008) Transforming growth factor-β in metastasis: in vitro and in vivo mechanisms. In: Jakowlew SB (ed) Transforming growth factor-beta in cancer therapy. The Humana, Totowa, pp 609–634

    Google Scholar 

  127. Arteaga CL (2006) Inhibition of TGFbeta signaling in cancer therapy. Curr Opin Genet Dev 16(1):30–37. doi:10.1016/j.gde.2005.12.009

    Article  CAS  PubMed  Google Scholar 

  128. Yingling JM, Blanchard KL, Sawyer JS (2004) Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov 3(12):1011–1022. doi:10.1038/nrd1580

    Article  CAS  PubMed  Google Scholar 

  129. MacCallum J, Bartlett JM, Thompson AM, Keen JC, Dixon JM, Miller WR (1994) Expression of transforming growth factor beta mRNA isoforms in human breast cancer. Br J Cancer 69(6):1006–1009

    CAS  PubMed  Google Scholar 

  130. Travers MT, Barrett-Lee PJ, Berger U, Luqmani YA, Gazet JC, Powles TJ et al (1988) Growth factor expression in normal, benign, and malignant breast tissue. Br Med J (Clin Res Ed) 296(6637):1621–1624

    Article  CAS  Google Scholar 

  131. Walker RA, Dearing SJ (1992) Transforming growth factor beta 1 in ductal carcinoma in situ and invasive carcinomas of the breast. Eur J Cancer 28:641–644. doi:10.1016/S0959-8049(05)80116-9

    Article  CAS  PubMed  Google Scholar 

  132. McCune BK, Mullin BR, Flanders KC, Jaffurs WJ, Mullen LT, Sporn MB (1992) Localization of transforming growth factor-beta isotypes in lesions of the human breast. Hum Pathol 23:13–20. doi:10.1016/0046-8177(92)90004-M

    Article  CAS  PubMed  Google Scholar 

  133. Dalal BI, Keown PA, Greenberg AH (1993) Immunocytochemical localization of secreted transforming growth factor-beta 1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma. Am J Pathol 143:381–389

    CAS  PubMed  Google Scholar 

  134. Auvinen P, Lipponen P, Johansson R, Syrjanen K (1995) Prognostic significance of TGF-beta 1 and TGF-beta 2 expressions in female breast cancer. Anticancer Res 15(6B):2627–2631

    CAS  PubMed  Google Scholar 

  135. de Jong JS, van Diest PJ, van der Valk P, Baak JP (1998) Expression of growth factors, growth inhibiting factors, and their receptors in invasive breast cancer. I: an inventory in search of autocrine and paracrine loops. J Pathol 184(1):44–52. doi:10.1002/(SICI)1096-9896(199801)184:1<44::AID-PATH984>3.0.CO;2-H

    Article  PubMed  Google Scholar 

  136. Gorsch SM, Memoli VA, Stukel TA, Gold LI, Arrick BA (1992) Immunohistochemical staining for transforming growth factor beta 1 associates with disease progression in human breast cancer. Cancer Res 52(24):6949–6952

    CAS  PubMed  Google Scholar 

  137. Sminia P, Barten AD, van Waarde MA, Vujaskovic Z, van Tienhoven G (1998) Plasma transforming growth factor beta levels in breast cancer patients. Oncol Rep 5(2):485–488

    CAS  PubMed  Google Scholar 

  138. Sheen-Chen SM, Chen HS, Sheen CW, Eng HL, Chen WJ (2001) Serum levels of transforming growth factor beta1 in patients with breast cancer. Arch Surg 136(8):937–940. doi:10.1001/archsurg.136.8.937

    Article  CAS  PubMed  Google Scholar 

  139. Kong FM, Anscher MS, Murase T, Abbott BD, Iglehart JD, Jirtle RL (1995) Elevated plasma transforming growth factor-beta 1 levels in breast cancer patients decrease after surgical removal of the tumor. Ann Surg 222(2):155–162. doi:10.1097/00000658-199508000-00007

    Article  CAS  PubMed  Google Scholar 

  140. Grau AM, Wen W, Ramroopsingh DS, Gao YT, Zi J, Cai Q et al (2007) Circulating transforming growth factor-beta-1 and breast cancer prognosis: results from the Shanghai breast cancer study. Breast Cancer Res Treat 106:205–213

    Article  CAS  Google Scholar 

  141. Baselga J, Rothenberg ML, Tabernero J, Seoane J, Daly T, Cleverly A et al (2008) TGF-beta signalling-related markers in cancer patients with bone metastasis. Biomarkers 13(2):217–236. doi:10.1080/13547500701676019

    Article  CAS  PubMed  Google Scholar 

  142. Chakravarthy D, Green AR, Green VL, Kerin MJ, Speirs V (1999) Expression and secretion of TGF-beta isoforms and expression of TGF- beta-receptors I, II and III in normal and neoplastic human breast. Int J Oncol 15(1):187–194

    CAS  PubMed  Google Scholar 

  143. Gobbi H, Dupont WD, Simpson JF, Plummer WD Jr, Schuyler PA, Olson SJ et al (1999) Transforming growth factor-beta and breast cancer risk in women with mammary epithelial hyperplasia. J Natl Cancer Inst 91(24):2096–2101. doi:10.1093/jnci/91.24.2096

    Article  CAS  PubMed  Google Scholar 

  144. Gobbi H, Arteaga CL, Jensen RA, Simpson JF, Dupont WD, Olson SJ et al (2000) Loss of expression of transforming growth factor beta type II receptor correlates with high tumour grade in human breast in-situ and invasive carcinomas. Histopathology 36(2):168–177. doi:10.1046/j.1365-2559.2000.00841.x

    Article  CAS  PubMed  Google Scholar 

  145. Buck MB, Fritz P, Dippon J, Zugmaier G, Knabbe C (2004) Prognostic significance of transforming growth factor beta receptor II in estrogen receptor-negative breast cancer patients. Clin Cancer Res 10(2):491–498. doi:10.1158/1078-0432.CCR-0320-03

    Article  CAS  PubMed  Google Scholar 

  146. Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F et al (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365(9460):671–679

    CAS  PubMed  Google Scholar 

  147. Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR et al (2008) TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133(1):66–77. doi:10.1016/j.cell.2008.01.046

    Article  CAS  PubMed  Google Scholar 

  148. Takenoshita S, Mogi A, Tani M, Osawa H, Sunaga H, Kakegawa H et al (1998) Absence of mutations in the analysis of coding sequences of the entire transforming growth factor-beta type II receptor gene in sporadic human breast cancers. Oncol Rep 5(2):367–371

    CAS  PubMed  Google Scholar 

  149. Chen T, Carter D, Garrigue-Antar L, Reiss M (1998) Transforming growth factor beta type I receptor kinase mutant associated with metastatic breast cancer. Cancer Res 58(21):4805–4810

    CAS  PubMed  Google Scholar 

  150. Lucke CD, Philpott A, Metcalfe JC, Thompson AM, Hughes-Davies L, Kemp PR et al (2001) Inhibiting mutations in the transforming growth factor beta type 2 receptor in recurrent human breast cancer. Cancer Res 61(2):482–485

    CAS  PubMed  Google Scholar 

  151. Baxter SW, Choong DY, Eccles DM, Campbell IG (2002) Transforming growth factor beta receptor 1 polyalanine polymorphism and exon 5 mutation analysis in breast and ovarian cancer. Cancer Epidemiol Biomarkers Prev 11(2):211–214

    CAS  PubMed  Google Scholar 

  152. Kang JS, Saunier EF, Akhurst RJ, Derynck R (2008) The type I TGF- β receptor is covalently modified and regulated by sumoylation. Nat Cell Biol 10(6):654–664

    Article  CAS  PubMed  Google Scholar 

  153. Stuelten CH, Buck MB, Dippon J, Roberts AB, Fritz P, Knabbe C (2006) Smad4-expression is decreased in breast cancer tissues: a retrospective study. BMC Cancer 6:25. doi:10.1186/1471-2407-6-25

    Article  PubMed  CAS  Google Scholar 

  154. Jeruss JS, Sturgis CD, Rademaker AW, Woodruff TK (2003) Down-regulation of activin, activin receptors, and Smads in high-grade breast cancer. Cancer Res 63(13):3783–3790

    CAS  PubMed  Google Scholar 

  155. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988. doi:10.1073/pnas.0530291100

    Article  CAS  PubMed  Google Scholar 

  156. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567. doi:10.1016/j.stem.2007.08.014

    Article  CAS  PubMed  Google Scholar 

  157. Kakarala M, Wicha MS (2008) Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol 26(17):2813–2820. doi:10.1200/JCO.2008.16.3931

    Article  PubMed  Google Scholar 

  158. Fillmore CM, Kuperwasser C (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10(2):R25. doi:10.1186/bcr1982

    Article  PubMed  CAS  Google Scholar 

  159. Horwitz KB, Dye WW, Harrell JC, Kabos P, Sartorius CA (2008) Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts. Proc Natl Acad Sci USA 105(15):5774–5779. doi:10.1073/pnas.0706216105

    Article  CAS  PubMed  Google Scholar 

  160. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T et al (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10(6):515–527. doi:10.1016/j.ccr.2006.10.008

    Article  CAS  PubMed  Google Scholar 

  161. Fillmore C, Kuperwasser C (2007) Human breast cancer stem cell markers CD44 and CD24: enriching for cells with functional properties in mice or in man? Breast Cancer Res 9(3):303. doi:10.1186/bcr1673

    Article  PubMed  CAS  Google Scholar 

  162. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    Article  CAS  PubMed  Google Scholar 

  163. Charafe-Jauffret E, Ginestier C, Monville F, Finetti P, Adelaide J, Cervera N et al (2006) Gene expression profiling of breast cell lines identifies potential new basal markers. Oncogene 25(15):2273–2284. doi:10.1038/sj.onc.1209254

    Article  CAS  PubMed  Google Scholar 

  164. Blick T, Widodo E, Hugo H, Waltham M, Lenburg ME, Neve RM et al (2008) Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin Exp Metastasis 25(6):629–642. doi:10.1007/s10585-008-9170-6

    Article  CAS  PubMed  Google Scholar 

  165. Elenbaas B, Spirio L, Koerner F, Fleming MD, Zimonjic DB, Donaher JL et al (2001) Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev 15(1):50–65. doi:10.1101/gad.828901

    Article  CAS  PubMed  Google Scholar 

  166. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359(6397):693–699. doi:10.1038/359693a0

    Article  CAS  PubMed  Google Scholar 

  167. Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J et al (1999) The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96(3):319–328. doi:10.1016/S0092-8674(00)80545-0

    Article  CAS  PubMed  Google Scholar 

  168. Teder P, Vandivier RW, Jiang D, Liang J, Cohn L, Pure E et al (2002) Resolution of lung inflammation by CD44. Science 296(5565):155–158. doi:10.1126/science.1069659

    Article  CAS  PubMed  Google Scholar 

  169. Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14(2):163–176

    PubMed  Google Scholar 

  170. Yu Q, Stamenkovic I (2004) Transforming growth factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival. Clin Exp Metastasis 21(3):235–242. doi:10.1023/B:CLIN.0000037705.25256.d3

    Article  CAS  PubMed  Google Scholar 

  171. Rouschop KM, Sewnath ME, Claessen N, Roelofs JJ, Hoedemaeker I, van der Neut R et al (2004) CD44 deficiency increases tubular damage but reduces renal fibrosis in obstructive nephropathy. J Am Soc Nephrol 15(3):674–686. doi:10.1097/01.ASN.0000115703.30835.96

    Article  CAS  PubMed  Google Scholar 

  172. Acharya PS, Majumdar S, Jacob M, Hayden J, Mrass P, Weninger W et al (2008) Fibroblast migration is mediated by CD44-dependent TGF beta activation. J Cell Sci 121(Pt 9):1393–1402. doi:10.1242/jcs.021683

    Article  CAS  PubMed  Google Scholar 

  173. Bourguignon LY, Singleton PA, Zhu H, Zhou B (2002) Hyaluronan promotes signaling interaction between CD44 and the transforming growth factor beta receptor I in metastatic breast tumor cells. J Biol Chem 277(42):39703–39712. doi:10.1074/jbc.M204320200

    Article  CAS  PubMed  Google Scholar 

  174. Mackillop WJ, Ciampi A, Till JE, Buick RN (1983) A stem cell model of human tumor growth: implications for tumor cell clonogenic assays. J Natl Cancer Inst 70(1):9–16

    CAS  PubMed  Google Scholar 

  175. James D, Levine AJ, Besser D, Hemmati-Brivanlou A (2005) TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 132(6):1273–1282. doi:10.1242/dev.01706

    Article  CAS  PubMed  Google Scholar 

  176. Poon E, Clermont F, Firpo MT, Akhurst RJ (2006) TGFbeta inhibition of yolk-sac-like differentiation of human embryonic stem-cell-derived embryoid bodies illustrates differences between early mouse and human development. J Cell Sci 119(Pt 4):759–768. doi:10.1242/jcs.02788

    Article  CAS  PubMed  Google Scholar 

  177. Kakarala M, Wicha MS (2007) Cancer stem cells: implications for cancer treatment and prevention. Cancer J 13(5):271–275. doi:10.1097/PPO.0b013e318156da4e

    Article  CAS  PubMed  Google Scholar 

  178. Norton L, Massague J (2006) Is cancer a disease of self-seeding? Nat Med 12(8):875–878. doi:10.1038/nm0806-875

    Article  CAS  PubMed  Google Scholar 

  179. Alexe G, Dalgin GS, Ganesan S, Delisi C, Bhanot G (2007) Analysis of breast cancer progression using principal component analysis and clustering. J Biosci 32(5):1027–1039. doi:10.1007/s12038-007-0102-4

    Article  CAS  PubMed  Google Scholar 

  180. Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B et al (2007) Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res 13(11):3207–3214. doi:10.1158/1078-0432.CCR-06-2765

    Article  CAS  PubMed  Google Scholar 

  181. Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J et al (2006) Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res 66(21):10292–10301. doi:10.1158/0008-5472.CAN-05-4414

    Article  CAS  PubMed  Google Scholar 

  182. Kenny P, Lee G, Myers C, Neve R, Semeiks J, Spellman P et al (2007) The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol Oncol 1(1):84–96. doi:10.1016/j.molonc.2007.02.004

    Article  CAS  PubMed  Google Scholar 

  183. Desai KV, Xiao N, Wang W, Gangi L, Greene J, Powell JI et al (2002) Initiating oncogenic event determines gene-expression patterns of human breast cancer models. Proc Natl Acad Sci USA 99(10):6967–6972. doi:10.1073/pnas.102172399

    Article  CAS  PubMed  Google Scholar 

  184. Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ et al (2003) Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 163(5):2113–2126

    PubMed  Google Scholar 

  185. Maglione JE, Moghanaki D, Young LJ, Manner CK, Ellies LG, Joseph SO et al (2001) Transgenic polyoma middle-T mice model premalignant mammary disease. Cancer Res 61(22):8298–8305

    CAS  PubMed  Google Scholar 

  186. Arteaga CL, Hurd SD, Winnier AR, Johnson MD, Fendly BM, Forbes JT (1993) Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression. J Clin Invest 92(6):2569–2576. doi:10.1172/JCI116871

    Article  CAS  PubMed  Google Scholar 

  187. Pinkas J, Teicher BA (2006) TGF-beta in cancer and as a therapeutic target. Biochem Pharmacol 72(5):523–529. doi:10.1016/j.bcp.2006.03.004

    Article  CAS  PubMed  Google Scholar 

  188. Nam JS, Suchar AM, Kang MJ, Stuelten CH, Tang B, Michalowska AM et al (2006) Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor beta in a mouse model of breast cancer. Cancer Res 66(12):6327–6335. doi:10.1158/0008-5472.CAN-06-0068

    Article  CAS  PubMed  Google Scholar 

  189. Nam JS, Terabe M, Kang MJ, Chae H, Voong N, Yang YA et al (2008) Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Res 68(10):3915–3923. doi:10.1158/0008-5472.CAN-08-0206

    Article  CAS  PubMed  Google Scholar 

  190. Nam JS, Terabe M, Mamura M, Kang MJ, Chae H, Stuelten C et al (2008) An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res 68(10):3835–3843. doi:10.1158/0008-5472.CAN-08-0215

    Article  CAS  PubMed  Google Scholar 

  191. Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J et al (2002) Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest 109(12):1551–1559

    CAS  PubMed  Google Scholar 

  192. Bandyopadhyay A, Zhu Y, Cibull ML, Bao L, Chen C, Sun L (1999) A soluble transforming growth factor beta type III receptor suppresses tumorigenicity and metastasis of human breast cancer MDA-MB-231 cells. Cancer Res 59(19):5041–5046

    CAS  PubMed  Google Scholar 

  193. Bandyopadhyay A, Lopez-Casillas F, Malik SN, Montiel JL, Mendoza V, Yang J et al (2002) Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res 62(16):4690–4695

    CAS  PubMed  Google Scholar 

  194. Bandyopadhyay A, Zhu Y, Malik SN, Kreisberg J, Brattain MG, Sprague EA et al (2002) Extracellular domain of TGFbeta type III receptor inhibits angiogenesis and tumor growth in human cancer cells. Oncogene 21(22):3541–3551. doi:10.1038/sj.onc.1205439

    Article  CAS  PubMed  Google Scholar 

  195. Park JA, Wang E, Kurt RA, Schluter SF, Hersh EM, Akporiaye ET (1997) Expression of an antisense transforming growth factor-beta-1 transgene reduces tumorigenicity of EMT6 mammary tumor cells. Cancer Gene Ther 4(1):42–50

    CAS  PubMed  Google Scholar 

  196. Schlingensiepen KH, Fischer-Blass B, Schmaus S, Ludwig S (2008) Antisense therapeutics for tumor treatment: the TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors. Recent Results in Cancer Res 177:137–150

    Article  CAS  Google Scholar 

  197. Hau P, Jachimczak P, Schlingensiepen R, Schulmeyer F, Jauch T, Steinbrecher A et al (2007) Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides 17(2):201–212. doi:10.1089/oli.2006.0053

    Article  CAS  PubMed  Google Scholar 

  198. Schlingensiepen KH, Schlingensiepen R, Steinbrecher A, Hau P, Bogdahn U, Fischer-Blass B et al (2006) Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009. Cytokine Growth factor Rev 17(1–2):129–139. doi:10.1016/j.cytogfr.2005.09.002

    Article  CAS  PubMed  Google Scholar 

  199. Schlingensiepen R, Goldbrunner M, Szyrach MN, Stauder G, Jachimczak P, Bogdahn U et al (2005) Intracerebral and intrathecal infusion of the TGF-beta 2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety. Oligonucleotides 15(2):94–104. doi:10.1089/oli.2005.15.94

    Article  CAS  PubMed  Google Scholar 

  200. DaCosta Byfield S, Major C, Laping NJ, Roberts AB (2004) SB-505124 is a selective inhibitor of transforming growth factor-{beta} type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol 65(3):744–752. doi:10.1124/mol.65.3.744

    Article  PubMed  Google Scholar 

  201. Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massague J (2001) The TGF beta receptor activation process: an inhibitor- to substrate-binding switch. Mol Cell 8(3):671–682. doi:10.1016/S1097-2765(01)00332-X

    Article  CAS  PubMed  Google Scholar 

  202. Bandyopadhyay A, Agyin JK, Wang L, Tang Y, Lei X, Story BM et al (2006) Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor. Cancer Res 66(13):6714–6721. doi:10.1158/0008-5472.CAN-05-3565

    Article  CAS  PubMed  Google Scholar 

  203. Mohammad K, Stebbins E, Kingsley L, Fournier P, Niewolna M, McKenna C et al (2008) Transforming growth factor β receptor I kinase inhibitor and bisphosphonates are additive to reduce breast cancer bone metastases. Cancer Treat Rev 34:37–38. doi:10.1016/j.ctrv.2008.03.106

    Article  Google Scholar 

  204. Vieth M, Brooks HB, Hamdouchi C, McMillen W, Sawyer JS, Yingling JM et al (2003) Combining medicinal chemistry with chemogenomic and computer-aided structure-based design in development of novel kinase inhibitors. Cell Mol Biol Lett 8(2A):566–567

    Google Scholar 

  205. Sawyer JS, Anderson BD, Beight DW, Campbell RM, Jones ML, Herron DK et al (2003) Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. J Med Chem 46(19):3953–3956. doi:10.1021/jm0205705

    Article  CAS  PubMed  Google Scholar 

  206. Sawyer JS, Beight DW, Britt KS, Anderson BD, Campbell RM, Goodson T Jr et al (2004) Synthesis and activity of new aryl- and heteroaryl-substituted 5, 6-dihydro-4H-pyrrolo[1, 2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. Bioorg Med Chem Lett 14(13):3581–3584. doi:10.1016/j.bmcl.2004.04.007

    Article  CAS  PubMed  Google Scholar 

  207. Peng SB, Yan L, Xia X, Watkins SA, Brooks HB, Beight D et al (2005) Kinetic characterization of novel pyrazole TGF-beta receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition. Biochemistry 44(7):2293–2304. doi:10.1021/bi048851x

    Article  CAS  PubMed  Google Scholar 

  208. Li HY, Wang Y, Heap CR, King CH, Mundla SR, Voss M et al (2006) Dihydropyrrolopyrazole transforming growth factor-beta type I receptor kinase domain inhibitors: a novel benzimidazole series with selectivity versus transforming growth factor-beta type II receptor kinase and mixed lineage kinase-7. J Med Chem 49(6):2138–2142. doi:10.1021/jm058209g

    Article  CAS  PubMed  Google Scholar 

  209. Li HY, McMillen WT, Heap CR, McCann DJ, Yan L, Campbell RM et al (2008) Optimization of a dihydropyrrolopyrazole series of transforming growth factor-beta type I receptor kinase domain inhibitors: discovery of an orally bioavailable transforming growth factor-beta receptor type I inhibitor as antitumor agent. J Med Chem 51(7):2302–2306. doi:10.1021/jm701199p

    Article  CAS  PubMed  Google Scholar 

  210. Bueno L, de Alwis DP, Pitou C, Yingling J, Lahn M, Glatt S et al (2008) Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. Eur J Cancer 44(1):142–150. doi:10.1016/j.ejca.2007.10.008

    Article  CAS  PubMed  Google Scholar 

  211. Ehata S, Hanyu A, Fujime M, Katsuno Y, Fukunaga E, Goto K et al (2007) Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line. Cancer Sci 98(1):127–133. doi:10.1111/j.1349-7006.2006.00357.x

    Article  CAS  PubMed  Google Scholar 

  212. Ohmori T, Yang JL, Price JO, Arteaga CL (1998) Blockade of tumor cell transforming growth factor-betas enhances cell cycle progression and sensitizes human breast carcinoma cells to cytotoxic chemotherapy. Exp Cell Res 245(2):350–359. doi:10.1006/excr.1998.4261

    Article  CAS  PubMed  Google Scholar 

  213. Teicher BA, Holden SA, Ara G, Chen G (1996) Transforming growth factor-beta in in vivo resistance. Cancer Chemother Pharmacol 37(6):601–609. doi:10.1007/s002800050435

    Article  CAS  PubMed  Google Scholar 

  214. Bandyopadhyay A, Wang L, Agyin J, De K, Sun L (2008) Enhanced inhibition of tumor growth and lung metastasis by the administration of a small molecule TGFβ inhibitor during doxorubicin treatment in a murine xenograft model of breast cancer. Proc Am Assoc Cancer Res 99: Abstract #1323

  215. Ehrhart EJ, Segarini P, Tsang ML, Carroll AG, Barcellos-Hoff MH (1997) Latent transforming growth factor beta1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiation. FASEB J 11(12):991–1002

    CAS  PubMed  Google Scholar 

  216. Hahn T, Akporiaye ET (2006) Targeting transforming growth factor beta to enhance cancer immunotherapy. Curr oncology (Toronto, Ont) 13(4):141–143

    CAS  Google Scholar 

  217. Kobie JJ, Wu RS, Kurt RA, Lou S, Adelman MK, Whitesell LJ et al (2003) Transforming growth factor beta inhibits the antigen-presenting functions and antitumor activity of dendritic cell vaccines. Cancer Res 63(8):1860–1864

    CAS  PubMed  Google Scholar 

  218. Seth P, Wang ZG, Pister A, Zafar MB, Kim S, Guise T et al (2006) Development of oncolytic adenovirus armed with a fusion of soluble transforming growth factor-beta receptor II and human immunoglobulin Fc for breast cancer therapy. Hum Gene Ther 17(11):1152–1160. doi:10.1089/hum.2006.17.1152

    Article  CAS  PubMed  Google Scholar 

  219. Wang ZG, Zhao W, Ramachandra M, Seth P (2006) An oncolytic adenovirus expressing soluble transforming growth factor-beta type II receptor for targeting breast cancer: in vitro evaluation. Mol Cancer Ther 5(2):367–373. doi:10.1158/1535-7163.MCT-05-0125

    Article  CAS  PubMed  Google Scholar 

  220. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC et al (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 90(2):770–774. doi:10.1073/pnas.90.2.770

    Article  CAS  PubMed  Google Scholar 

  221. Gorelik L, Flavell RA (2000) Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12(2):171–181. doi:10.1016/S1074-7613(00)80170-3

    Article  CAS  PubMed  Google Scholar 

  222. Ruzek MC, Hawes M, Pratt B, McPherson J, Ledbetter S, Richards SM et al (2003) Minimal effects on immune parameters following chronic anti-TGF-beta monoclonal antibody administration to normal mice. Immunopharmacol Immunotoxicol 25(2):235–257. doi:10.1081/IPH-120020473

    Article  CAS  PubMed  Google Scholar 

  223. Takaku K, Oshima M, Miyoshi H, Matsui M, Seldin MF, Taketo MM (1998) Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92(5):645–656. doi:10.1016/S0092-8674(00)81132-0

    Article  CAS  PubMed  Google Scholar 

  224. Arteaga CL, McPherson JM (2008) Development of TGFß-based therapeutic agents: capitalizing on TGFß’s mechanisms of action and signal transduction pathways. In: Derynck R, Miyazono K (eds) The TGF-β family. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 1023–1061

    Google Scholar 

  225. Xiao H, Zhang YY (2008) Understanding the role of transforming growth factor-beta signalling in the heart: overview of studies using genetic mouse models. Clin Exp Pharmacol Physiol 35(3):335–341. doi:10.1111/j.1440-1681.2007.04876.x

    Article  CAS  PubMed  Google Scholar 

  226. Khan R, Sheppard R (2006) Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology 118(1):10–24. doi:10.1111/j.1365-2567.2006.02336.x

    Article  CAS  PubMed  Google Scholar 

  227. Maratea K, Donnelly K, Reams R, Snyder P (2007) Evidence of enhanced TGF-beta signaling in heart valve lesions of Sprague–Dawley rats treated with a TGF-beta receptor I (ALK5) kinase inhibitor. Vet Pathol 44:733. doi:10.1354/vp.44-4-513

    Article  Google Scholar 

  228. Mizuguchi T, Matsumoto N (2007) Recent progress in genetics of Marfan syndrome and Marfan-associated disorders. J Hum Genet 52(1):1–12. doi:10.1007/s10038-006-0078-1

    Article  CAS  PubMed  Google Scholar 

  229. Padgett RW, Reiss M (2007) TGF{beta} superfamily signaling: notes from the desert. Development 134(20):3565–3569. doi:10.1242/dev.005926

    Article  CAS  PubMed  Google Scholar 

  230. Hilbig A, Seufferlein T, Schmid RM, Luger T, Oettle H, Schneider G et al (2008) Preliminary results of a phase I/II study in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinoma using systemic i.v. administration of AP 12009. J Clin Oncol 26: Abstract 4621

  231. Morris J, Shapiro G, Tan AR, Lawrence D, Olencki T, Dezube B et al (2008) Phase 1/2 Study of GC1008: a human anti transforming growth factor-beta (TGFβ) monoclonal antibody (MAb) in patients with advanced malignant melanoma or renal cell Carcinoma. J Clin Oncol 26: Abstract# 9028

  232. Calvo-Aller E, Baselga J, Glatt S, Cleverly A, Lahn M, Arteaga CL et al (2008) First human dose escalation study in patients with metastatic malignancies to determine safety and pharmacokinetics of LY2157299, a small molecule inhibitor of the transforming growth factor-beta receptor I kinase. J Clin Oncol 26: Abstract 14554

  233. Farrington DL, Yingling JM, Fill JA, Yan L, Qian YW, Shou J et al (2007) Development and validation of a phosphorylated SMAD ex vivo stimulation assay. Biomarkers 12(3):313–330. doi:10.1080/13547500601162441

    Article  CAS  PubMed  Google Scholar 

  234. Jayson GC, Zweit J, Jackson A, Mulatero C, Julyan P, Ranson M et al (2002) Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies. J Natl Cancer Inst 94(19):1484–1493

    CAS  PubMed  Google Scholar 

  235. Nagengast WB, de Vries EG, Hospers GA, Mulder NH, de Jong JR, Hollema H et al (2007) In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. J Nucl Med 48(8):1313–1319. doi:10.2967/jnumed.107.041301

    Article  CAS  PubMed  Google Scholar 

  236. van Dongen GA, Visser GW, Lub-de Hooge MN, de Vries EG, Perk LR (2007) Immuno-PET: a navigator in monoclonal antibody development and applications. Oncologist 12(12):1379–1389. doi:10.1634/theoncologist.12-12-1379

    Article  PubMed  CAS  Google Scholar 

  237. Akhurst RJ (2006) Large- and small-molecule inhibitors of transforming growth factor-beta signaling. Curr Opin Investig Drugs 7(6):513–521

    CAS  PubMed  Google Scholar 

  238. Biswas S, Criswell TL, Wang SE, Arteaga CL (2006) Inhibition of transforming growth factor-{beta} signaling in human cancer: targeting a tumor suppressor network as a therapeutic strategy. Clin Cancer Res 12(14):4142–4146. doi:10.1158/1078-0432.CCR-06-0952

    Article  CAS  PubMed  Google Scholar 

  239. Reiss M (2006) Targeting transforming growth factor-β in metastasis: in vitro and in vivo mechanisms. In: Jakowlew SB (ed) Transforming growth factor-beta in cancer therapy. The Humana, Totowa

    Google Scholar 

  240. Bonniaud P, Margetts PJ, Kolb M, Schroeder JA, Kapoun AM, Damm D et al (2005) Progressive transforming growth factor {beta}1-induced lung fibrosis is blocked by an orally active alk5 kinase inhibitor. Am J Respir Crit Care Med 171(8):889–898. doi:10.1164/rccm.200405-612OC

    Article  PubMed  Google Scholar 

  241. de Gouville AC, Boullay V, Krysa G, Pilot J, Brusq JM, Loriolle F et al (2005) Inhibition of TGF-beta signaling by an ALK5 inhibitor protects rats from dimethylnitrosamine-induced liver fibrosis. Br J Pharmacol 145(2):166–177. doi:10.1038/sj.bjp.0706172

    Article  PubMed  CAS  Google Scholar 

  242. de Gouville AC, Huet S (2006) Inhibition of ALK5 as a new approach to treat liver fibrotic diseases. Drug News Perspect 19(2):85–90. doi:10.1358/dnp.2006.19.2.977444

    Article  PubMed  CAS  Google Scholar 

  243. Gagliardini E, Benigni A (2006) Role of anti-TGF-beta antibodies in the treatment of renal injury. Cytokine Growth factor Rev 17(1–2):89–96. doi:10.1016/j.cytogfr.2005.09.005

    Article  CAS  PubMed  Google Scholar 

  244. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK et al (2006) Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312(5770):117–121. doi:10.1126/science.1124287

    Article  CAS  PubMed  Google Scholar 

  245. Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A et al (2006) X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9(2):121–132. doi:10.1016/j.ccr.2006.01.013

    Article  CAS  PubMed  Google Scholar 

  246. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550. doi:10.1073/pnas.0506580102

    Article  CAS  PubMed  Google Scholar 

  247. Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov JP (2007) GSEA-P: a desktop application for gene set enrichment analysis. Bioinformatics 23(23):3251–3253. doi:10.1093/bioinformatics/btm369

    Article  CAS  PubMed  Google Scholar 

  248. Fakhrai H, Mantil JC, Liu L, Nicholson GL, Murphy-Satter CS, Ruppert J et al (2006) Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma. Cancer Gene Ther 13(12):1052–1060. doi:10.1038/sj.cgt.7700975

    Article  CAS  PubMed  Google Scholar 

  249. Nemunaitis J, Dillman RO, Schwarzenberger PO, Senzer N, Cunningham C, Cutler J et al (2006) Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol 24(29):4721–4730. doi:10.1200/JCO.2005.05.5335

    Article  CAS  PubMed  Google Scholar 

  250. Cordeiro MF, Mead A, Ali RR, Alexander RA, Murray S, Chen C et al (2003) Novel antisense oligonucleotides targeting TGF-beta inhibit in vivo scarring and improve surgical outcome. Gene Ther 10(1):59–71. doi:10.1038/sj.gt.3301865

    Article  CAS  PubMed  Google Scholar 

  251. Mead AL, Wong TT, Cordeiro MF, Anderson IK, Khaw PT (2003) Evaluation of anti-TGF-beta2 antibody as a new postoperative anti-scarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci 44(8):3394–3401. doi:10.1167/iovs.02-0978

    Article  PubMed  Google Scholar 

  252. Benigni A, Zoja C, Corna D, Zatelli C, Conti S, Campana M et al (2003) Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol 14(7):1816–1824. doi:10.1097/01.ASN.0000074238.61967.B7

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Public Health Service Awards CA-41556, CA-120623 and CA-129125 to MR from the National Cancer Institute, as well as by the Cancer Center Support Grant CA-72720 from the National Cancer Institute.

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  1. Division of Medical Oncology, Department of Internal Medicine, UMDNJ-Robert Wood Johnson Medical School and The Cancer Institute of New Jersey, Room 2007, 195 Little Albany Street, New Brunswick, NJ, 08903, USA

    Antoinette R. Tan & Michael Reiss

  2. Department of Human Genetics and Clinical Biomarkers, Bristol-Myers Squibb, Princeton, NJ, USA

    Gabriela Alexe

  3. Department of Molecular Genetics, Microbiology & Immunology, UMDNJ-Robert Wood Johnson Medical School and The Cancer Institute of New Jersey, Room 2007, 195 Little Albany Street, New Brunswick, NJ, 08903, USA

    Michael Reiss

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  1. Antoinette R. Tan
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Correspondence to Michael Reiss.

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Tan, A.R., Alexe, G. & Reiss, M. Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer?. Breast Cancer Res Treat 115, 453–495 (2009). https://doi.org/10.1007/s10549-008-0184-1

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