Proteoglycans: Potential Agents in Mammographic Density and the Associated Breast Cancer Risk

  • Michael S. Shawky
  • Carmela Ricciardelli
  • Megan Lord
  • John Whitelock
  • Vito Ferro
  • Kara Britt
  • Erik W. Thompson


Although increased mammographic density (MD) has been well established as a marker for increased breast cancer (BC) risk, its pathobiology is far from understood. Altered proteoglycan (PG) composition may underpin the physical properties of MD, and may contribute to the associated increase in BC risk. Numerous studies have investigated PGs, which are a major stromal matrix component, in relation to MD and BC and reported results that are sometimes discordant. Our review summarises these results and highlights discrepancies between PG associations with BC and MD, thus serving as a guide for identifying PGs that warrant further research towards developing chemo-preventive or therapeutic agents targeting pre-invasive or invasive breast lesions, respectively.


Breast cancer Mammographic density Proteoglycans Extracellular matrix Syndecan Versican Perlecan Glypican Heparanase 



EWT is supported in part by the National Breast Cancer Foundation (Australia). KB is supported by the National Breast Cancer Foundation (Australia). This study benefited from support from the Victorian Government’s Operational Infrastructure Support Program.


  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.PubMedCrossRefGoogle Scholar
  2. 2.
    Australia BCN. Current Statistics in Australian Breast Cancer. n.p., n.d. Web. Jan. 2015.Google Scholar
  3. 3.
    Yaghjyan L, Colditz GA, Rosner B, Tamimi RM. Mammographic breast density and breast cancer risk: interactions of percent density, absolute dense, and non-dense areas with breast cancer risk factors. Breast Cancer Res Treat. 2015:1–9.Google Scholar
  4. 4.
    Mirette H, Caroline D. Is mammographic density a biomarker to study the molecular causes of breast cancer? INTECH Open Access Publisher; 2012.Google Scholar
  5. 5.
    Huo CW, Chew GL, Britt KL, Ingman WV, Henderson MA, Hopper JL, et al. Mammographic density-a review on the current understanding of its association with breast cancer. Breast Cancer Res Treat. 2014;144(3):479–502.PubMedCrossRefGoogle Scholar
  6. 6.
    Britt K, Ingman W, Huo C, Chew G, Thompson E. The pathobiology of mammographic density. J Cancer Biol Res. 2014;2(1):1021.Google Scholar
  7. 7.
    Acerbi I, Au A, Chen Y-Y, Hwang S, Weaver V. P2-10-01: extracellular matrix stiffness and mammographic density in the human breast. Cancer Res. 2011;71(24 Supplement):P2-10-01.CrossRefGoogle Scholar
  8. 8.
    Provenzano PP, Inman DR, Eliceiri KW, Keely PJ. Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene. 2009;28(49):4326–43.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005;8(3):241–54.PubMedCrossRefGoogle Scholar
  10. 10.
    Oskarsson T. Extracellular matrix components in breast cancer progression and metastasis. Breast. 2013;22:S66–72.PubMedCrossRefGoogle Scholar
  11. 11.
    Li T, Sun L, Miller N, Nicklee T, Woo J, Hulse-Smith L, et al. The association of measured breast tissue characteristics with mammographic density and other risk factors for breast cancer. Cancer Epidemiol Biomarkers Prev. 2005;14(2):343–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139(5):891–906.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression. Nat Rev Cancer. 2009;9(2):108–22.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Lyons TR, O’Brien J, Borges V, Conklin MW, Keely PJ, Eliceiri KW, et al. Postpartum mammary gland involution drives DCIS progression through collagen and COX-2. Nat Med. 2011;17(9):1109–15.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Maller O, Hansen KC, Lyons TR, Acerbi I, Weaver VM, Prekeris R, et al. Collagen architecture in pregnancy-induced protection from breast cancer. J Cell Sci. 2013;126(Pt 18):4108–10.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, et al. Collagen density promotes mammary tumor initiation and progression. BMC Med. 2008;6:11.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, et al. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat Cell Biol. 2013;15(6):677–87.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Karousou E, D’Angelo ML, Kouvidi K, Vigetti D, Viola M, Nikitovic D, et al. Collagen VI and hyaluronan: the common role in breast cancer. Biomed Res Int. 2014;2014:10.CrossRefGoogle Scholar
  19. 19.
    Stoeckelhuber M, Stumpf P, Hoefter EA, Welsch U. Proteoglycan-collagen associations in the non-lactating human breast connective tissue during the menstrual cycle. Histochem Cell Biol. 2002;118(3):221–30.PubMedGoogle Scholar
  20. 20.
    Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci. 2010;123(24):4195–200.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Theocharis AD, Skandalis SS, Neill T, Multhaupt HAB, Hubo M, Frey H, et al. Insights into the key roles of proteoglycans in breast cancer biology and translational medicine. Biochim Biophys Acta. 2015;1855(2):276–300.PubMedGoogle Scholar
  22. 22.
    Choi S, Kang DH, Oh ES. Targeting syndecans: a promising strategy for the treatment of cancer. Expert Opin Ther Targets. 2013;17(6):695–705.PubMedCrossRefGoogle Scholar
  23. 23.
    Theocharis AD, Skandalis SS, Tzanakakis GN, Karamanos NK. Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J. 2010;277(19):3904–23.PubMedCrossRefGoogle Scholar
  24. 24.
    Goldoni S, Seidler DG, Heath J, Fassan M, Baffa R, Thakur ML, et al. An antimetastatic role for decorin in breast cancer. Am J Pathol. 2008;173(3):844–55.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Schaefer L, Schaefer R. Proteoglycans: from structural compounds to signaling molecules. Cell Tissue Res. 2010;339(1):237–46.PubMedCrossRefGoogle Scholar
  26. 26.
    Iozzo RV. Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem. 1998;67(1):609–52.PubMedCrossRefGoogle Scholar
  27. 27.
    Pérez S, Sarkar A, Rivet A, Breton C, Imberty A. Glyco3D: a portal for structural glycosciences. In: Lütteke T, Frank M, editors. Glycoinformatics. New York: Springer; 2015. p. 241–58.Google Scholar
  28. 28.
    Uchimura K. Keratan sulfate: biosynthesis, structures, and biological functions. In: Balagurunathan K, Nakato H, Desai UR, editors. Glycosaminoglycans. New York: Springer; 2015. p. 389–400.Google Scholar
  29. 29.
    Anower EKMF, Kimata K. Human blood glycosaminoglycans: isolation and analysis. Methods Mol Biol. 2015;1229:95–103.CrossRefGoogle Scholar
  30. 30.
    Iozzo RV, Schaefer L. Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol. 2015(0).Google Scholar
  31. 31.
    Sainio A, Järveläinen H. extracellular matrix macromolecules in tumour microenvironment with special reference to desmoplastic reaction and the role of matrix proteoglycans and hyaluronan. J Carcinogene Mutagene S. 2013;13.Google Scholar
  32. 32.
    Maller O, Martinson H, Schedin P. Extracellular matrix composition reveals complex and dynamic stromal-epithelial interactions in the mammary gland. J Mammary Gland Biol Neoplasia. 2010;15(3):301–18.PubMedCrossRefGoogle Scholar
  33. 33.
    Leygue E, Snell L, Dotzlaw H, Troup S, Hiller-Hitchcock T, Murphy LC, et al. Lumican and decorin are differentially expressed in human breast carcinoma. J Pathol. 2000;192(3):313–20.PubMedCrossRefGoogle Scholar
  34. 34.
    Stamov DR, Muller A, Wegrowski Y, Brezillon S, Franz CM. Quantitative analysis of type I collagen fibril regulation by lumican and decorin using AFM. J Struct Biol. 2013;183(3):394–403.PubMedCrossRefGoogle Scholar
  35. 35.
    Brézillon S, Pietraszek K, Maquart FX, Wegrowski Y. Lumican effects in the control of tumour progression and their links with metalloproteinases and integrins. FEBS J. 2013;280(10):2369–81.PubMedCrossRefGoogle Scholar
  36. 36.
    Naito Z. Role of the small leucine-rich proteoglycan (SLRP) family in pathological lesions and cancer cell growth. J Nippon Med Sch. 2005;72(3):137–45.PubMedCrossRefGoogle Scholar
  37. 37.
    Ishiwata T, Cho K, Kawahara K, Yamamoto T, Fujiwara Y, Uchida E, et al. Role of lumican in cancer cells and adjacent stromal tissues in human pancreatic cancer. Oncol Rep. 2007;18(3):537–43.PubMedGoogle Scholar
  38. 38.
    Sharma B, Ramus MD, Kirkwood CT, Sperry EE, Chu PH, Kao WW, et al. Lumican exhibits anti-angiogenic activity in a context specific manner. Cancer Microenviron. 2013;6(3):263–71.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Somiari RI, Sullivan A, Russell S, Somiari S, Hu H, Jordan R, et al. High-throughput proteomic analysis of human infiltrating ductal carcinoma of the breast. Proteomics. 2003;3(10):1863–73.PubMedCrossRefGoogle Scholar
  40. 40.
    Eshchenko TY, Rykova VI, Chernakov AE, Sidorov SV, Grigorieva EV. Expression of different proteoglycans in human breast tumors. Biochemistry (Mosc). 2007;72(9):1016–20.CrossRefGoogle Scholar
  41. 41.
    Leygue E, Snell L, Dotzlaw H, Hole K, Hiller-Hitchcock T, Roughley PJ, et al. Expression of lumican in human breast carcinoma. Cancer Res. 1998;58(7):1348–52.PubMedGoogle Scholar
  42. 42.
    Troup S, Njue C, Kliewer EV, Parisien M, Roskelley C, Chakravarti S, et al. Reduced expression of the small leucine-rich proteoglycans, lumican, and decorin is associated with poor outcome in node-negative invasive breast cancer. Clin Cancer Res. 2003;9(1):207–14.PubMedGoogle Scholar
  43. 43.
    Alowami S, Troup S, Al-Haddad S, Kirkpatrick I, Watson PH. Mammographic density is related to stroma and stromal proteoglycan expression. Breast Cancer Res. 2003;5(5):R129–35.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Neame* PJ, Kay CJ, McQuillan DJ, Beales MP, Hassell JR. Independent modulation of collagen fibrillogenesis by decorin and lumican. Cell Mol Life Sci CMLS. 2000;57(5):859–63.PubMedCrossRefGoogle Scholar
  45. 45.
    Huo CW, Chew G, Hill P, Huang D, Ingman W, Hodson L, et al. High mammographic density is associated with an increase in stromal collagen and immune cells within the mammary epithelium. Breast Cancer Res BCR. 2015;17(1):79.PubMedCrossRefGoogle Scholar
  46. 46.
    Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature. 1990;346(6281):281–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Grant DS, Yenisey C, Rose RW, Tootell M, Santra M, Iozzo RV. Decorin suppresses tumor cell-mediated angiogenesis. Oncogene. 2002;21(31):4765–77.PubMedCrossRefGoogle Scholar
  48. 48.
    Goldoni S, Iozzo RV. Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs. Int J Cancer. 2008;123(11):2473–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Oda G, Sato T, Ishikawa T, Kawachi H, Nakagawa T, Kuwayama T, et al. Significance of stromal decorin expression during the progression of breast cancer. Oncol Rep. 2012;28(6):2003–8.PubMedGoogle Scholar
  50. 50.
    Skandalis SS, Labropoulou VT, Ravazoula P, Likaki-Karatza E, Dobra K, Kalofonos HP, et al. Versican but not decorin accumulation is related to malignancy in mammographically detected high density and malignant-appearing microcalcifications in non-palpable breast carcinomas. BMC Cancer. 2011;11(1):314.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Hallberg G, Andersson E, Naessén T, Ordeberg GE. Research the expression of syndecan-1, syndecan-4 and decorin in healthy human breast tissue during the menstrual cycle. Reprod Biol Endocrinol. 2010.Google Scholar
  52. 52.
    Ursin G, Parisky YR, Pike MC, Spicer DV. Mammographic density changes during the menstrual cycle. Cancer Epidemiol Biomarkers Prev. 2001;10(2):141–2.PubMedGoogle Scholar
  53. 53.
    Buist DSM, Aiello EJ, Miglioretti DL, White E. Mammographic breast density, dense area, and breast area differences by phase in the menstrual cycle. Cancer Epidemiol Biomarkers Prev. 2006;15(11):2303–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Neill T, Schaefer L, Iozzo RV. Decorin: a guardian from the matrix. Am J Pathol. 2012;181(2):380–7.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Wadhwa S, Embree MC, Bi Y, Young MF. Regulation, regulatory activities, and function of biglycan. Crit Rev Eukaryot Gene Expr. 2004;14(4):301–15.PubMedCrossRefGoogle Scholar
  56. 56.
    Sainio A, Järveläinen H. Extracellular matrix macromolecules: potential tools and targets in cancer gene therapy. Mol Cell Ther. 2014;2(1):14.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    La Creis RK, Rogers EN, Yeyeodu ST, Jones DZ, Kimbro KS. Contribution of toll-like receptor signaling pathways to breast tumorigenesis and treatment. Breast Cancer. 2013;5:43.Google Scholar
  58. 58.
    González-Reyes S, Marín L, González L, González LO, del Casar JM, Lamelas ML, et al. Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC Cancer. 2010;10(1):665.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Yang H, Wang B, Wang T, Xu L, He C, Wen H, et al. Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis. PLoS ONE. 2014;9(10):e109980.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Van Bockstal M, Lambein K, Van Gele M, De Vlieghere E, Limame R, Braems G, et al. Differential regulation of extracellular matrix protein expression in carcinoma-associated fibroblasts by TGF-β1 regulates cancer cell spreading but not adhesion. Oncoscience. 2014;1(10):634.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Recktenwald CV, Leisz S, Steven A, Mimura K, Müller A, Wulfänger J, et al. HER-2/neu-mediated down-regulation of biglycan associated with altered growth properties. J Biol Chem. 2012;287(29):24320–9.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Esses G, Margolies L, Jaffer S, Esses S, Sonnenblick E, Szabo J. Breast density and its correlation with invasive breast cancer prognostic indicators. Research. 2014;1:1019.Google Scholar
  63. 63.
    Lope V, Pérez-Gómez B, Sánchez-Contador C, Santamariña M, Moreo P, Vidal C, et al. Obstetric history and mammographic density: a population-based cross-sectional study in Spain (DDM-Spain). Breast Cancer Res Treat. 2012;132(3):1137–46.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Boyd NF, Lockwood GA, Byng JW, Tritchler DL, Yaffe MJ. Mammographic densities and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1998;7(12):1133–44.PubMedGoogle Scholar
  65. 65.
    Martin LJ, Boyd NF. Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. Breast Cancer Res. 2008;10(1):201.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Chew GL, Huang D, Huo CW, Blick T, Hill P, Cawson J, et al. Dynamic changes in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers during various murine peripartum states and over time. Breast Cancer Res Treat. 2013;140(2):285–97.PubMedCrossRefGoogle Scholar
  67. 67.
    Iozzo RV, Murdoch AD. Proteoglycans of the extracellular environment: clues from the gene and protein side offer novel perspectives in molecular diversity and function. FASEB J. 1996;10(5):598–614.PubMedGoogle Scholar
  68. 68.
    Wight TN. Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol. 2002;14(5):617–23.PubMedCrossRefGoogle Scholar
  69. 69.
    Sotoodehnejadnematalahi F, Burke B. Structure, function and regulation of versican: the most abundant type of proteoglycan in the extracellular matrix. Acta Med Iran. 2013;51(11):740–50.PubMedGoogle Scholar
  70. 70.
    Nikitovic D, Kouvidi K, Voudouri K, Berdiaki A, Karousou E, Passi A, et al. The motile breast cancer phenotype roles of proteoglycans/glycosaminoglycans. BioMed Res Int. 2014;2014.Google Scholar
  71. 71.
    Nara Y, Kato Y, Torii Y, Tsuji Y, Nakagaki S, Goto S, et al. Immunohistochemical localization of extracellular matrix components in human breast tumours with special reference to PG-M/versican. Histochem J. 1997;29(1):21–30.PubMedCrossRefGoogle Scholar
  72. 72.
    Du WW, Fang L, Yang X, Sheng W, Yang BL, Seth A, et al. The role of versican in modulating breast cancer cell self-renewal. Mol Cancer Res. 2013;11(5):443–55.PubMedCrossRefGoogle Scholar
  73. 73.
    Du WW, Yang B, Seth A, Yee A. Versican G3 domain enhances breast cancer cell invasion and bone metastasis. J Bone Joint Surg (Br). 2012;94-B(SUPP XXXVIII):38.Google Scholar
  74. 74.
    Ricciardelli C, Sakko AJ, Ween MP, Russell DL, Horsfall DJ. The biological role and regulation of versican levels in cancer. Cancer Metastasis Rev. 2009;28(1-2):233–45.PubMedCrossRefGoogle Scholar
  75. 75.
    Ricciardelli C, Brooks JH, Suwiwat S, Sakko AJ, Mayne K, Raymond WA, et al. Regulation of stromal versican expression by breast cancer cells and importance to relapse-free survival in patients with node-negative primary breast cancer. Clin Cancer Res. 2002;8(4):1054–60.PubMedGoogle Scholar
  76. 76.
    Pinheiro MC, Mora OA, Caldini EG, Battlehner CN, Joazeiro PP, Toledo OM. Ultrastructural, immunohistochemical and biochemical analysis of glycosaminoglycans and proteoglycans in the mouse pubic symphysis during pregnancy. Cell Biol Int. 2005;29(6):458–71.PubMedCrossRefGoogle Scholar
  77. 77.
    Kuhl H, Schneider H. Progesterone-promoter or inhibitor of breast cancer. Climacteric. 2013;16(S1):54–68.PubMedCrossRefGoogle Scholar
  78. 78.
    Blackmore KM, Knight JA, Walter J, Lilge L. The association between breast tissue optical content and mammographic density in pre- and post-menopausal women. PLoS ONE. 2015;10(1):e0115851.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Meier-Abt F, Brinkhaus H, Bentires-Alj M. Early but not late pregnancy induces lifelong reductions in the proportion of mammary progesterone sensing cells and epithelial Wnt signaling. AGE. 2014;10(20):30.Google Scholar
  80. 80.
    Kusafuka K, Muramatsu K, Kasami M, Kuriki K, Hirobe K, Hayashi I, et al. Cartilaginous features in matrix-producing carcinoma of the breast: four cases report with histochemical and immunohistochemical analysis of matrix molecules. Mod Pathol. 2008;21(10):1282–92.PubMedCrossRefGoogle Scholar
  81. 81.
    Yan D, Yan X-F, Chang X-T. Expression of ADAMTS-4 and its product ARGxx in breast cancer [J]. Shandong Med J. 2011;22:017.Google Scholar
  82. 82.
    Murdoch AD, Liu B, Schwarting R, Tuan RS, Iozzo RV. Widespread expression of perlecan proteoglycan in basement membranes and extracellular matrices of human tissues as detected by a novel monoclonal antibody against domain III and by in situ hybridization. J Histochem Cytochem. 1994;42(2):239–49.PubMedCrossRefGoogle Scholar
  83. 83.
    Mongiat M, Otto J, Oldershaw R, Ferrer F, Sato JD, Iozzo RV. Fibroblast growth factor-binding protein is a novel partner for perlecan protein core. J Biol Chem. 2001;276(13):10263–71.PubMedCrossRefGoogle Scholar
  84. 84.
    Iozzo RV, San Antonio JD. Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena. J Clin Invest. 2001;108(3):349–55.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Clarke DN, Al Ahmad A, Lee B, Parham C, Auckland L, Fertala A, et al. Perlecan domain V induces VEGf secretion in brain endothelial cells through integrin α(5)β(1) and ERK-dependent signaling pathways. PLoS ONE. 2012;7(9):e45257.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Ishijima M, Suzuki N, Hozumi K, Matsunobu T, Kosaki K, Kaneko H, et al. Perlecan modulates VEGF signaling and is essential for vascularization in endochondral bone formation. Matrix Biol. 2012;31(4):234–45.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Goyal A, Pal N, Concannon M, Paul M, Doran M, Poluzzi C, et al. Endorepellin, the angiostatic module of perlecan, interacts with both the alpha2beta1 integrin and vascular endothelial growth factor receptor 2 (VEGFR2): a dual receptor antagonism. J Biol Chem. 2011;286(29):25947–62.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Mongiat M, Sweeney SM, San Antonio JD, Fu J, Iozzo RV. Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan. J Biol Chem. 2003;278(6):4238–49.PubMedCrossRefGoogle Scholar
  89. 89.
    Poluzzi C, Casulli J, Goyal A, Mercer TJ, Neill T, Iozzo RV. Endorepellin evokes autophagy in endothelial cells. J Biol Chem. 2014;289(23):16114–28.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Goyal A, Poluzzi C, Willis CD, Smythies J, Shellard A, Neill T, et al. Endorepellin affects angiogenesis by antagonizing diverse vascular endothelial growth factor receptor 2 (VEGFR2)-evoked signaling pathways: transcriptional repression of hypoxia-inducible factor 1α and VEGFA and concurrent inhibition of nuclear factor of activated T cell 1 (NFAT1) activation. J Biol Chem. 2012;287(52):43543–56.PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Woodall BP, Nyström A, Iozzo RA, Eble JA, Niland S, Krieg T, et al. Integrin α2β1 is the required receptor for endorepellin angiostatic activity. J Biol Chem. 2008;283(4):2335–43.PubMedCrossRefGoogle Scholar
  92. 92.
    Bix G, Fu J, Gonzalez EM, Macro L, Barker A, Campbell S, et al. Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through α2β1 integrin. J Cell Biol. 2004;166(1):97–109.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Willis CD, Poluzzi C, Mongiat M, Iozzo RV. Endorepellin LG1/2 domains bind Ig3-5 of VEGFR2 and block proangiogenic signaling by VEGFA in endothelial cells. FEBS J. 2013;280(10):2271–84.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Lee B, Clarke D, Al Ahmad A, Kahle M, Parham C, Auckland L, et al. Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents. J Clin Invest. 2011;121(8):3005–23.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Lord MS, Jung M, Cheng B, Whitelock JM. Transcriptional complexity of the HSPG2 gene in the human mast cell line, HMC-1. Matrix Biol. 2014;35:123–31.PubMedCrossRefGoogle Scholar
  96. 96.
    Bix G, Iozzo RV. Novel interactions of perlecan: unraveling perlecan’s role in angiogenesis. Microsc Res Tech. 2008;71(5):339–48.PubMedCrossRefGoogle Scholar
  97. 97.
    Nerlich A, Wiest I, Wagner E, Sauer U, Schleicher E. Gene expression and protein deposition of major basement membrane components and TGF-beta 1 in human breast cancer. Anticancer Res. 1996;17(6D):4443–9.Google Scholar
  98. 98.
    Nerlich A, Lebeau A, Hagedorn H, Sauer U, Schleicher E. Morphological aspects of altered basement membrane metabolism in invasive carcinomas of the breast and the larynx. Anticancer Res. 1997;18(5A):3515–20.Google Scholar
  99. 99.
    Iozzo RV, Cohen IR, Grässel S, Murdoch AD. The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem J. 1994;302(Pt 3):625.PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Jansson M, Ohlund D, Sund M. 190. Expression and circulating levels of perlecan in breast cancer. Eur J Surg Oncol. 2014;40(11):S81.CrossRefGoogle Scholar
  101. 101.
    Chang JW, Kang UB, Kim DH, Yi JK, Lee JW, Noh DY, et al. Identification of circulating endorepellin LG3 fragment: potential use as a serological biomarker for breast cancer. Proteomics Clin Appl. 2008;2(1):23–32.PubMedCrossRefGoogle Scholar
  102. 102.
    Lisanti MP, Tsirigos A, Pavlides S, Reeves KJ, Peiris-Pages M, Chadwick AL, et al. JNK1 stress signaling is hyper-activated in high breast density and the tumor stroma: connecting fibrosis, inflammation, and stemness for cancer prevention. Cell Cycle. 2014;13(4):580–99.PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Teng YH, Aquino RS, Park PW. Molecular functions of syndecan-1 in disease. Matrix Biol. 2012;31(1):3–16.PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Ramani VC, Pruett PS, Thompson CA, DeLucas LD, Sanderson RD. Heparan sulfate chains of syndecan-1 regulate ectodomain shedding. J Biol Chem. 2012;287(13):9952–61.PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Manon-Jensen T, Itoh Y, Couchman JR. Proteoglycans in health and disease: the multiple roles of syndecan shedding. FEBS J. 2010;277(19):3876–89.PubMedCrossRefGoogle Scholar
  106. 106.
    Lendorf ME, Manon-Jensen T, Kronqvist P, Multhaupt HAB, Couchman JR. Syndecan-1 and syndecan-4 are independent indicators in breast carcinoma. J Histochem Cytochem. 2011;59(6):615–29.PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Lofgren L, Sahlin L, Jiang S, Von Schoultz B, Fernstad R, Skoog L, et al. Expression of syndecan-1 in paired samples of normal and malignant breast tissue from postmenopausal women. Anticancer Res. 2007;27(5A):3045–50.PubMedGoogle Scholar
  108. 108.
    Baba F, Swartz K, van Buren R, Eickhoff J, Zhang Y, Wolberg W, et al. Syndecan-1 and syndecan-4 are overexpressed in an estrogen receptor-negative, highly proliferative breast carcinoma subtype. Breast Cancer Res Treat. 2006;98(1):91–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Lim HC, Multhaupt HA, Couchman JR. Cell surface heparan sulfate proteoglycans control adhesion and invasion of breast carcinoma cells. Mol Cancer. 2015;14(1):15.PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Lim HC, Couchman JR. Syndecan-2 regulation of morphology in breast carcinoma cells is dependent on RhoGTPases. Biochim Biophys Acta. 2014;1840(8):2482–90.PubMedCrossRefGoogle Scholar
  111. 111.
    Lim HC, Multhaupt H, Couchman J. Syndecan-2 regulates the invasive phenotype of human breast carcinoma cells. FASEB J. 2013;27(1_MeetingAbstracts):650.3.Google Scholar
  112. 112.
    Barbouri D, Afratis N, Gialeli C, Vynios DH, Theocharis AD, Karamanos N. Syndecans as modulators and potential pharmacological targets in cancer progression. Front Oncol. 2014;4.Google Scholar
  113. 113.
    Wu ZS, Pandey V, Wu WY, Ye S, Zhu T, Lobie PE. Prognostic significance of the expression of GFRalpha1, GFRalpha3 and syndecan-3, proteins binding ARTEMIN, in mammary carcinoma. BMC Cancer. 2013;13:34.PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Kousidou OC, Berdiaki A, Kletsas D, Zafiropoulos A, Theocharis AD, Tzanakakis GN, et al. Estradiol–estrogen receptor: a key interplay of the expression of syndecan-2 and metalloproteinase-9 in breast cancer cells. Mol Oncol. 2008;2(3):223–32.PubMedCrossRefGoogle Scholar
  115. 115.
    Lundstrom E, Sahlin L, Skoog L, Hagerstrom T, Svane G, Azavedo E, et al. Expression of Syndecan-1 in histologically normal breast tissue from postmenopausal women with breast cancer according to mammographic density. Climacteric. 2006;9(4):277–82.PubMedCrossRefGoogle Scholar
  116. 116.
    Heusinger K, Jud S, Häberle L, Hack C, Fasching P, Meier-Meitinger M, et al. Association of mammographic density with the proliferation marker Ki-67 in a cohort of patients with invasive breast cancer. Breast Cancer Res Treat. 2012;135(3):885–92.PubMedCrossRefGoogle Scholar
  117. 117.
    Ding J, Warren R, Girling A, Thompson D, Easton D. Mammographic density, estrogen receptor status and other breast cancer tumor characteristics. Breast J. 2010;16(3):279–89.PubMedCrossRefGoogle Scholar
  118. 118.
    Guo Y-P, Martin LJ, Hanna W, Banerjee D, Miller N, Fishell E, et al. Growth factors and stromal matrix proteins associated with mammographic densities. Cancer Epidemiol Biomarkers Prev. 2001;10(3):243–8.PubMedGoogle Scholar
  119. 119.
    Hallberg G, Lundström E, Andersson E, Ekman-Ordeberg G. Mammographic breast density and the expression of androgen receptor, caspase 3, Ki67 and proteoglycans in pre-menopausal women. DiVA. 2011.Google Scholar
  120. 120.
    Xian X, Gopal S, Couchman J. Syndecans as receptors and organizers of the extracellular matrix. Cell Tissue Res. 2010;339(1):31–46.PubMedCrossRefGoogle Scholar
  121. 121.
    Filmus J, Capurro M. The role of glypicans in Hedgehog signaling. Matrix Biol. 2014;35:248–52.PubMedCrossRefGoogle Scholar
  122. 122.
    Traister A, Shi W, Filmus J. Mammalian Notum induces the release of glypicans and other GPI-anchored proteins from the cell surface. Biochem J. 2008;410:503–11.PubMedCrossRefGoogle Scholar
  123. 123.
    Filmus J, Capurro M, Rast J. Glypicans. Genome Biol. 2008;9(5):224.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Matsuda K, Maruyama H, Guo F, Kleeff J, Itakura J, Matsumoto Y, et al. Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells. Cancer Res. 2001;61(14):5562–9.PubMedGoogle Scholar
  125. 125.
    Xiang YY, Ladeda V, Filmus J. Glypican-3 expression is silenced in human breast cancer. Oncogene. 2001;20(50):7408–12.PubMedCrossRefGoogle Scholar
  126. 126.
    Peters MG, Farias E, Colombo L, Filmus J, Puricelli L, Bal de Kier Joffe E. Inhibition of invasion and metastasis by glypican-3 in a syngeneic breast cancer model. Breast Cancer Res Treat. 2003;80(2):221–32.PubMedCrossRefGoogle Scholar
  127. 127.
    Buchanan C, Stigliano I, Garay-Malpartida HM, Rodrigues Gomes L, Puricelli L, Sogayar MC, et al. Glypican-3 reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating PI3K/Akt and p38MAPK signaling pathways. Breast Cancer Res Treat. 2010;119(3):559–74.PubMedCrossRefGoogle Scholar
  128. 128.
    Okolicsanyi RK, van Wijnen AJ, Cool SM, Stein GS, Griffiths LR, Haupt LM. Heparan sulfate proteoglycans and human breast cancer epithelial cell tumorigenicity. J Cell Biochem. 2014;115(5):967–76.PubMedCentralPubMedCrossRefGoogle Scholar
  129. 129.
    Gomes AM, Stelling MP, Pavão MS. Heparan sulfate and heparanase as modulators of breast cancer progression. BioMed Res Int. 2013;2013.Google Scholar
  130. 130.
    Javed A, Lteif A. Development of the human breast. Semin Plast Surg. 2013;27(1):5–12.PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Kolset SO, Tveit H. Serglycin--structure and biology. Cell Mol Life Sci. 2008;65(7-8):1073–85.PubMedCrossRefGoogle Scholar
  132. 132.
    Korpetinou A, Skandalis SS, Moustakas A, Happonen KE, Tveit H, Prydz K, et al. Serglycin is implicated in the promotion of aggressive phenotype of breast cancer cells. PLoS ONE. 2013;8(10):e78157.PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Korpetinou A, Skandalis SS, Labropoulou VT, Smirlaki G, Noulas A, Karamanos NK, et al. Serglycin: at the crossroad of inflammation and malignancy. Front Oncol. 2014;3:327.PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Iida J, Dorchak J, Clancy R, Slavik J, Ellsworth R, Katagiri Y, et al. Role for chondroitin sulfate glycosaminoglycan in NEDD9-mediated breast cancer cell growth. Exp Cell Res. 2015;330(2):358–70.PubMedCrossRefGoogle Scholar
  135. 135.
    McLaughlin SL, Ice RJ, Rajulapati A, Kozyulina PY, Livengood RH, Kozyreva VK, et al. NEDD9 depletion leads to MMP14 inactivation by TIMP2 and prevents invasion and metastasis. Mol Cancer Res. 2014;12(1):69–81.PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Gill JK, Maskarinec G, Pagano I, Kolonel LN. The association of mammographic density with ductal carcinoma in situ of the breast: the multiethnic cohort. Breast Cancer Res. 2006;8(3):R30.PubMedCentralPubMedCrossRefGoogle Scholar
  137. 137.
    Sarrazin S, Lamanna WC, Esko JD. Heparan sulfate proteoglycans. Cold Spring Harb Perspect Biol. 2011;3(7):a004952.PubMedCentralPubMedCrossRefGoogle Scholar
  138. 138.
    Cohen I, Pappo O, Elkin M, San T, Bar-Shavit R, Hazan R, et al. Heparanase promotes growth, angiogenesis and survival of primary breast tumors. Int J Cancer. 2006;118(7):1609–17.PubMedCrossRefGoogle Scholar
  139. 139.
    Maxhimer JB, Quiros RM, Stewart R, Dowlatshahi K, Gattuso P, Fan M, et al. Heparanase-1 expression is associated with the metastatic potential of breast cancer. Surgery. 2002;132(2):326–33.PubMedCrossRefGoogle Scholar
  140. 140.
    Yang Y, Macleod V, Miao HQ, Theus A, Zhan F, Shaughnessy Jr JD, et al. Heparanase enhances syndecan-1 shedding: a novel mechanism for stimulation of tumor growth and metastasis. J Biol Chem. 2007;282(18):13326–33.PubMedCrossRefGoogle Scholar
  141. 141.
    Endo K, Takino T, Miyamori H, Kinsen H, Yoshizaki T, Furukawa M, et al. Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J Biol Chem. 2003;278(42):40764–70.PubMedCrossRefGoogle Scholar
  142. 142.
    Su G, Blaine SA, Qiao D, Friedl A. Membrane type 1 matrix metalloproteinase-mediated stromal syndecan-1 shedding stimulates breast carcinoma cell proliferation. Cancer Res. 2008;68(22):9558–65.PubMedCentralPubMedCrossRefGoogle Scholar
  143. 143.
    Thompson CA, Purushothaman A, Ramani VC, Vlodavsky I, Sanderson RD. Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J Biol Chem. 2013;288(14):10093–9.PubMedCentralPubMedCrossRefGoogle Scholar
  144. 144.
    Roucourt B, Meeussen S, Bao J, Zimmermann P, David G. Heparanase activates the syndecan-syntenin-ALIX exosome pathway. Cell Res. 2015;25(4):412–28.PubMedCentralPubMedCrossRefGoogle Scholar
  145. 145.
    Kazarin O, Ilan N, Naroditzky I, Ben-Itzhak O, Vlodavsky I, Bar-Sela G. Expression of heparanase in soft tissue sarcomas of adults. J Exp Clin Cancer Res. 2014;33:39.PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Elkin M, Cohen I, Zcharia E, Orgel A, Guatta-Rangini Z, Peretz T, et al. Regulation of heparanase gene expression by estrogen in breast cancer. Cancer Res. 2003;63(24):8821–6.PubMedGoogle Scholar
  147. 147.
    Chen JH, Hsu FT, Shih HN, Hsu CC, Chang D, Nie K, et al. Does breast density show difference in patients with estrogen receptor-positive and estrogen receptor-negative breast cancer measured on MRI? Ann Oncol. 2009;20(8):1447–9.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Michael S. Shawky
    • 1
    • 2
  • Carmela Ricciardelli
    • 3
  • Megan Lord
    • 4
  • John Whitelock
    • 4
  • Vito Ferro
    • 5
  • Kara Britt
    • 6
    • 7
  • Erik W. Thompson
    • 8
    • 9
  1. 1.Department of Head and Neck and Endocrine Surgery, Faculty of MedicineUniversity of AlexandriaAlexandriaEgypt
  2. 2.Department of SurgeryWaikato HospitalHamiltonNew Zealand
  3. 3.School of Medicine, Robinson Research InstituteUniversity of AdelaideAdelaideAustralia
  4. 4.Graduate School of Biomedical EngineeringUniversity of New South WalesSydneyAustralia
  5. 5.School of Chemistry and Molecular BiosciencesUniversity of QueenslandBrisbaneAustralia
  6. 6.Peter MacCallum Cancer CentreMelbourneAustralia
  7. 7.The Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneAustralia
  8. 8.Institute of Health and Biomedical Innovation and School of Biomedical ScienceQueensland University of TechnologyBrisbaneAustralia
  9. 9.Department of Surgery, St Vincent’s HospitalUniversity of MelbourneMelbourneAustralia

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