Skip to main content
SpringerLink
Log in
Book cover

Breast Cancer in the Post-Genomic Era pp 137–149Cite as

TGF-β Signaling

A Novel Target for Treatment of Breast Cancer?

  • Chapter
  • First Online:

  • 568 Accesses

Part of the book series: Current Clinical Oncology ((CCO))

Summary

Targeted therapies for breast cancer rely on an understanding of cellular signaling in both normal and neoplastic tissue. The transforming growth factor-beta (TGF-β) signaling pathway is an important regulator of both normal mammary gland development and mammary carcinogenesis. The TGF-β signaling pathway regulates numerous cellular processes in breast tissue, including proliferation, apoptosis, migration, and invasion, in addition to contributing to angiogenesis and modulation of the immune system. TGF-β often has opposing effects on these cellular processes, with its effects being both cell and context specific. Moreover, TGF-β possesses a unique dichotomy of function in breast cancer progression, acting as a tumor suppressor early in breast cancer carcinogenesis and then as a tumor promoter in the later stages of breast cancer progression. Highlighting the complexities inherent in TGF-β signaling, along with our current efforts to better our understanding of it, we outline several strategies that may enable us to create focused therapies in the prevention and treatment of breast cancer.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Kamangar F, Dores GM, Anderson WF. Patterns of Cancer Incidence, Mortality, and Prevalence Across Five Continents: Defining Priorities to Reduce Cancer Disparities in Different Geographic Regions of the World. J Clin Oncol 2006;24:2137–50.

    Article  PubMed  Google Scholar 

  2. Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998;67:753–91.

    Article  CAS  PubMed  Google Scholar 

  3. Hannon GJ, Beach D. pl5INK4B is a potential effector of TGF-[beta]-induced cell cycle arrest. Nature 1994;371:257–61.

    Article  CAS  PubMed  Google Scholar 

  4. Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang X. Transforming Growth Factor {beta} Induces the Cyclin-Dependent Kinase Inhibitor p21 through a p53-Independent Mechanism. Proceedings of the National Academy of Sciences 1995;92:5545–9.

    Article  CAS  Google Scholar 

  5. Pietenpol JA, Stein RW, Moran E, TGF-[beta]1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell 1990;61:777–85.

    Article  CAS  PubMed  Google Scholar 

  6. Siegel PM, Ryan ED, Cardiff RD, Muller WJ. Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBO J 1999;18:2149–64.

    Article  CAS  PubMed  Google Scholar 

  7. Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J. Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A 2003;100:8430–5.

    Article  CAS  PubMed  Google Scholar 

  8. Lagna G, Nguyen PH, Ni W, Hata A. BMP-dependent activation of caspase-9 and caspase-8 mediates apoptosis in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2006;291:L1059–67.

    Article  CAS  PubMed  Google Scholar 

  9. Inman GJ, Allday MJ. Apoptosis induced by TGF-beta 1 in Burkitt’s lymphoma cells is caspase 8 dependent but is death receptor independent. J Immunol 2000;165:2500–10.

    CAS  PubMed  Google Scholar 

  10. Motyl T, Grzelkowska K, Zimowska W, Expression of bcl-2 and bax in TGF-beta 1-induced apoptosis of L1210 leukemic cells. Eur J Cell Biol 1998;75:367–74.

    CAS  PubMed  Google Scholar 

  11. Zhang S, Ekman M, Thakur N, TGFbeta1-induced activation of ATM and p53 mediates apoptosis in a Smad7-dependent manner. Cell Cycle 2006;5:2787–95.

    Article  CAS  PubMed  Google Scholar 

  12. Lei X, Yang J, Nichols RW, Sun LZ. Abrogation of TGF[beta] signaling induces apoptosis through the modulation of MAP kinase pathways in breast cancer cells. Experimental Cell Research 2007;313:1687–95.

    Article  CAS  PubMed  Google Scholar 

  13. Blobe GC, Schiemann WP, Lodish HF. Role of Transforming Growth Factor {beta} in Human Disease. N Engl J Med 2000;342:1350–8.

    Article  CAS  PubMed  Google Scholar 

  14. Desruisseau S, Ghazarossian-Ragni E, Chinot O, Martin PM. Divergent effect of TGFbeta1 on growth and proteolytic modulation of human prostatic-cancer cell lines. Int J Cancer 1996;66:796–801.

    Article  CAS  PubMed  Google Scholar 

  15. Dalal BI, Keown PA, Greenberg AH. 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 1993;143:381–9.

    CAS  PubMed  Google Scholar 

  16. Kim E-S, Sohn Y-W, Moon A. TGF-[beta]-induced transcriptional activation of MMP-2 is mediated by activating transcription factor (ATF)2 in human breast epithelial cells. Cancer Letters 2007;252:147–56.

    Article  CAS  PubMed  Google Scholar 

  17. Kim ES, Kim MS, Moon A. TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 2004;25:1375–82.

    CAS  PubMed  Google Scholar 

  18. Kalo E, Buganim Y, Shapira KE, et al. Mutant p53 attenuates the SMAD-dependent TGF-{beta}1 signaling pathway by repressing the expression of TGF-{beta} receptor type II. Mol Cell Biol 2007:MCB.00374–07.

    Google Scholar 

  19. Yamamoto T, Kozawa O, Tanabe K, Involvement of p38 MAP kinase in TGF-beta-stimulated VEGF synthesis in aortic smooth muscle cells. J Cell Biochem 2001;82:591–8.

    Article  CAS  PubMed  Google Scholar 

  20. McAllister KA, Grogg KM, Johnson DW, Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994;8:345–51.

    Article  CAS  PubMed  Google Scholar 

  21. Johnson DW, Berg JN, Baldwin MA, Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996;13:189–95.

    Article  CAS  PubMed  Google Scholar 

  22. Dong M, How T, Kirkbride KC, The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest 2007;117:206–17.

    Article  CAS  PubMed  Google Scholar 

  23. Safina A, Vandette E, Bakin AV. ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene 2006;26:2407–22.

    Article  PubMed  Google Scholar 

  24. Classen S, Zander T, Eggle D, Human resting CD4+ T cells are constitutively inhibited by TGF beta under steady-state conditions. J Immunol 2007;178:6931–40.

    CAS  PubMed  Google Scholar 

  25. Cheng ML, Chen HW, Tsai JP, Clonal restriction of the expansion of antigen-specific CD8+ memory T cells by transforming growth factor-{beta}. J Leukoc Biol 2006;79:1033–42.

    Article  CAS  PubMed  Google Scholar 

  26. Chen W, Jin W, Hardegen N, Conversion of Peripheral CD4+ CD25- Naive T Cells to CD4+ CD25+ Regulatory T Cells by TGF-{beta} Induction of Transcription Factor Foxp3. J Exp Med 2003;198:1875–86.

    Article  CAS  PubMed  Google Scholar 

  27. Mangan PR, Harrington LE, O’Quinn DB, Transforming growth factor-[beta] induces development of the TH17 lineage. Nature 2006;441:231–4.

    Article  CAS  PubMed  Google Scholar 

  28. Travis MA, Reizis B, Melton AC, Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice. Nature 2007;449:361–5.

    Article  CAS  PubMed  Google Scholar 

  29. Bogdan C, Paik J, Vodovotz Y, Nathan C. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem 1992;267:23301–8.

    CAS  PubMed  Google Scholar 

  30. Borkowski TA, Letterio JJ, Mackall CL, Langerhans cells in the TGF beta 1 null mouse. Adv Exp Med Biol 1997;417:307–10.

    CAS  PubMed  Google Scholar 

  31. Bierie B, Moses H. TGF-beta and cancer. Cytokine & growth factor reviews 2006;17:29–40.

    Article  CAS  Google Scholar 

  32. Chen T, Jackson CR, Link A, Int7G24A variant of transforming growth factor-beta receptor type I is associated with invasive breast cancer. Clin Cancer Res 2006;12:392–7.

    Article  CAS  PubMed  Google Scholar 

  33. Xu Y, Pasche B. TGF-beta signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet 2007;16 Spec No 1:R14–20.

    Article  CAS  PubMed  Google Scholar 

  34. Markowitz S, Wang J, Myeroff L, Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 1995;268:1336–8.

    Article  CAS  PubMed  Google Scholar 

  35. Lucke CD, Philpott A, Metcalfe JC, Inhibiting mutations in the transforming growth factor beta type 2 receptor in recurrent human breast cancer. Cancer Res 2001;61:482–5.

    CAS  PubMed  Google Scholar 

  36. Gobbi H, Dupont WD, Simpson JF, Transforming Growth Factor-{beta} and Breast Cancer Risk in Women With Mammary Epithelial Hyperplasia. J Natl Cancer Inst 1999;91:2096–101.

    Article  CAS  PubMed  Google Scholar 

  37. Gobbi, Arteaga, Jensen, 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 2000;36:168–77.

    Article  CAS  PubMed  Google Scholar 

  38. Turley RS, Finger EC, Hempel N, How T, Fields TA, Blobe GC. The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostate cancer. Cancer Res 2007;67:1090–8.

    Article  CAS  PubMed  Google Scholar 

  39. Hempel N, How T, Dong M, Murphy SK, Fields TA, Blobe GC. Loss of betaglycan expression in ovarian cancer: role in motility and invasion. Cancer Res 2007;67:5231–8.

    Article  CAS  PubMed  Google Scholar 

  40. Xie W, Mertens JC, Reiss DJ, Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. Cancer Res 2002;62:497–505.

    CAS  PubMed  Google Scholar 

  41. Kopp A, Jonat W, Schmahl M, Knabbe C. Transforming growth factor beta 2 (TGF-beta 2) levels in plasma of patients with metastatic breast cancer treated with tamoxifen. Cancer Res 1995;55:4512–5.

    CAS  PubMed  Google Scholar 

  42. Ghellal A, Li C, Hayes M, Byrne G, Bundred N, Kumar S. Prognostic significance of TGF beta 1 and TGF beta 3 in human breast carcinoma. Anticancer Res 2000;20:4413–8.

    CAS  PubMed  Google Scholar 

  43. Buijs JT, Henriquez NV, van Overveld PG, Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. Cancer Res 2007;67:8742–51.

    Article  CAS  PubMed  Google Scholar 

  44. Kong FM, Anscher MS, Murase T, Abbott BD, Iglehart JD, Jirtle RL. Elevated plasma transforming growth factor-beta 1 levels in breast cancer patients decrease after surgical removal of the tumor. Ann Surg 1995;222:155–62.

    Article  CAS  PubMed  Google Scholar 

  45. Shipitsin M, Campbell LL, Argani P, Molecular Definition of Breast Tumor Heterogeneity. Cancer Cell 2007;11:259–73.

    Article  CAS  PubMed  Google Scholar 

  46. Benson JR. Role of transforming growth factor beta in breast carcinogenesis. Lancet Oncol 2004;5:229–39.

    Article  CAS  PubMed  Google Scholar 

  47. Bottinger EP, Jakubczak JL, Haines DC, Bagnall K, Wakefield LM. Transgenic Mice Overexpressing a Dominant-negative Mutant Type II Transforming Growth Factor {beta} Receptor Show Enhanced Tumorigenesis in the Mammary Gland and Lung in Response to the Carcinogen 7,12-Dimethylbenz-[a]-anthracene. Cancer Res 1997;57:5564–70.

    CAS  PubMed  Google Scholar 

  48. Stover D, Bierie B, Moses H. A delicate balance: TGF-beta and the tumor microenvironment. Journal of Cellular Biochemistry 2007;101:851–61.

    Article  CAS  PubMed  Google Scholar 

  49. Bhowmick NA, Chytil A, Plieth D, TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004;303:848–51.

    Article  CAS  PubMed  Google Scholar 

  50. Cheng N, Bhowmick NA, Chytil A, Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene 2005;24:5053–68.

    Article  CAS  PubMed  Google Scholar 

  51. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003;15:740–6.

    Article  CAS  PubMed  Google Scholar 

  52. Gordon KJ, Dong M, Chislock EM, Fields TA, Blobe GC. Loss of Type III Transforming Growth Factor {beta} Receptor Expression Increases Motility and Invasiveness associated with Epithelial to Mesenchymal Transition during Pancreatic Cancer Progression. Carcinogenesis 2007:bgm249.

    Google Scholar 

  53. Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 2000;275:36803–10.

    Article  CAS  PubMed  Google Scholar 

  54. Oft M, Heider KH, Beug H. TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 1998;8:1243–52.

    Article  CAS  PubMed  Google Scholar 

  55. Butta A, MacLennan K, Flanders KC, Induction of transforming growth factor beta 1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res 1992;52:4261–4.

    CAS  PubMed  Google Scholar 

  56. Buck MB, Knabbe C. TGF-beta signaling in breast cancer. Ann N Y Acad Sci 2006;1089:119–26.

    Article  CAS  PubMed  Google Scholar 

  57. Lee BI, Park SH, Kim JW, MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor expression in human breast cancer cells. Cancer Res 2001;61:931–4.

    CAS  PubMed  Google Scholar 

  58. Matsuyama S, Iwadate M, Kondo M, SB-431542 and Gleevec inhibit transforming growth factor-beta-induced proliferation of human osteosarcoma cells. Cancer Res 2003;63:7791–8.

    CAS  PubMed  Google Scholar 

  59. Callahan JF, Burgess JL, Fornwald JA, Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5). J Med Chem 2002;45:999–1001.

    Article  CAS  PubMed  Google Scholar 

  60. Yakymovych I, Engstrom U, Grimsby S, Heldin CH, Souchelnytskyi S. Inhibition of transforming growth factor-beta signaling by low molecular weight compounds interfering with ATP- or substrate-binding sites of the TGF beta type I receptor kinase. Biochemistry 2002;41:11000–7.

    Article  CAS  PubMed  Google Scholar 

  61. Ehata S, Hanyu A, Fujime M, 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 2007;98:127–33.

    Article  CAS  PubMed  Google Scholar 

  62. Arteaga CL, Carty-Dugger T, Moses HL, Hurd SD, Pietenpol JA. Transforming growth factor beta 1 can induce estrogen-independent tumorigenicity of human breast cancer cells in athymic mice. Cell Growth Differ 1993;4:193–201.

    CAS  PubMed  Google Scholar 

  63. Arteaga CL, Dugger TC, Winnier AR, Forbes JT. Evidence for a positive role of transforming growth factor-beta in human breast cancer cell tumorigenesis. J Cell Biochem Suppl 1993;17G:187–93.

    Article  CAS  Google Scholar 

  64. Muraoka RS, Dumont N, Ritter CA, Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest 2002;109:1551–9.

    CAS  PubMed  Google Scholar 

  65. Bandyopadhyay A, Lopez-Casillas F, Malik SN, Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res 2002;62:4690–5.

    CAS  PubMed  Google Scholar 

  66. Lei X, Bandyopadhyay A, Le T, Sun L. Autocrine TGFbeta supports growth and survival of human breast cancer MDA-MB-231 cells. Oncogene 2002;21:7514–23.

    Article  CAS  PubMed  Google Scholar 

  67. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 2001;7:1118–22.

    Article  CAS  PubMed  Google Scholar 

  68. Zhang Q, Yang X, Pins M, Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. Cancer Res 2005;65:1761–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, 221B MSRB Research Drive, Durham, NC, 27710, USA

    Jason D. Lee

  2. Department of Medicine, Duke University Medical Center, Durham, NC, 27710, USA

    Gerard C. Blobe

Authors
  1. Jason D. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerard C. Blobe
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    Lee, J.D., Blobe, G.C. (2009). TGF-β Signaling. In: Giordano, A., Normanno, N. (eds) Breast Cancer in the Post-Genomic Era. Current Clinical Oncology. Humana Press. https://doi.org/10.1007/978-1-60327-945-1_9

    Download citation

    • DOI: https://doi.org/10.1007/978-1-60327-945-1_9

    • Published:

    • Publisher Name: Humana Press

    • Print ISBN: 978-1-60327-944-4

    • Online ISBN: 978-1-60327-945-1

    • eBook Packages: MedicineMedicine (R0)

    Publish with us

    Policies and ethics

    Search

    Navigation