Abstract
There is a general consensus that breast cancer is a rising trend disease in the world. It is one of the most common cancer types and is the leading cause of death among women’s cancers. There are several reasons for this high rate of mortality including metastasis which is responsible for about 90 % of cancer-related mortality. Therefore, recognition and understanding of metastatic process is important, and by considering the key role of pathophysiological route in metastasis as a multistep cascade of “invasion–metastasis,” it might modify and improve our insight toward this complex phenomenon. Moreover, it can provide novel approaches for designing advanced targeted therapies. The present work aimed to review the published papers regarding molecular basis of metastatic process of breast cancer to brain metastasis, especially related genes and signaling network. Furthermore, the use of molecular aspects of metastatic breast cancer to brain was discussed in horizon of future treatment of breast cancer.
Similar content being viewed by others
References
Fidler IJ, Balasubramanian K, Lin Q, Kim SW, Kim S-J (2010) The brain microenvironment and cancer metastasis. Mol Cell 30(2):93–98
Nguyen DX, Massagué J (2007) Genetic determinants of cancer metastasis. Nat Rev Genet 8(5):341–352
Fazilaty H, Mehdipour P (2014) Genetics of breast cancer bone metastasis: a sequential multistep pattern. Clin Exp Metastasis 31(5):595–612
Fidler IJ, Poste G (2008) The “seed and soil” hypothesis revisited. Lancet Oncol 9(8):808
Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30
Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5(8):591–602
Pelletier EM, Shim B, Goodman S, Amonkar MM (2008) Epidemiology and economic burden of brain metastases among patients with primary breast cancer: results from a US claims data analysis. Breast Cancer Res Treat 108(2):297–305
M-m S, Liu J, Vong JS, Niu Y, Germin B, Tang P, Chan AW, Lui PC, Law BK, Tan P-H (2011) A subset of breast cancer predisposes to brain metastasis. Med Mol Morphol 44(1):15–20
Miller K, Weathers T, Haney L, Timmerman R, Dickler M, Shen J, Sledge G Jr (2003) Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival. Ann Oncol 14(7):1072–1077
Aragon-Ching JB, Zujewski JA (2007) CNS metastasis: an old problem in a new guise. Clin Cancer Res 13(6):1644–1647
Gril B, Evans L, Palmieri D, Steeg PS (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):1204–1210
Stemmler H-J, Heinemann V (2008) Central nervous system metastases in HER-2-overexpressing metastatic breast cancer: a treatment challenge. Oncologist 13(7):739–750
Evans A, James J, Cornford E, Chan S, Burrell H, Pinder S, Gutteridge E, Robertson J, Hornbuckle J, Cheung K (2004) Brain metastases from breast cancer: identification of a high-risk group. Clin Oncol 16(5):345–349
Pestalozzi B, Zahrieh D, Price K, Holmberg S, Lindtner J, Collins J, Crivellari D, Fey M, Murray E, Pagani O (2006) Identifying breast cancer patients at risk for central nervous system (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG). Ann Oncol 17(6):935–944
Park B-B, Uhm JE, Cho EY, La Choi Y, Ji SH, Lee JI, Park W, Huh SJ, Park YH, Ahn JS (2009) Prognostic factor analysis in patients with brain metastases from breast cancer: how can we improve the treatment outcomes? Cancer Chemother Pharmacol 63(4):627–633
Liu M-T, Hsieh C-Y, Wang A-Y, Chang T-H, Pi C-P, Huang C-C, Huang C-Y, Liou C-H (2006) Prognostic factors affecting the outcome of brain metastases from breast cancer. Support Care Cancer 14(9):936–942
YAN M, H-m LÜ, Z-z LIU, LIU H, M-w ZHANG, X-b SUN, S-d CUI (2013) High risk factors of brain metastases in 295 patients with advanced breast cancer. Chin Med J (Engl) 126(7):1269–1275
Sezgin C, Gokmen E, Esassolak M, Ozdemir N, Goker E (2007) Risk factors for central nervous system metastasis in patients with metastatic breast cancer. Med Oncol 24(2):155–161
Slimane K, Andre F, Delaloge S, Dunant A, Perez A, Grenier J, Massard C, Spielmann M (2004) Risk factors for brain relapse in patients with metastatic breast cancer. Ann Oncol 15(11):1640–1644
Gaedcke J, Traub F, Milde S, Wilkens L, Stan A, Ostertag H, Christgen M, von Wasielewski R, Kreipe HH (2007) Predominance of the basal type and HER-2/neu type in brain metastasis from breast cancer. Mod Pathol 20(8):864–870
Khaitan D, Sankpal UT, Weksler B, Meister EA, Romero IA, Couraud P-O, Ningaraj NS (2009) Role of KCNMA1 gene in breast cancer invasion and metastasis to brain. BMC Cancer 9(1):258
Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, Sherlock G, Lewicki J, Shedden K, Clarke MF (2007) The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 356(3):217–226
Alison MR, Lin W-R, Lim SM, Nicholson LJ (2012) Cancer stem cells: in the line of fire. Cancer Treat Rev 38(6):589–598
Clarke MF, Fuller M (2006) Stem cells and cancer: two faces of eve. Cell 124(6):1111–1115
Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea—a paradigm shift. Cancer Res 66(4):1883–1890
Mani SA, Guo W, Liao M-J, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715
Nakaya Y, Sheng G (2013) EMT in developmental morphogenesis. Cancer Lett
Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890
De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13(2):97–110
Fazilaty H, Gardaneh M, Bahrami T, Salmaninejad A, Behnam B (2013) Crosstalk between breast cancer stem cells and metastatic niche: emerging molecular metastasis pathway? Tumor Biol:1–12
Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4(6):448–456
Spano D, Heck C, De Antonellis P, Christofori G, Zollo M (2012) Molecular networks that regulate cancer metastasis. In: Semin Cancer Biol. vol 3. Elsevier, pp 234–249
Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 133(3421):571–573
Langley RR, Fidler IJ (2011) The seed and soil hypothesis revisited—the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer 128(11):2527–2535
Scheel C, Weinberg RA (2012) Cancer stem cells and epithelial–mesenchymal transition: concepts and molecular links. In: Semin Cancer Biol. vol 5. Elsevier, pp 396–403
Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J (2008) Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 68(4):989–997
Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454
Fidler IJ, Yano S, R-d Z, Fujimaki T, Bucana CD (2002) The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 3(1):53–57
Valiente M, Obenauf AC, Jin X, Chen Q, Zhang XH-F, Lee DJ, Chaft JE, Kris MG, Huse JT, Brogi E (2014) Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156(5):1002–1016
Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292
Spano D, Zollo M (2012) Tumor microenvironment: a main actor in the metastasis process. Clin Exp Metastasis 29(4):381–395
Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9(4):285–293
Tarin D (2012) Clinical and biological implications of the tumor microenvironment. Cancer Microenviron 5(2):95–112
Lu X, Kang Y (2007) Organotropism of breast cancer metastasis. J Mammary Gland Biol Neoplasia 12(2–3):153–162
Hess KR, Varadhachary GR, Taylor SH, Wei W, Raber MN, Lenzi R, Abbruzzese JL (2006) Metastatic patterns in adenocarcinoma. Cancer 106(7):1624–1633
Hu G, Kang Y, Wang X-F (2009) From breast to the brain: unraveling the puzzle of metastasis organotropism. J Mol Cell Biol 1(1):3–5
Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752
Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, Foekens JA, Martens JW (2008) Subtypes of breast cancer show preferential site of relapse. Cancer Res 68(9):3108–3114
Sørlie T, Tibshirani R, Parker J, Hastie T, Marron J, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci 100(14):8418–8423
Nam B-H, Kim SY, Han H-S, Kwon Y, Lee KS, Kim TH, Ro J (2008) Breast cancer subtypes and survival in patients with brain metastases. Breast Cancer Res 10(1):R20
Schnitt SJ (2010) Classification and prognosis of invasive breast cancer: from morphology to molecular taxonomy. Mod Pathol 23:S60–S64
Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci 98(19):10869–10874
Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360(8):790–800
Kennecke H, Yerushalmi R, Woods R, Cheang MCU, Voduc D, Speers CH, Nielsen TO, Gelmon K (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28(20):3271–3277
Sanna G, Franceschelli L, Rotmensz N, Botteri E, Adamoli L, Marenghi C, Munzone E, Rocca MC, Verri E, Minchella I (2007) Brain metastases in patients with advanced breast cancer. Anticancer Res 27(4C):2865–2869
Bollig-Fischer A, Michelhaugh S, Ali-Fehmi R, Mittal S The molecular genomics of metastatic brain tumours
Klein A, Olendrowitz C, Schmutzler R, Hampl J, Schlag PM, Maass N, Arnold N, Wessel R, Ramser J, Meindl A (2009) Identification of brain- and bone-specific breast cancer metastasis genes. Cancer Lett 276(2):212–220
Tanaka T, Bai Z, Srinoulprasert Y, Yang B, Hayasaka H, Miyasaka M (2005) Chemokines in tumor progression and metastasis. Cancer Sci 96(6):317–322
Zlotnik A (2014) Chemokines in neoplastic progression. In: Semin Cancer Biol. vol 3. Elsevier, pp 181–185
Andre F, Cabioglu N, Assi H, Sabourin J, Delaloge S, Sahin A, Broglio K, Spano J, Combadiere C, Bucana C (2006) Expression of chemokine receptors predicts the site of metastatic relapse in patients with axillary node positive primary breast cancer. Ann Oncol 17(6):945–951
SALCEDO R, RESAU JH, HALVERSON D, HUDSON EA, DAMBACH M, POWELL D, Wasserman K, OPPENHEIM JJ (2000) Differential expression and responsiveness of chemokine receptors (CXCR1–3) by human microvascular endothelial cells and umbilical vein endothelial cells. FASEB J 14(13):2055–2064
Kakinuma T, Hwang ST (2006) Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol 79(4):639–651
Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56
Ben-Baruch A (2008) Organ selectivity in metastasis: regulation by chemokines and their receptors. Clin Exp Metastasis 25(4):345–356
Helbig G, Christopherson KW, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE, Nakshatri H (2003) NF-κB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 278(24):21631–21638
Lee B-C, Lee T-H, Avraham S, Avraham HK (2004) Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1α in breast cancer cell migration through human brain microvascular endothelial Cells1 1NIH grant NS39558 (S. Avraham), the Susan G. Komen Fellowship (S. Avraham), the Milheim Foundation (S. Avraham), CA97153 (H. Avraham), and K18 PAR-02-069 (H. Avraham). Note: this work was done during the term of an established investigatorship from the American Heart Association (H. Avraham). This article is dedicated to Charlene Engelhard for her continuing friendship and support for our research program. Mol Cancer Res 2(6):327–338
Ali S, Lazennec G (2007) Chemokines: novel targets for breast cancer metastasis. Cancer Metastasis Rev 26(3–4):401–420
Hinton CV, Avraham S, Avraham HK (2010) Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain. Clin Exp Metastasis 27(2):97–105
Kim SW, Choi HJ, Lee H-J, He J, Wu Q, Langley RR, Fidler IJ, Kim S-J (2014) Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells. Neuro-oncol:nou128
Kim S-J, Kim J-S, Park ES, Lee J-S, Lin Q, Langley RR, Maya M, He J, Kim S-W, Weihua Z (2011) Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia 13(3):286–298
Kang H, Ko J, Jang S-W (2012) The role of annexin A1 in expression of matrix metalloproteinase-9 and invasion of breast cancer cells. Biochem Biophys Res Commun 423(1):188–194
Marlow R, Strickland P, Lee JS, Wu X, PeBenito M, Binnewies M, Le EK, Moran A, Macias H, Cardiff RD (2008) SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium. Cancer Res 68(19):7819–7827
Schmid BC, Rezniczek GA, Fabjani G, Yoneda T, Leodolter S, Zeillinger R (2007) The neuronal guidance cue Slit2 induces targeted migration and may play a role in brain metastasis of breast cancer cells. Breast Cancer Res Treat 106(3):333–342
Shuman Moss LA, Jensen-Taubman S, Stetler-Stevenson WG (2012) Matrix metalloproteinases: changing roles in tumor progression and metastasis. The American journal of pathology
Zhang M, X-d T, X-x G, Z-g L, J-g H, Yao L (2013) Expression of tissue levels of matrix metalloproteinases and their inhibitors in breast cancer. Breast 22(3):330–334
Mohammad MA, Zeeneldin AA, Elmageed ZYA, Khalil EH, Mahdy SM, Sharada HM, Sharawy SK, Abdel-Wahab A-HA (2012) Clinical relevance of cyclooxygenase-2 and matrix metalloproteinases (MMP-2 and MT1-MMP) in human breast cancer tissue. Mol Cell Biochem 366(1–2):269–275
Mendes O, Kim H-T, Stoica G (2005) Expression of MMP2, MMP9 and MMP3 in breast cancer brain metastasis in a rat model. Clin Exp Metastasis 22(3):237–246
Vasaturo F, Solai F, Malacrino C, Nardo T, Vincenzi B, Modesti M, Scarpa S (2013) Plasma levels of matrix metalloproteinases 2 and 9 correlate with histological grade in breast cancer patients. Oncol Lett 5(1):316–320
Tester AM, Waltham M, Oh S-J, Bae S-N, Bills MM, Walker EC, Kern FG, Stetler-Stevenson WG, Lippman ME, Thompson EW (2004) Pro-matrix metalloproteinase-2 transfection increases orthotopic primary growth and experimental metastasis of MDA-MB-231 human breast cancer cells in nude mice. Cancer Res 64(2):652–658
Mendes O, Kim H-T, Lungu G, Stoica G (2007) MMP2 role in breast cancer brain metastasis development and its regulation by TIMP2 and ERK1/2. Clin Exp Metastasis 24(5):341–351
Sevenich L, Bowman RL, Mason SD, Quail DF, Rapaport F, Elie BT, Brogi E, Brastianos PK, Hahn WC, Holsinger LJ (2014) Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol
Bos PD, Zhang XH-F, Nadal C, Shu W, Gomis RR, Nguyen DX, Minn AJ, van de Vijver MJ, Gerald WL, Foekens JA (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459(7249):1005–1009
Rodrigues-Ferreira S, Abdelkarim M, Dillenburg-Pilla P, Luissint A-C, di-Tommaso A, Deshayes F, Pontes CLS, Molina A, Cagnard N, Letourneur F (2012) Angiotensin II facilitates breast cancer cell migration and metastasis. PLoS One 7(4):e35667
Fatunmbi M, Shelton J, Aronica SM (2012) MMP-9 increases HER2/neu expression and alters apoptosis levels in human mammary epithelial cells (HMEC). Breast Cancer Res Treat 135(2):519–530
Liu T, Sun B, Zhao X, Gu Q, Dong X, Yao Z, Zhao N, Chi J, Liu N, Sun R (2013) HER2/neu expression correlates with vasculogenic mimicry in invasive breast carcinoma. J Cell Mol Med 17(1):116–122
Worzfeld T, Swiercz JM, Looso M, Straub BK, Sivaraj KK, Offermanns S (2012) ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis. J Clin Invest 122(4):1296
Yu D, Hung M-C (2000) Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 19(53):6115
Kwon M, Park S, Choi J, Oh E, Kim Y, Park Y, Cho E, Nam S, Im Y, Shin Y (2012) Clinical significance of CD151 overexpression in subtypes of invasive breast cancer. Br J Cancer 106(5):923–930
Chen Y, Chen L, Li J-Y, Mukaida N, Wang Q, Yang C, Yin W-J, X-h Z, Jin W, Z-m S (2011) ERβ and PEA3 co-activate IL-8 expression and promote the invasion of breast cancer cells. Cancer Biol Ther 11(5):497–511
Kim LS, Huang S, Lu W, Lev DC, Price JE (2004) Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Clin Exp Metastasis 21(2):107–118
Nishizuka I, Ishikawa T, Hamaguchi Y, Kamiyama M, Ichikawa Y, Kadota K, Miki R, Tomaru Y, Mizuno Y, Tominaga N (2002) Analysis of gene expression involved in brain metastasis from breast cancer using cDNA microarray. Breast Cancer 9(1):26–32
Chow A, Arteaga CL, Wang SE (2011) When tumor suppressor TGFβ meets the HER2 (ERBB2) oncogene. J Mammary Gland Biol Neoplasia 16(2):81–88
Lee T-H, Avraham HK, Jiang S, Avraham S (2003) Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. J Biol Chem 278(7):5277–5284
Fokas E, Steinbach JP, Rödel C (2012) Biology of brain metastases and novel targeted therapies: time to translate the research. Biochim Biophys Acta (BBA) Rev Cancer
Marques JB (2009) Treatment of brain metastases in patients with HER2+ breast cancer. Adv Ther 26(1):18–26
Savad S, Mehdipour P, Miryounesi M, Shirkoohi R, Fereidooni F, Mansouri F, Modarressi MH (2012) Expression analysis of MiR-21, MiR-205, and MiR-342 in breast cancer in Iran. Asian Pac J Cancer Prev 13:873–877
Smith ML, Lee JY (2007) Stereotactic radiosurgery in the management of brain metastasis. Neurosurg Focus 22(3):1–8
Khuntia D, Brown P, Li J, Mehta MP (2006) Whole-brain radiotherapy in the management of brain metastasis. J Clin Oncol 24(8):1295–1304
Ogawa K, Yoshii Y, Nishimaki T, Tamaki N, Miyaguni T, Tsuchida Y, Kamada Y, Toita T, Kakinohana Y, Tamaki W (2008) Treatment and prognosis of brain metastases from breast cancer. J Neurooncol 86(2):231–238
Soffietti R, Trevisan E, Rudà R (2012) Targeted therapy in brain metastasis. Curr Opin Oncol 24(6):679–686
Gabos Z, Sinha R, Hanson J, Chauhan N, Hugh J, Mackey JR, Abdulkarim B (2006) Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. J Clin Oncol 24(36):5658–5663
Gril B, Palmieri D, Bronder JL, Herring JM, Vega-Valle E, Feigenbaum L, Liewehr DJ, Steinberg SM, Merino MJ, Rubin SD (2008) Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the brain. J Natl Cancer Inst 100(15):1092–1103
Williams L, Davis-Dusenbery B, Eggan K (2012) SnapShot: directed differentiation of pluripotent stem cells. Cell 149(5):1174
Acknowledgments
We would like to thank the colleagues whose works fill the gaps in metastatic processes.
Conflict of Interest
Both authors have no conflicts of interests.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tayyeb, B., Parvin, M. Pathogenesis of Breast Cancer Metastasis to Brain: a Comprehensive Approach to the Signaling Network. Mol Neurobiol 53, 446–454 (2016). https://doi.org/10.1007/s12035-014-9023-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-014-9023-z