Skip to main content
SpringerLink
Log in

The Immune System in Breast Cancer Initiation and Progression: Role of Epithelial to Mesenchymal Transition

  • Chapter
  • First Online:
Cell and Molecular Biology of Breast Cancer

  • 2430 Accesses

Abstract

The mammary gland is a complex organ necessary for providing nutrition and immunity to the newborn. Understanding the normal physiology and architecture of the mammary gland is essential because it is an anatomic site that is often diseased in humans. Cancer remains one of the dominant diseases detected in breast tissue. Worldwide, breast cancer is responsible for over 400,000 deaths annually. Despite our tremendous efforts, the molecular and cellular pathways to initiation and progression of breast cancer remain poorly understood. What has become increasingly clear is the microenvironment in the normal and malignant breast can have a profound influence on malignancy. While there are data that suggest that one component of the microenvironment, the immune system, protects against breast cancer, other data support a pathological role. In this review the authors take a comprehensive approach in defining this paradoxical, double-edged, role of the immune system.

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

Access this chapter

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 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
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

Institutional subscriptions

References

  1. Wellings SR, Jensen HM. On the origin and progression of ductal carcinoma in the human breast. J Natl Cancer Inst. 1973;50(5):1111–8.

    PubMed  CAS  Google Scholar 

  2. Wellings SR, Jensen HM, Marcum RG. An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. J Natl Cancer Inst. 1975;55(2): 231–73.

    PubMed  CAS  Google Scholar 

  3. Wellings SR, Jentoft VL. Organ cultures of normal, dysplastic, hyperplastic, and neoplastic human mammary tissues. J Natl Cancer Inst. 1972;49(2):329–38.

    PubMed  CAS  Google Scholar 

  4. Keller PJ, Arendt LM, Skibinski A, et al. Defining the cellular precursors to human breast cancer. Proc Natl Acad Sci USA. 2012;109(8):2772–7.

    PubMed  CAS  Google Scholar 

  5. Burstein HJ, Polyak K, Wong JS, et al. Ductal carcinoma in situ of the breast. N Engl J Med. 2004;350(14):1430–41.

    PubMed  CAS  Google Scholar 

  6. Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, et al. Breast cancer precursors revisited: molecular features and progression pathways. Histopathology. 2010;57(2):171–92.

    PubMed  Google Scholar 

  7. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004;432(7015):332–7.

    PubMed  CAS  Google Scholar 

  8. Brandtzaeg P. The mucosal immune system and its integration with the mammary glands. J Pediatr. 2010;156(2 Suppl):S8–15.

    PubMed  CAS  Google Scholar 

  9. Goldman AS. The immune system of human milk: antimicrobial, antiinflammatory and immunomodulating properties. Pediatr Infect Dis J. 1993;12(8):664–71.

    PubMed  CAS  Google Scholar 

  10. Spencer JP. Management of mastitis in breastfeeding women. Am Fam Physician. 2008;78(6):727–31.

    PubMed  Google Scholar 

  11. Cheroutre H, Madakamutil L. Acquired and natural memory T cells join forces at the mucosal front line. Nat Rev Immunol. 2004;4(4):290–300.

    PubMed  CAS  Google Scholar 

  12. Ghajar CM. On leukocytes in mammary development and cancer. Cold Spring Harb Perspect Biol. 2012;4(5):a013276.

    Google Scholar 

  13. Reed JR, Schwertfeger KL. Immune cell location and function during post-natal mammary gland development. J Mammary Gland Biol Neoplasia. 2010;15(3):329–39.

    PubMed  Google Scholar 

  14. Shankaran V, Ikeda H, Bruce AT, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410(6832):1107–11.

    PubMed  CAS  Google Scholar 

  15. Pabst R, Rothkotter HJ. Structure and function of the gut mucosal immune system. Adv Exp Med Biol. 2006;579:1–14.

    PubMed  CAS  Google Scholar 

  16. Goldblum RM, Ahlstedt S, Carlsson B, et al. Antibody-forming cells in human colostrum after oral immunisation. Nature. 1975;257(5529):797–8.

    PubMed  CAS  Google Scholar 

  17. Brandtzaeg P. Mucosal immunity: induction, dissemination, and effector functions. Scand J Immunol. 2009;70(6):505–15.

    PubMed  CAS  Google Scholar 

  18. Wirt DP, Adkins LT, Palkowetz KH, et al. Activated and memory T lymphocytes in human milk. Cytometry. 1992;13(3):282–90.

    PubMed  CAS  Google Scholar 

  19. Schieferdecker HL, Ullrich R, Hirseland H, et al. T cell differentiation antigens on lymphocytes in the human intestinal lamina propria. J Immunol. 1992;149(8):2816–22.

    PubMed  CAS  Google Scholar 

  20. Zeitz M, Schieferdecker HL, Ullrich R, et al. Phenotype and function of lamina propria T lymphocytes. Immunol Res. 1991;10(3–4):199–206.

    PubMed  CAS  Google Scholar 

  21. Regnault A, Kourilsky P, Cumano A. The TCR-beta chain repertoire of gut-derived T lymphocytes. Semin Immunol. 1995;7(5):307–19.

    PubMed  CAS  Google Scholar 

  22. Blumberg RS, Yockey CE, Gross GG, et al. Human intestinal intraepithelial lymphocytes are derived from a limited number of T cell clones that utilize multiple V beta T cell receptor genes. J Immunol. 1993;150(11):5144–53.

    PubMed  CAS  Google Scholar 

  23. Montufar-Solis D, Garza T, Klein JR. T-cell activation in the intestinal mucosa. Immunol Rev. 2007;215:189–201.

    PubMed  CAS  Google Scholar 

  24. Rocha B, Vassalli P, Guy-Grand D. The V beta repertoire of mouse gut homodimeric alpha CD8+ intraepithelial T cell receptor alpha/beta + lymphocytes reveals a major extrathymic pathway of T cell differentiation. J Exp Med. 1991;173(2):483–6.

    PubMed  CAS  Google Scholar 

  25. Leishman AJ, Gapin L, Capone M, et al. Precursors of functional MHC class I- or class II-restricted CD8alphaalpha(+) T cells are positively selected in the thymus by agonist self-peptides. Immunity. 2002;16(3):355–64.

    PubMed  CAS  Google Scholar 

  26. Taylor BC, Dellinger JD, Cullor JS, et al. Bovine milk lymphocytes display the phenotype of memory T cells and are predominantly CD8+. Cell Immunol. 1994;156(1):245–53.

    PubMed  CAS  Google Scholar 

  27. Khaled WT, Read EK, Nicholson SE, et al. The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development. Development. 2007;134(15):2739–50.

    PubMed  CAS  Google Scholar 

  28. Suzuki K, Kawamoto S, Maruya M, et al. GALT: organization and dynamics leading to IgA synthesis. Adv Immunol. 2010;107:153–85.

    PubMed  CAS  Google Scholar 

  29. Stein T, Morris JS, Davies CR, et al. Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res. 2004;6(2):R75–91.

    PubMed  CAS  Google Scholar 

  30. Coussens LM, Pollard JW. Leukocytes in mammary development and cancer. Cold Spring Harb Perspect Biol. 2011;3(3):a003285.

    Google Scholar 

  31. Gouon-Evans V, Rothenberg ME, Pollard JW. Postnatal mammary gland development requires macrophages and eosinophils. Development. 2000;127(11):2269–82.

    PubMed  CAS  Google Scholar 

  32. Lilla JN, Werb Z. Mast cells contribute to the stromal microenvironment in mammary gland branching morphogenesis. Dev Biol. 2010;337(1):124–33.

    PubMed  CAS  Google Scholar 

  33. Ingman WV, Wyckoff J, Gouon-Evans V, et al. Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev Dyn. 2006;235(12): 3222–9.

    PubMed  CAS  Google Scholar 

  34. Lin EY, Gouon-Evans V, Nguyen AV, et al. The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia. 2002;7(2):147–62.

    PubMed  Google Scholar 

  35. Pollard JW, Hennighausen L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc Natl Acad Sci USA. 1994;91(20):9312–6.

    PubMed  CAS  Google Scholar 

  36. O'Brien J, Lyons T, Monks J, et al. Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species. Am J Pathol. 2010;176(3):1241–55.

    PubMed  Google Scholar 

  37. Saleh M, Trinchieri G. Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nat Rev Immunol. 2011;11(1):9–20.

    PubMed  CAS  Google Scholar 

  38. Wei WZ, Gill RF, Wang H. Mouse mammary tumor virus associated antigens and superantigens–immuno-molecular correlates of neoplastic progression. Semin Cancer Biol. 1993;4(3):205–13.

    PubMed  CAS  Google Scholar 

  39. Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. Int J Cancer. 2007;121(11):2373–80.

    PubMed  CAS  Google Scholar 

  40. Philip M, Rowley DA, Schreiber H. Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol. 2004;14(6):433–9.

    PubMed  CAS  Google Scholar 

  41. Stewart T, Tsai SC, Grayson H, et al. Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet. 1995;346(8978):796–8.

    PubMed  CAS  Google Scholar 

  42. Engels EA, Pfeiffer RM, Fraumeni Jr JF, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011;306(17):1891–901.

    PubMed  CAS  Google Scholar 

  43. Adami J, Gabel H, Lindelof B, et al. Cancer risk following organ transplantation: a nationwide cohort study in Sweden. Br J Cancer. 2003;89(7):1221–7.

    PubMed  CAS  Google Scholar 

  44. Birkeland SA, Storm HH, Lamm LU, et al. Cancer risk after renal transplantation in the Nordic countries, 1964–1986. Int J Cancer. 1995;60(2):183–9.

    PubMed  CAS  Google Scholar 

  45. Kelly DM, Emre S, Guy SR, et al. Liver transplant recipients are not at increased risk for nonlymphoid solid organ tumors. Cancer. 1998;83(6):1237–43.

    PubMed  CAS  Google Scholar 

  46. Xu XC. COX-2 inhibitors in cancer treatment and prevention, a recent development. Anticancer Drugs. 2002;13(2):127–37.

    PubMed  CAS  Google Scholar 

  47. Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 2012;13(5):518–27.

    PubMed  CAS  Google Scholar 

  48. Monson RR, Yen S, MacMahon B. Chronic mastitis and carcinoma of the breast. Lancet. 1976;2(7979):224–6.

    PubMed  CAS  Google Scholar 

  49. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340(6):448–54.

    PubMed  CAS  Google Scholar 

  50. Ridker PM. Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutr Rev. 2007;65(12 Pt 2):S253–9.

    Google Scholar 

  51. Siemes C, Visser LE, Coebergh JW, et al. C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol. 2006;24(33):5216–22.

    PubMed  CAS  Google Scholar 

  52. Zhang SM, Lin J, Cook NR, et al. C-reactive protein and risk of breast cancer. J Natl Cancer Inst. 2007;99(11):890–4.

    PubMed  CAS  Google Scholar 

  53. Heikkila K, Harris R, Lowe G, et al. Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis. Cancer Causes Control. 2009;20(1):15–26.

    PubMed  Google Scholar 

  54. Dunning AM, Ellis PD, McBride S, et al. A transforming growth factor beta1 signal peptide variant increases secretion in vitro and is associated with increased incidence of invasive breast cancer. Cancer Res. 2003;63(10):2610–5.

    PubMed  CAS  Google Scholar 

  55. Kaarvatn MH, Vrbanec J, Kulic A, et al. Single nucleotide polymorphism in the interleukin 12B gene is associated with risk for breast cancer development. Scand J Immunol. 2012;76(3):329–35.

    PubMed  CAS  Google Scholar 

  56. Slattery ML, Curtin K, Baumgartner R, et al. IL6, aspirin, nonsteroidal anti-inflammatory drugs, and breast cancer risk in women living in the southwestern United States. Cancer Epidemiol Biomarkers Prev. 2007;16(4):747–55.

    PubMed  CAS  Google Scholar 

  57. Asiedu MK, Ingle JN, Behrens MD, et al. TGFbeta/TNF(alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. Cancer Res. 2011;71(13):4707–19.

    PubMed  CAS  Google Scholar 

  58. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4(1):71–8.

    PubMed  CAS  Google Scholar 

  59. Langrish CL, McKenzie BS, Wilson NJ, et al. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev. 2004;202:96–105.

    PubMed  CAS  Google Scholar 

  60. Korn T, Bettelli E, Oukka M, et al. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517.

    PubMed  CAS  Google Scholar 

  61. Sumarac-Dumanovic M, Stevanovic D, Ljubic A, et al. Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women. Int J Obes. 2009;33(1):151–6.

    CAS  Google Scholar 

  62. Anderson GL, Neuhouser ML. Obesity and the risk for premenopausal and postmenopausal breast cancer. Cancer Prev Res. 2012;5(4):515–21.

    Google Scholar 

  63. Winer S, Paltser G, Chan Y, et al. Obesity predisposes to Th17 bias. Eur J Immunol. 2009;39(9):2629–35.

    PubMed  CAS  Google Scholar 

  64. Wang L, Jiang Y, Zhang Y, et al. Association analysis of IL-17A and IL-17F polymorphisms in Chinese Han women with breast cancer. PLoS One. 2012;7(3):e34400.

    PubMed  CAS  Google Scholar 

  65. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99.

    PubMed  CAS  Google Scholar 

  66. Cole SW. Chronic inflammation and breast cancer recurrence. J Clin Oncol. 2009;27(21):3418–9.

    PubMed  Google Scholar 

  67. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–8.

    PubMed  CAS  Google Scholar 

  68. Albuquerque KV, Price MR, Badley RA, et al. Pre-treatment serum levels of tumour markers in metastatic breast cancer: a prospective assessment of their role in predicting response to therapy and survival. Eur J Surg Oncol. 1995;21(5):504–9.

    PubMed  CAS  Google Scholar 

  69. Al Murri AM, Bartlett JM, Canney PA, et al. Evaluation of an inflammation-based prognostic score (GPS) in patients with metastatic breast cancer. Br J Cancer. 2006;94(2):227–30.

    PubMed  CAS  Google Scholar 

  70. Pierce BL, Ballard-Barbash R, Bernstein L, et al. Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol. 2009;27(21):3437–44.

    PubMed  CAS  Google Scholar 

  71. Schultz DR, Arnold PI. Properties of four acute phase proteins: C-reactive protein, serum amyloid A protein, alpha 1-acid glycoprotein, and fibrinogen. Semin Arthritis Rheum. 1990;20(3):129–47.

    PubMed  CAS  Google Scholar 

  72. Malle E, Sodin-Semrl S, Kovacevic A. Serum amyloid A: an acute-phase protein involved in tumour pathogenesis. Cell Mol Life Sci. 2009;66(1):9–26.

    PubMed  CAS  Google Scholar 

  73. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40(7):1830–5.

    PubMed  CAS  Google Scholar 

  74. Bachelot T, Ray-Coquard I, Menetrier-Caux C, et al. Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients. Br J Cancer. 2003;88(11):1721–6.

    PubMed  CAS  Google Scholar 

  75. Salgado R, Junius S, Benoy I, et al. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer. 2003;103(5):642–6.

    PubMed  CAS  Google Scholar 

  76. Hulkkonen J, Pertovaara M, Antonen J, et al. Elevated interleukin-6 plasma levels are regulated by the promoter region polymorphism of the IL6 gene in primary Sjogren’s syndrome and correlate with the clinical manifestations of the disease. Rheumatology. 2001;40(6):656–61.

    PubMed  CAS  Google Scholar 

  77. Gonzalez-Zuloeta Ladd AM, Arias Vasquez A, Witteman J, et al. Interleukin 6 G-174 C polymorphism and breast cancer risk. Eur J Epidemiol. 2006;21(5):373–6.

    PubMed  CAS  Google Scholar 

  78. Madeleine MM, Johnson LG, Malkki M, et al. Genetic variation in proinflammatory cytokines IL6, IL6R, TNF-region, and TNFRSF1A and risk of breast cancer. Breast Cancer Res Treat. 2011;129(3):887–99.

    PubMed  CAS  Google Scholar 

  79. Kraus S, Arber N. Inflammation and colorectal cancer. Curr Opin Pharmacol. 2009;9(4):405–10.

    PubMed  CAS  Google Scholar 

  80. Mohammed ZM, Going JJ, Edwards J, et al. The role of the tumour inflammatory cell infiltrate in predicting recurrence and survival in patients with primary operable breast cancer. Cancer Treat Rev. 2012;38(8):943–55.

    PubMed  CAS  Google Scholar 

  81. Geissmann F, Manz MG, Jung S, et al. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327(5966):656–61.

    PubMed  CAS  Google Scholar 

  82. Pollard JW. Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol. 2008;84(3):623–30.

    PubMed  CAS  Google Scholar 

  83. Buckner JH, Ziegler SF. Regulating the immune system: the induction of regulatory T cells in the periphery. Arthritis Res Ther. 2004;6(5):215–22.

    PubMed  CAS  Google Scholar 

  84. Kronenberg M, Rudensky A. Regulation of immunity by self-reactive T cells. Nature. 2005;435(7042):598–604.

    PubMed  CAS  Google Scholar 

  85. Mills KH, McGuirk P. Antigen-specific regulatory T cells–their induction and role in infection. Semin Immunol. 2004;16(2):107–17.

    PubMed  CAS  Google Scholar 

  86. Wing K, Suri-Payer E, Rudin A. CD4+CD25+-regulatory T cells from mouse to man. Scand J Immunol. 2005;62(1):1–15.

    PubMed  CAS  Google Scholar 

  87. Gregori S, Bacchetta R, Hauben E, et al. Regulatory T cells: prospective for clinical application in hematopoietic stem cell transplantation. Curr Opin Hematol. 2005;12(6):451–6.

    PubMed  Google Scholar 

  88. Bacchetta R, Gregori S, Roncarolo MG. CD4+ regulatory T cells: mechanisms of induction and effector function. Autoimmun Rev. 2005;4(8):491–6.

    PubMed  Google Scholar 

  89. Maggi E, Cosmi L, Liotta F, et al. Thymic regulatory T cells. Autoimmun Rev. 2005;4(8):579–86.

    PubMed  CAS  Google Scholar 

  90. Lan RY, Ansari AA, Lian ZX, et al. Regulatory T cells: development, function and role in autoimmunity. Autoimmun Rev. 2005;4(6):351–63.

    PubMed  CAS  Google Scholar 

  91. Mahmoud SM, Paish EC, Powe DG, et al. An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Res Treat. 2011;127(1):99–108.

    PubMed  CAS  Google Scholar 

  92. Ladoire S, Mignot G, Dabakuyo S, et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol. 2011;224(3):389–400.

    PubMed  CAS  Google Scholar 

  93. Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373–80.

    PubMed  Google Scholar 

  94. de Kruijf EM, van Nes JG, Sajet A, et al. The predictive value of HLA class I tumor cell expression and presence of intratumoral Tregs for chemotherapy in patients with early breast cancer. Clin Cancer Res. 2010;16(4):1272–80.

    PubMed  Google Scholar 

  95. Gobert M, Treilleux I, Bendriss-Vermare N, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 2009;69(5):2000–9.

    PubMed  CAS  Google Scholar 

  96. Liu F, Lang R, Zhao J, et al. CD8 cytotoxic T cell and FOXP3 regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat. 2011;130(2):645–55.

    PubMed  CAS  Google Scholar 

  97. Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol. 2002;20:323–70.

    PubMed  CAS  Google Scholar 

  98. Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58(16):3491–4.

    PubMed  CAS  Google Scholar 

  99. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.

    PubMed  CAS  Google Scholar 

  100. Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102(51):18538–43.

    PubMed  CAS  Google Scholar 

  101. Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29(15):1949–55.

    PubMed  Google Scholar 

  102. Murri AM, Hilmy M, Bell J, et al. The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer. Br J Cancer. 2008;99(7):1013–9.

    PubMed  CAS  Google Scholar 

  103. Matkowski R, Gisterek I, Halon A, et al. The prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in breast cancer. Anticancer Res. 2009;29(7):2445–51.

    PubMed  CAS  Google Scholar 

  104. Behrens MD, Wagner WM, Krco CJ, et al. The endogenous danger signal, crystalline uric acid, signals for enhanced antibody immunity. Blood. 2007;111(3):1472–9.

    PubMed  Google Scholar 

  105. Santisteban M, Reiman JM, Asiedu MK, et al. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res. 2009;69(7):2887–95.

    PubMed  CAS  Google Scholar 

  106. Radisky DC. Epithelial-mesenchymal transition. J Cell Sci. 2005;118(Pt 19):4325–6.

    PubMed  CAS  Google Scholar 

  107. Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003;120(11):1351–83.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  109. Duband JL. Neural crest delamination and migration: integrating regulations of cell interactions, locomotion, survival and fate. Adv Exp Med Biol. 2006;589:45–77.

    PubMed  CAS  Google Scholar 

  110. Runyan RB, Heimark RL, Camenisch TD, et al. Epithelial-mesenchymal transformation in the embryonic heart. In: Savagner P, editor. Rise and fall of epithelial phenotype. New York: Springer; 2005. p. 40–55.

    Google Scholar 

  111. Fata JE, Werb Z, Bissell MJ. Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast Cancer Res. 2004;6(1):1–11.

    PubMed  CAS  Google Scholar 

  112. Sternlicht MD, Kouros-Mehr H, Lu P, et al. Hormonal and local control of mammary branching morphogenesis. Differentiation. 2006;74(7):365–81.

    PubMed  CAS  Google Scholar 

  113. Wiseman BS, Werb Z. Stromal effects on mammary gland development and breast cancer. Science. 2002;296(5570):1046–9.

    PubMed  CAS  Google Scholar 

  114. Kouros-Mehr H, Werb Z. Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn. 2006;235(12):3404–12.

    PubMed  CAS  Google Scholar 

  115. Wiseman BS, Sternlicht MD, Lund LR, et al. Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. J Cell Biol. 2003;162(6):1123–33.

    PubMed  CAS  Google Scholar 

  116. Sympson CJ, Talhouk RS, Alexander CM, et al. Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J Cell Biol. 1994;125(3):681–93.

    PubMed  CAS  Google Scholar 

  117. Wang YA, Shen K, Wang Y, et al. Retinoic acid signaling is required for proper morphogenesis of mammary gland. Dev Dyn. 2005;234(4):892–9.

    PubMed  CAS  Google Scholar 

  118. Perez-Moreno M, Fuchs E. Catenins: keeping cells from getting their signals crossed. Dev Cell. 2006;11(5):601–12.

    PubMed  CAS  Google Scholar 

  119. Chanson L, Brownfield D, Garbe JC, et al. Self-organization is a dynamic and lineage-intrinsic property of mammary epithelial cells. Proc Natl Acad Sci USA. 2011;108(8):3264–9.

    PubMed  CAS  Google Scholar 

  120. LaBarge MA, Nelson CM, Villadsen R, et al. Human mammary progenitor cell fate decisions are products of interactions with combinatorial microenvironments. Integr Biol. 2009;1(1): 70–9.

    CAS  Google Scholar 

  121. Cukierman E, Pankov R, Stevens DR, et al. Taking cell-matrix adhesions to the third dimension. Science. 2001;294(5547):1708–12.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  123. Shirakihara T, Horiguchi K, Miyazawa K, et al. TGF-beta regulates isoform switching of FGF receptors and epithelial-mesenchymal transition. EMBO J. 2011;30(4):783–95.

    PubMed  CAS  Google Scholar 

  124. Radisky ES, Radisky DC. Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer. J Mammary Gland Biol Neoplasia. 2010;15(2):201–12.

    PubMed  Google Scholar 

  125. Lochter A, Galosy S, Muschler J, et al. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol. 1997;139(7):1861–72.

    PubMed  CAS  Google Scholar 

  126. Lochter A, Srebrow A, Sympson CJ, et al. Misregulation of stromelysin-1 expression in mouse mammary tumor cells accompanies acquisition of stromelysin-1-dependent invasive properties. J Biol Chem. 1997;272(8):5007–15.

    PubMed  CAS  Google Scholar 

  127. Lopez-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009;1(6–7):303–14.

    PubMed  CAS  Google Scholar 

  128. Nieto MA. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol. 2011;27:347–76.

    PubMed  CAS  Google Scholar 

  129. Sanjabi S, Zenewicz LA, Kamanaka M, et al. Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol. 2009;9(4):447–53.

    PubMed  CAS  Google Scholar 

  130. Acloque H, Adams MS, Fishwick K, et al. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest. 2009;119(6): 1438–49.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  132. Sieweke MH, Stoker AW, Bissell MJ. Evaluation of the cocarcinogenic effect of wounding in Rous sarcoma virus tumorigenesis. Cancer Res. 1989;49(22):6419–24.

    PubMed  CAS  Google Scholar 

  133. Sieweke MH, Thompson NL, Sporn MB, et al. Mediation of wound-related Rous sarcoma virus tumorigenesis by TGF-beta. Science. 1990;248(4963):1656–60.

    PubMed  CAS  Google Scholar 

  134. Fuxe J, Vincent T, Garcia de Herreros A. Transcriptional crosstalk between TGFbeta and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell Cycle. 2010;9(12):2363–74.

    PubMed  CAS  Google Scholar 

  135. Bates RC, Mercurio AM. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell. 2003;14(5):1790–800.

    PubMed  CAS  Google Scholar 

  136. Souslova V, Townsend PA, Mann J, et al. Allele-specific regulation of matrix metalloproteinase-3 gene by transcription factor NFkappaB. PLoS One. 2010;5(3):e9902.

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  138. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005;132(14):3151–61.

    PubMed  CAS  Google Scholar 

  139. Carver EA, Jiang R, Lan Y, et al. The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol. 2001;21(23):8184–8.

    PubMed  CAS  Google Scholar 

  140. Rowe RG, Li XY, Hu Y, et al. Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs. J Cell Biol. 2009;184(3):399–408.

    PubMed  CAS  Google Scholar 

  141. de Herreros AG, Peiro S, Nassour M, et al. Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. J Mammary Gland Biol Neoplasia. 2010;15(2):135–47.

    PubMed  Google Scholar 

  142. Przybylo JA, Radisky DC. Matrix metalloproteinase-induced epithelial-mesenchymal transition: tumor progression at Snail's pace. Int J Biochem Cell Biol. 2007;39(6):1082–8.

    PubMed  CAS  Google Scholar 

  143. Franco DL, Mainez J, Vega S, et al. Snail1 suppresses TGF-beta-induced apoptosis and is sufficient to trigger EMT in hepatocytes. J Cell Sci. 2010;123(Pt 20):3467–77.

    PubMed  CAS  Google Scholar 

  144. Sullivan NJ, Sasser AK, Axel AE, et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene. 2009;28(33):2940–7.

    PubMed  CAS  Google Scholar 

  145. Fuchs E, Tumbar T, Guasch G. Socializing with the neighbors: stem cells and their niche. Cell. 2004;116(6):769–78.

    PubMed  CAS  Google Scholar 

  146. Kakarala M, Wicha MS. Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol. 2008;26(17):2813–20.

    PubMed  Google Scholar 

  147. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645–8.

    PubMed  CAS  Google Scholar 

  148. Hollier BG, Evans K, Mani SA. The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia. 2009;14(1):29–43.

    PubMed  Google Scholar 

  149. Creighton CJ, Li X, Landis M, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 2009;106(33):13820–5.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  151. Morel AP, Lievre M, Thomas C, et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One. 2008;3(8):e2888.

    PubMed  Google Scholar 

  152. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21(2):137–48.

    PubMed  CAS  Google Scholar 

  153. Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation. Nature. 2008;454(7203):436–44.

    PubMed  CAS  Google Scholar 

  154. Tan TT, Coussens LM. Humoral immunity, inflammation and cancer. Curr Opin Immunol. 2007;19(2):209–16.

    PubMed  CAS  Google Scholar 

  155. Reiman JM, Kmieciak M, Manjili MH, et al. Tumor immunoediting and immunosculpting pathways to cancer progression. Semin Cancer Biol. 2007;17(4):275–87.

    PubMed  CAS  Google Scholar 

  156. Reiman JM, Knutson KL, Radisky DC. Immune promotion of epithelial-mesenchymal transition and generation of breast cancer stem cells. Cancer Res. 2010;70(8):3005–8.

    PubMed  Google Scholar 

  157. Kmieciak M, Knutson KL, Dumur CI, et al. HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses. Eur J Immunol. 2007;37(3):675–85.

    PubMed  CAS  Google Scholar 

  158. Knutson KL, Lu H, Stone B, et al. Immunoediting of cancers may lead to epithelial to mesenchymal transition. J Immunol. 2006;177(3):1526–33.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This author’s work was supported by a generous gift from Martha and Bruce Atwater (KLK), support from the Susan B. Komen Foundation (FAS0703855, DCR), and the National Cancer Institute (Howard Temin Award [K01-CA100764, KLK]; R01-CA122086, DCR; P50-CA116201, KLK; and P50-CA136393, KLK).

Author information

Authors and Affiliations

  1. Vaccine and Gene Therapy Institute of Florida, 9801 SW Discovery Way, Port St. Lucie, FL, 34987, USA

    Keith L. Knutson

  2. Department of Immunology, Mayo Clinic, Rochester, MN, 55906, USA

    Keith L. Knutson

  3. Department of Biochemistry and Molecular Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Derek C. Radisky

Authors
  1. Keith L. Knutson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Derek C. Radisky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keith L. Knutson .

Editor information

Editors and Affiliations

  1. University of Missouri-Columbia Dept. Veterinary Pathobiology, Columbia, Missouri, USA

    Heide Schatten

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Knutson, K.L., Radisky, D.C. (2013). The Immune System in Breast Cancer Initiation and Progression: Role of Epithelial to Mesenchymal Transition. In: Schatten, H. (eds) Cell and Molecular Biology of Breast Cancer. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-634-4_3

Download citation

Publish with us

Policies and ethics

Search

Navigation