Cellular and Molecular Mechanisms Involved in Breaching of the Blood–Brian Barrier by Circulating Breast Cancer Cells

  • Hava Karsenty Avraham
  • Shuxian Jiang
  • Lili Wang
  • Yigong Fu
  • Shalom Avraham


Brain metastases are prevalent in lung, melanoma and breast cancers and are associated with high morbidity and mortality. Therefore, targeted treatments and preventative strategies of brain metastasis are needed. Brain metastases of breast cancer confer significant morbidity and appear to be increasing in incidence (~35 %) in subpopulations of metastatic breast cancer patients, particularly those with Her2+ or “triple-negative” breast cancer (TNBC). Current therapy for brain metastases of breast cancer involves radiation, surgery and chemotherapy. Unfortunately, both disease progression in brain and treatments cause significant patient morbidity, including cognitive defects. The main question is how are circulating breast tumor cells (CBTCs) able to penetrate the blood–brain barrier (BBB) and gain access to the brain parenchyma, forming brain metastases. The BBB is a dynamic and highly selective barrier due to existence of tight junctions and adherens junctions between adjacent brain microvascular endothelial cells (BMECs). Although, the disruption of the BBB by brain metastases of human triple-negative and basal-type breast cancer was observed, very little is known on the cellular and molecular mechanisms involved in the process of CBTC infiltration through the BBB. This review focuses on the BBB and BMECs as well as several biological determinants by which breast tumor cells infiltrate the BBB and activate BMECs, resulting in co-option and colonization of tumor cells in brain.


Brain microvascular endothelial cells (BMECs) Blood–brain barrier (BBB) Breast cancer Circulating breast tumor cells (CBTCs) Metastasis Colonization “Triple-negative” breast cancer (TNBC) Transendothelial electrical resistance (TEER) Tight junction (TJ) protein complexes Transmembrane proteins Blood–tumor barrier (BTB) V = vascular endothelial growth factor A (VEGF-A or VEGF) Angiopoietins Substance P (SP) Integrins 







Alpha smooth muscle actin


Blood–brain barrier


Breast cancer metastasis


Breast cancer metastasis in brain


Brain microvascular endothelial cells


Blood–tumor barrier


Circulating breast tumor cells


Central nervous system


Dermal microvascular endothelial cells


Endothelial cells


Estrogen receptor negative


Glyceraldehyde-3-phosphate dehydrogenase


Human umbilical vein endothelial cells


Human brain microvascular endothelial cells






Laser capture microdissection


Progesterone receptor negative


Reverse transcription polymerase chain reaction


Tight junctions


Trans-endothelial electrical resistance


Triple negative and basal type breast cancer


Vascular endothelial growth factor


Vascular endothelial growth factor receptor 2


Western blotting



This research was supported in part by CA135226, DOD Idea Awards (HA), and BC102246, and BC-094909.


  1. 1.
    Steeg PS, Camphausen KA, Smith QR (2011) Brain metastases as preventive and therapeutic targets. Nat Rev Cancer 11(5):352–363PubMedCrossRefGoogle Scholar
  2. 2.
    Fidler IJ (2011) The role of the organ microenvironment in brain metastasis. Semin Cancer Biol 21(2):107–112PubMedCrossRefGoogle Scholar
  3. 3.
    Gril B et al (2010) Translational research in brain metastasis is identifying molecular pathways that may lead to the development of new therapeutic strategies. Eur J Cancer 46(7):1204–1210PubMedCrossRefGoogle Scholar
  4. 4.
    Nguyen DX, Bos PD, Massagué J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9(4):274–284PubMedCrossRefGoogle Scholar
  5. 5.
    Arshad F et al (2010) Blood–brain barrier integrity and breast cancer metastasis to the brain. Pathol Res Int 2011:920509Google Scholar
  6. 6.
    Lesniak MS, Brem H (2004) Targeted therapy for brain tumors. Nat Rev Drug Discov 3(6):499–508PubMedCrossRefGoogle Scholar
  7. 7.
    Chodosh LA (2011) Breast cancer: current state and future promise. Breast Cancer Res 13(6):113PubMedCrossRefGoogle Scholar
  8. 8.
    Rakha EA, Chan S (2011) Metastatic triple-negative breast cancer. Clin Oncol R Coll Radiol 23(9):587–600PubMedCrossRefGoogle Scholar
  9. 9.
    Teng YH et al (2011) Therapeutic targets in triple negative breast cancer—where are we now? Recent Pat Anticancer Drug Discov 6(2):196–209PubMedCrossRefGoogle Scholar
  10. 10.
    Stark A et al (2010) African ancestry and higher prevalence of triple-negative breast cancer: findings from an international study. Cancer 116(21):4926–4932PubMedCrossRefGoogle Scholar
  11. 11.
    Dolle JM et al (2009) Risk factors for tripe-negative breast cancer in women under age 45. Cancer Epidemiol Biomarkers Prev 18(4):1157–1166PubMedCrossRefGoogle Scholar
  12. 12.
    Carotenuto P et al, Triple negative breast cancer: from molecular portrait to therapeutic intervention. Crit Rev Eukaryot Gene Expr 20(1):17–34 Google Scholar
  13. 13.
    Tosoni A, Franceschi E, Brandes AA (2008) Chemotherapy in breast cancer patients with brain metastases: have new chemotherapic agents changed the clinical outcome? Crit Rev Oncol Hematol 68(3):212–221PubMedCrossRefGoogle Scholar
  14. 14.
    Sharma M, Abraham J (2007) CNS metastasis in primary breast cancer. Expert Rev Anticancer Ther 7(11):1561–1566PubMedCrossRefGoogle Scholar
  15. 15.
    Cheng X, Hung MC (2007) Breast cancer brain metastases. Cancer Metastasis Rev 26(3–4):635–643PubMedCrossRefGoogle Scholar
  16. 16.
    Eichler AF, Loeffler JS (2007) Multidisciplinary management of brain metastases. Oncologist 12(7):884–898PubMedCrossRefGoogle Scholar
  17. 17.
    Kaal EC, Vecht CJ (2007) CNS complications of breast cancer: current and emerging treatment options. CNS Drugs 21(7):559–579PubMedCrossRefGoogle Scholar
  18. 18.
    Amos KD, Adamo B, Anders CK (2012) Triple-negative breast cancer: an update on neoadjuvant clinical trials. Int J Breast Cancer 2012:385978 Google Scholar
  19. 19.
    Metzger-Filho O et al (2012) Dissecting the heterogeneity of triple-negative breast cancer. J Clin Oncol 30(15):1879–1887Google Scholar
  20. 20.
    Gucalp A, Traina TA (2011) Triple-negative breast cancer: adjuvant therapeutic options. Chemother Res Pract 2011:696208Google Scholar
  21. 21.
    Park Y et al (2012) Triple-negative breast cancer and Poly(ADP-ribose) polymerase inhibitors. Anticancer Agents Med Chem 12(6):672–677Google Scholar
  22. 22.
    Santarosa M, Maestro R (2011) BRACking news on triple-negative/basal-like breast cancers: how BRCA1 deficiency may result in the development of a selective tumor subtype. Cancer Metastasis RevGoogle Scholar
  23. 23.
    Fornier M, Fumoleau P (2012) The paradox of triple negative breast cancer: novel approaches to treatment. Breast J 18(1):41–51PubMedCrossRefGoogle Scholar
  24. 24.
    Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7(1):41–53PubMedCrossRefGoogle Scholar
  25. 25.
    Hawkins BT, Davis TP (2005) The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57(2):173–185PubMedCrossRefGoogle Scholar
  26. 26.
    Greenwood J (1991) Mechanisms of blood–brain barrier breakdown. Neuroradiology 33(2):95–100PubMedCrossRefGoogle Scholar
  27. 27.
    Yonemori K et al (2010) Disruption of the blood brain barrier by brain metastases of triple-negative and basal-type breast cancer but not HER2/neu-positive breast cancer. Cancer 2:302–308CrossRefGoogle Scholar
  28. 28.
    Alvarez JI et al (2011) The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence. Science 334(6063):1727–1731PubMedCrossRefGoogle Scholar
  29. 29.
    Daneman R et al (2012) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468(7323):562–566CrossRefGoogle Scholar
  30. 30.
    Lin NU, Bellon JR, Winer EP (2004) CNS metastases in breast cancer. J Clin Oncol 22(17):3608–3617PubMedCrossRefGoogle Scholar
  31. 31.
    Lin NU, Winer EP (2007) Brain metastases: the HER2 paradigm. Clin Cancer Res 13(6):1648–1655PubMedCrossRefGoogle Scholar
  32. 32.
    Weil RJ et al (2005) Breast cancer metastasis to the central nervous system. Am J Pathol 167(4):913–920PubMedCrossRefGoogle Scholar
  33. 33.
    Bendell JC et al (2003) Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 97(12):2972–2977PubMedCrossRefGoogle Scholar
  34. 34.
    Lin NU et al (2008) Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer 113(10):2638–2645PubMedCrossRefGoogle Scholar
  35. 35.
    Kienast Y et al (2010) Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 16(1):116–122PubMedCrossRefGoogle Scholar
  36. 36.
    Lockman PR et al (2010) Heterogeneous blood–tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res 16(23):5664–5678PubMedCrossRefGoogle Scholar
  37. 37.
    Reddy BY et al (2010) The microenvironmental effect in the progression, metastasis, and dormancy of breast cancer: a model system within bone marrow. Int J Breast Cancer 721659Google Scholar
  38. 38.
    Martin TA, Mason MD, Jiang WG (2011) Tight junctions in cancer metastasis. Front Biosci 16:898–936PubMedCrossRefGoogle Scholar
  39. 39.
    Phares TW et al (2006) Regional differences in blood–brain barrier permeability changes and inflammation in the apathogenic clearance of virus from the central nervous system. J Immunol 176(12):7666–7675PubMedGoogle Scholar
  40. 40.
    Begley DJ (2004) Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol Ther 104(1):29–45PubMedCrossRefGoogle Scholar
  41. 41.
    Machein MR, Plate KH (2000) VEGF in brain tumors. J Neurooncol 50(1–2):109–120 PubMedCrossRefGoogle Scholar
  42. 42.
    Carbonell WS et al (2009) The vascular basement membrane as “soil” in brain metastasis. PLoS One 4(6):e5857PubMedCrossRefGoogle Scholar
  43. 43.
    Hu G, Kang Y, Wang XF, From breast to the brain: Unraveling the puzzle of metastasis organotropism. J Mol Cell Biol 1(1):3–5 Google Scholar
  44. 44.
    Bos PD, Nguyen DX, Massagué J (2010) Modeling metastasis in the mouse. Curr Opin Pharmacol 10(5):571–577PubMedCrossRefGoogle Scholar
  45. 45.
    Lorger M, Felding-Habermann B (2010) Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am J Pathol 176(6):2958–2971PubMedCrossRefGoogle Scholar
  46. 46.
    Cascone T, Heymach JV (2012) Targeting the angiopoietin/Tie2 pathway: cutting tumor vessels with a double-edged sword? J Clin Oncol 30(4):441–444PubMedCrossRefGoogle Scholar
  47. 47.
    Hashizume H et al (2010) Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res 70(6):2213–2223PubMedCrossRefGoogle Scholar
  48. 48.
    Imanishi Y et al (2011) Angiopoietin-2, an angiogenic regulator, promotes initial growth and survival of breast cancer metastases to the lung through the integrin-linked kinase (ILK)-AKT-B cell lymphoma 2 (Bcl-2) pathway. J Biol Chem 286(33):29249–29260PubMedCrossRefGoogle Scholar
  49. 49.
    Falcón BL et al (2009) Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am J Pathol 175(5):2159–2170PubMedCrossRefGoogle Scholar
  50. 50.
    Vates GE et al (2005) Angiogenesis in the brain during development: the effects of vascular endothelial growth factor and angiopoietin-2 in an animal model. J Neurosurg 103(1):136–450PubMedCrossRefGoogle Scholar
  51. 51.
    Schulz P et al (2011) Angiopoietin-2 drives lymphatic metastasis of pancreatic cancer. FASEB J 25(10):3325–3335PubMedCrossRefGoogle Scholar
  52. 52.
    Saharinen P, Bry M, Alitalo K (2010) How do angiopoietins tie in with vascular endothelial growth factors? Curr Opin Hematol 17(3):198–205PubMedGoogle Scholar
  53. 53.
    Thomas M et al (2010) Angiopoietin-2 stimulation of endothelial cells induces alphavbeta3 integrin internalization and degradation. J Biol Chem 285(31):23842–23849PubMedCrossRefGoogle Scholar
  54. 54.
    Saharinen P et al (2008) Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell–cell and cell–matrix contacts. Nat Cell Biol 10(5):527–537PubMedCrossRefGoogle Scholar
  55. 55.
    Fukuhara S et al (2008) Differential function of Tie2 at cell–cell contacts and cell–substratum contacts regulated by angiopoietin-1. Nat Cell Biol 10(5):513–526PubMedCrossRefGoogle Scholar
  56. 56.
    Rameshwar P (2012) The tachykinergic system as avenues for drug intervention. Recent Pat CNS Drug DiscovGoogle Scholar
  57. 57.
    Muñoz M, Coveñas R (2011) NK-1 receptor antagonists: a new paradigm in pharmacological therapy. Curr Med Chem 18(12):1820–1831PubMedCrossRefGoogle Scholar
  58. 58.
    Muñoz M, Rosso M, Coveñas R (2011) The NK-1 receptor: a new target in cancer therapy. Curr Drug Targets 12(6):909–921PubMedCrossRefGoogle Scholar
  59. 59.
    Harford-Wright E, Lewis KM, Vink R (2011) Towards drug discovery for brain tumors: interaction of kinins and tumors at the blood brain barrier interface. Recent Pat CNS Drug Discov 6(1):31–40PubMedCrossRefGoogle Scholar
  60. 60.
    White DE, Muller WJ (2007) Multifaceted roles of integrins in breast cancer metastasis. J Mammary Gland Biol Neoplasia 12(2–3):135–142PubMedCrossRefGoogle Scholar
  61. 61.
    Lu W, Bucana CD, Schroit AJ (2007) Pathogenesis and vascular integrity of breast cancer brain metastasis. Int J Cancer 120(5):1023–1026PubMedCrossRefGoogle Scholar
  62. 62.
    Zhang C, Yu D (2011) Microenvironment determinants of brain metastasis. Cell Biosci 1(1):8PubMedCrossRefGoogle Scholar
  63. 63.
    Hariharan S et al (2007) Assessment of the biological and pharmacological effects of the αvβ3 and αvβ5 integrin receptor antagonist, cilengitide (EMD 121974)m, in patients with advanced solid tumors. Ann Oncol 18(8):1400–1407PubMedCrossRefGoogle Scholar
  64. 64.
    Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci 24(12):719–725Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Hava Karsenty Avraham
    • 1
  • Shuxian Jiang
    • 1
  • Lili Wang
    • 1
  • Yigong Fu
    • 1
  • Shalom Avraham
    • 1
  1. 1.The Division of Experimental MedicineBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA

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