Skip to main content

Breast Cancer Microenvironment and the Metastatic Process

  • Chapter
  • First Online:
Breast Cancer

Abstract

Metastases are the main cause of breast cancer-related death: hence, the clinical need to prevent and to stop metastasis is of outmost importance. Evidence has accumulated that the propensity of breast cancer cells to metastasize depends on multiple interactions with the microenvironment. Exactly how breast cancer cells communicate with their neighboring “normal” cells is an exciting area of research. Many insights have been gained in recent years from genetically engineered mouse models (GEMMs) as well as from in vitro cell line studies and from breast cancer xenograft models. The tumor stroma not only supports the development of metastases but may also prime metastases for specific organs. Here, we highlight the importance of the tumor microenvironment and discuss the mechanisms by which stromal cells within breast carcinomas cooperate in the multistep metastatic process.

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

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
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

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108

    Article  PubMed  Google Scholar 

  2. Early Breast Cancer Trialists’ Collaborative, G (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717

    Article  CAS  Google Scholar 

  3. Bazargani YT, de Boer A, Schellens JH, Leufkens HG, Mantel-Teeuwisse AK (2015) Essential medicines for breast cancer in low and middle income countries. BMC Cancer 15:591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Biganzoli L, Blackwell KL et al (2014) ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast 23:489–502

    Article  CAS  PubMed  Google Scholar 

  5. El Saghir NS, Adebamowo CA, Anderson BO, Carlson RW, Bird PA, Corbex M, Badwe RA, Bushnaq MA, Eniu A, Gralow JR et al (2011) Breast cancer management in low resource countries (LRCs): consensus statement from the Breast Health Global Initiative. Breast 20(Suppl 2):S3–11

    Article  PubMed  Google Scholar 

  6. Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ (2012) WHO classification of tumours of the breast, 4th edn. IARC Press, France, pp 13–59

    Google Scholar 

  7. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  CAS  PubMed  Google Scholar 

  8. Sinn HP, Kreipe H (2013) A brief overview of the WHO classification of breast tumors, 4th edition, focusing on issues and updates from the 3rd edition. Breast Care 8:149–154

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, Nielsen TO, Gelmon K (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28:3271–3277

    Article  PubMed  Google Scholar 

  11. Arpino G, Bardou VJ, Clark GM, Elledge RM (2004) Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res 6:R149–R156

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  13. Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147:275–292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vanharanta S, Massague J (2013) Origins of metastatic traits. Cancer Cell 24:410–421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zardavas D, Baselga J, Piccart M (2013) Emerging targeted agents in metastatic breast cancer. Nat Rev Clin Oncol 10:191–210

    Google Scholar 

  16. Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252

    Article  CAS  PubMed  Google Scholar 

  17. Pein M, Oskarsson T (2015) Microenvironment in metastasis: roadblocks and supportive niches. Am J Physiol Cell Physiol 309:C627–C638

    Article  CAS  PubMed  Google Scholar 

  18. Place AE, Jin Huh S, Polyak K (2011) The microenvironment in breast cancer progression: biology and implications for treatment. Breast Cancer Res 13:227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Massague J, Obenauf AC (2016) Metastatic colonization by circulating tumour cells. Nature 529:298–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Proia DA, Kuperwasser C (2006) Reconstruction of human mammary tissues in a mouse model. Nat Protoc 1:206–214

    Article  CAS  PubMed  Google Scholar 

  21. Kocaturk B, Versteeg HH (2015) Orthotopic injection of breast cancer cells into the mammary fat pad of mice to study tumor growth. J Vis Exp. doi:10.3791/51967

    PubMed  PubMed Central  Google Scholar 

  22. Neville MC, Medina D, Monks J, Hovey RC (1998) The mammary fat pad. J Mammary Gland Biol Neoplasia 3:109–116

    Article  CAS  PubMed  Google Scholar 

  23. Nieto MA (2011) The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 27:347–376

    Article  CAS  PubMed  Google Scholar 

  24. Hay ED (1995) An overview of epithelio-mesenchymal transformation. Acta Anat 154:8–20

    Article  CAS  PubMed  Google Scholar 

  25. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273

    Article  CAS  PubMed  Google Scholar 

  28. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454

    Article  CAS  PubMed  Google Scholar 

  29. Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, Zhou A, Eyob H, Balakrishnan S, Wang CY et al (2015) Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 526:131–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J et al (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527:472–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bissell MJ, Hines WC (2011) Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17:320–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    Article  CAS  PubMed  Google Scholar 

  34. Dumont N, Liu B, Defilippis RA, Chang H, Rabban JT, Karnezis AN, Tjoe JA, Marx J, Parvin B, Tlsty TD (2013) Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia 15:249–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432:332–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kuperwasser C, Chavarria T, Wu M, Magrane G, Gray JW, Carey L, Richardson A, Weinberg RA (2004) Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci USA 101:4966–4971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ronnov-Jessen L, Petersen OW (1993) Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Invest 68:696–707

    CAS  PubMed  Google Scholar 

  38. Avgustinova A, Iravani M, Robertson D, Fearns A, Gao Q, Klingbeil P, Hanby AM, Speirs V, Sahai E, Calvo F, Isacke CM (2016) Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness. Nat Commun 7:10305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Erez N, Truitt M, Olson P, Arron ST, Hanahan D (2010) Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 17:135–147

    Article  CAS  PubMed  Google Scholar 

  40. Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, Onder TT, Wang ZC, Richardson AL, Weinberg RA, Orimo A (2010) Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci USA 107:20009–20014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555

    Article  CAS  PubMed  Google Scholar 

  42. Knowles HJ, Harris AL (2001) Hypoxia and oxidative stress in breast cancer. Hypoxia and tumourigenesis. Breast Cancer Res 3:318–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470:548–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Oskarsson T, Batlle E, Massague J (2014) Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14:306–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, Smid M, Foekens JA, Massague J (2013) Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 154:1060–1073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, Foekens JA, Massague J (2009) Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16:67–78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bergfeld SA, DeClerck YA (2010) Bone marrow-derived mesenchymal stem cells and the tumor microenvironment. Cancer Metastasis Rev 29:249–261

    Article  PubMed  Google Scholar 

  48. Fox JM, Chamberlain G, Ashton BA, Middleton J (2007) Recent advances into the understanding of mesenchymal stem cell trafficking. Br J Haematol 137:491–502

    Article  CAS  PubMed  Google Scholar 

  49. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348

    Article  CAS  PubMed  Google Scholar 

  50. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449:557–563

    Article  CAS  PubMed  Google Scholar 

  51. Trujillo ME, Scherer PE (2006) Adipose tissue-derived factors: impact on health and disease. Endocr Rev 27:762–778

    Article  CAS  PubMed  Google Scholar 

  52. Wang YY, Lehuede C, Laurent V, Dirat B, Dauvillier S, Bochet L, Le Gonidec S, Escourrou G, Valet P, Muller C (2012) Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer. Cancer Lett 324:142–151

    Article  CAS  PubMed  Google Scholar 

  53. Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, Wang YY, Meulle A, Salles B, Le Gonidec S et al (2011) Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res 71:2455–2465

    Article  CAS  PubMed  Google Scholar 

  54. Brandebourg T, Hugo E, Ben-Jonathan N (2007) Adipocyte prolactin: regulation of release and putative functions. Diabetes Obes Metab 9:464–476

    Article  CAS  PubMed  Google Scholar 

  55. Ma CX, Reinert T, Chmielewska I, Ellis MJ (2015) Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer 15:261–275

    Article  CAS  PubMed  Google Scholar 

  56. Surmacz E (2013) Leptin and adiponectin: emerging therapeutic targets in breast cancer. J Mammary Gland Biol Neoplasia 18:321–332

    Article  PubMed  Google Scholar 

  57. Bochet L, Meulle A, Imbert S, Salles B, Valet P, Muller C (2011) Cancer-associated adipocytes promotes breast tumor radioresistance. Biochem Biophys Res Commun 411:102–106

    Article  CAS  PubMed  Google Scholar 

  58. Picon-Ruiz M, Pan C, Drews-Elger K, Jang K, Besser AH, Zhao D, Morata-Tarifa C, Kim M, Ince TA, Azzam DJ et al (2016) Interactions between adipocytes and breast cancer cells stimulate cytokine production and drive Src/Sox2/miR-302b-mediated malignant progression. Cancer Res 76:491–504

    Article  CAS  PubMed  Google Scholar 

  59. Arendt LM, Kuperwasser C (2015) Working stiff: how obesity boosts cancer risk. Sci Transl Med 7:301fs334

    Article  Google Scholar 

  60. Seo BR, Bhardwaj P, Choi S, Gonzalez J, Andresen Eguiluz RC, Wang K, Mohanan S, Morris PG, Du B, Zhou XK et al (2015) Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Science Transl Med 7:301ra130

    Article  CAS  Google Scholar 

  61. Arendt LM, McCready J, Keller PJ, Baker DD, Naber SP, Seewaldt V, Kuperwasser C (2013) Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis. Cancer Res 73:6080–6093

    Article  CAS  PubMed  Google Scholar 

  62. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364

    Article  CAS  PubMed  Google Scholar 

  63. Cooke VG, LeBleu VS, Keskin D, Khan Z, O’Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S et al (2012) Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21:66–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309–322

    Article  CAS  PubMed  Google Scholar 

  65. Keskin D, Kim J, Cooke VG, Wu CC, Sugimoto H, Gu C, De Palma M, Kalluri R, LeBleu VS (2015) Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep 10:1066–1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ehrlich P (1909) Über den jetzigen stand der karzinomforschung. Ned Tijdschr Geneeskd

    Google Scholar 

  67. Kitamura T, Qian BZ, Pollard JW (2015) Immune cell promotion of metastasis. Nat Rev Immunol 15:73–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Tanos T, Sflomos G, Echeverria PC, Ayyanan A, Gutierrez M, Delaloye JF, Raffoul W, Fiche M, Dougall W, Schneider P et al (2013) Progesterone/RANKL is a major regulatory axis in the human breast. Sci Transl Med 5:182ra155

    Article  CAS  Google Scholar 

  70. Coffelt SB, Kersten K, Doornebal CW, Weiden J, Vrijland K, Hau CS, Verstegen NJ, Ciampricotti M, Hawinkels LJ, Jonkers J, de Visser KE (2015) IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522:345–348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Leliefeld PH, Koenderman L, Pillay J (2015) How neutrophils shape adaptive immune responses. Front Immunol 6:471

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Wculek SK, Malanchi I (2015) Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528(7582):413–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496:445–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. De Palma M, Lewis CE (2013) Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23:277–286

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  77. Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, Liu B, Deng H, Wang F, Lin L et al (2011) CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 19:541–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Cameron MD, Schmidt EE, Kerkvliet N, Nadkarni KV, Morris VL, Groom AC, Chambers AF, MacDonald IC (2000) Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res 60:2541–2546

    CAS  PubMed  Google Scholar 

  80. Malanchi I, Santamaria-Martinez A, Susanto E, Peng H, Lehr HA, Delaloye JF, Huelsken J (2012) Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481:85–89

    Article  CAS  Google Scholar 

  81. Gay LJ, Felding-Habermann B (2011) Contribution of platelets to tumour metastasis. Nat Rev Cancer 11:123–134

    Article  CAS  PubMed  Google Scholar 

  82. Nieswandt B, Hafner M, Echtenacher B, Mannel DN (1999) Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 59:1295–1300

    CAS  PubMed  Google Scholar 

  83. Tesfamariam B (2016) Involvement of platelets in tumor cell metastasis. Pharmacol Ther 157:112–119

    Article  CAS  PubMed  Google Scholar 

  84. Labelle M, Begum S, Hynes RO (2011) Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20(5):576–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mitrugno A, Williams D, Kerrigan SW, Moran N (2014) A novel and essential role for FcgammaRIIa in cancer cell-induced platelet activation. Blood 123:249–260

    Article  CAS  PubMed  Google Scholar 

  86. Tesfamariam B (2015) Involvement of platelets in tumor cell metastasis. Pharmacol Ther 157:112–119

    Article  PubMed  CAS  Google Scholar 

  87. Kelly T, Suva LJ, Huang Y, Macleod V, Miao HQ, Walker RC, Sanderson RD (2005) Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases. Cancer Res 65:5778–5784

    Article  CAS  PubMed  Google Scholar 

  88. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S et al (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527:329–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, Li P, Li M, Wang X, Zhang C et al (2015) Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527:100–104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang H, Yu C, Gao X, Welte T, Muscarella AM, Tian L, Zhao H, Zhao Z, Du S, Tao J et al (2015) The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. Cancer Cell 27:193–210

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Langley RR, Fidler IJ (2007) Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev 28:297–321

    Article  CAS  PubMed  Google Scholar 

  92. Kuznetsov HS, Marsh T, Markens BA, Castano Z, Greene-Colozzi A, Hay SA, Brown VE, Richardson AL, Signoretti S, Battinelli EM, McAllister SS (2012) Identification of luminal breast cancers that establish a tumor-supportive macroenvironment defined by proangiogenic platelets and bone marrow-derived cells. Cancer Discov 2:1150–1165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chan DA, Giaccia AJ (2007) Hypoxia, gene expression, and metastasis. Cancer Metastasis Rev 26:333–339

    Article  CAS  PubMed  Google Scholar 

  94. Cox TR, Rumney RM, Schoof EM, Perryman L, Hoye AM, Agrawal A, Bird D, Latif NA, Forrest H, Evans HR et al (2015) The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522:106–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yang MH, Wu KJ (2008) TWIST activation by hypoxia inducible factor-1 (HIF-1): implications in metastasis and development. Cell Cycle 7:2090–2096

    Article  CAS  PubMed  Google Scholar 

  97. King HW, Michael MZ, Gleadle JM (2012) Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 12:421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Liao D, Johnson RS (2007) Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 26:281–290

    Article  CAS  PubMed  Google Scholar 

  99. Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70

    Article  CAS  Google Scholar 

  100. Ciriello G, Gatza ML, Beck AH, Wilkerson MD, Rhie SK, Pastore A, Zhang H, McLellan M, Yau C, Kandoth C et al (2015) Comprehensive molecular portraits of invasive lobular breast cancer. Cell 163:506–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cowper-Sal lari R, Zhang X, Wright JB, Bailey SD, Cole MD, Eeckhoute J, Moore JH, Lupien M (2012) Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nat Genet 44:1191–1198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A, Tarazona N, Fenwick K, Kozarewa I, Lopez-Knowles E, Ribas R et al (2015) Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci Transl Med 7:313ra182

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, Minn AJ, van de Vijver MJ, Gerald WL, Foekens JA, Massague J (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459:1005–1009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massague J (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Weilbaecher KN, Guise TA, McCauley LK (2011) Cancer to bone: a fatal attraction. Nat Rev Cancer 11:411–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ng CK, Martelotto LG, Gauthier A, Wen HC, Piscuoglio S, Lim RS, Cowell CF, Wilkerson PM, Wai P, Rodrigues DN et al (2015) Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification. Genome Biol 16:107

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Nguyen LV, Cox CL, Eirew P, Knapp DJ, Pellacani D, Kannan N, Carles A, Moksa M, Balani S, Shah S et al (2014) DNA barcoding reveals diverse growth kinetics of human breast tumour subclones in serially passaged xenografts. Nat Commun 5:5871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhang QX, Borg A, Wolf DM, Oesterreich S, Fuqua SA (1997) An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res 57:1244–1249

    CAS  PubMed  Google Scholar 

  109. Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X, Kalyana-Sundaram S, Wang R, Ning Y, Hodges L et al (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45:1446–1451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, Li Z, Gala K, Fanning S, King TA et al (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45:1439–1445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, He X, Liu S, Hoog J, Lu C et al (2013) Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep 4:1116–1130

    Article  CAS  PubMed  Google Scholar 

  112. Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT, Van Allen EM, Lawrence MS, Horowitz PM, Cibulskis K et al (2015) Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov 5:1164–1177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Klemm F, Joyce JA (2015) Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol 25:198–213

    Article  PubMed  Google Scholar 

  114. Usary J, Llaca V, Karaca G, Presswala S, Karaca M, He X, Langerod A, Karesen R, Oh DS, Dressler LG et al (2004) Mutation of GATA3 in human breast tumors. Oncogene 23:7669–7678

    Article  CAS  PubMed  Google Scholar 

  115. Chou J, Lin JH, Brenot A, Kim JW, Provot S, Werb Z (2013) GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression. Nat Cell Biol 15:201–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Dydensborg AB, Rose AA, Wilson BJ, Grote D, Paquet M, Giguere V, Siegel PM, Bouchard M (2009) GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis. Oncogene 28:2634–2642

    Article  CAS  PubMed  Google Scholar 

  117. Magnani L, Eeckhoute J, Lupien M (2011) Pioneer factors: directing transcriptional regulators within the chromatin environment. Trends Genet 27:465–474

    Article  CAS  PubMed  Google Scholar 

  118. Yan W, Cao QJ, Arenas RB, Bentley B, Shao R (2010) GATA3 inhibits breast cancer metastasis through the reversal of epithelial-mesenchymal transition. J Biol Chem 285:14042–14051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Yoon NK, Maresh EL, Shen D, Elshimali Y, Apple S, Horvath S, Mah V, Bose S, Chia D, Chang HR, Goodglick L (2010) Higher levels of GATA3 predict better survival in women with breast cancer. Hum Pathol 41:1794–1801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J et al (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559

    Article  CAS  PubMed  Google Scholar 

  121. Albiges L, Andre F, Balleyguier C, Gomez-Abuin G, Chompret A, Delaloge S (2005) Spectrum of breast cancer metastasis in BRCA1 mutation carriers: highly increased incidence of brain metastases. Ann Oncol 16:1846–1847

    Article  CAS  PubMed  Google Scholar 

  122. Pollari S, Kakonen SM, Edgren H, Wolf M, Kohonen P, Sara H, Guise T, Nees M, Kallioniemi O (2011) Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat 125:421–430

    Article  CAS  PubMed  Google Scholar 

  123. Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK et al (2011) Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476:346–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhao YH, Zhou M, Liu H, Ding Y, Khong HT, Yu D, Fodstad O, Tan M (2009) Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth. Oncogene 28:3689–3701

    Article  CAS  PubMed  Google Scholar 

  125. Pencheva N, Tavazoie SF (2013) Control of metastatic progression by microRNA regulatory networks. Nat Cell Biol 15:546–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massague J (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451:147–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lujambio A, Calin GA, Villanueva A, Ropero S, Sanchez-Cespedes M, Blanco D, Montuenga LM, Rossi S, Nicoloso MS, Faller WJ et al (2008) A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA 105:13556–13561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hidalgo M, Amant F, Biankin AV, Budinska E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Maelandsmo GM et al (2014) Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov 4:998–1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Vargo-Gogola T, Rosen JM (2007) Modelling breast cancer: one size does not fit all. Nat Rev Cancer 7:659–672

    Article  CAS  PubMed  Google Scholar 

  130. Ogba N, Manning NG, Bliesner BS, Ambler SK, Haughian JM, Pinto MP, Jedlicka P, Joensuu K, Heikkila P, Horwitz KB (2014) Luminal breast cancer metastases and tumor arousal from dormancy are promoted by direct actions of estradiol and progesterone on the malignant cells. Breast Cancer Res 16:489

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Sflomos G, Dormoy V, Metsalu T, Jeitziner R, Battista L, Scabia V, Raffoul W, Delaloye JF, Treboux A, Fiche M, Vilo J, Ayyanan A, Brisken C (2016) A preclinical model for ERa-positive breast cancer points to the epithelial microenvironment as determinant of luminal phenotype and hormone response. Cancer Cell 29:407–422

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Özden Yalçın Özuysal of Izmir Institute of Technology and Maryse Fiche of University Hospital of Lausanne for critical comments. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking (grant agreement n°115188) for the PREDECT consortium (www.predect.eu) resources composed of financial contribution from EU-FP7 and EFPIA companies in kind contribution. The web address of the Innovative Medicines Initiative is http://www.imi.europa.eu/.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Cathrin Brisken .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Sflomos, G., Brisken, C. (2017). Breast Cancer Microenvironment and the Metastatic Process. In: Veronesi, U., Goldhirsch, A., Veronesi, P., Gentilini, O., Leonardi, M. (eds) Breast Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-48848-6_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-48848-6_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-48846-2

  • Online ISBN: 978-3-319-48848-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics