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The Role of Lipid Rafts in Mediating the Anticancer Effects of γ-Tocotrienol

  • Paul W. SylvesterEmail author
Chapter
Part of the Nutrition and Health book series (NH)

Abstract

γ-Tocotrienol, a natural isoform within the vitamin E family of compounds, displays potent antiproliferative and apoptotic activity against a wide range of cancers, particularly breast cancer. A large percentage of human breast cancers characteristically display aberrant receptor tyrosine kinase activity, including receptors within the HER family, c-Met, and VEGF among others. Lipid rafts are specialized microdomains within the plasma membrane that are required for receptor tyrosine kinase dimerization, activation, and signal transduction. Recent studies demonstrate that the anticancer effects of γ-tocotrienol are associated with its accumulation in the lipid raft microdomain where it appears to interfere with the receptor tyrosine kinase dimerization and activation in human breast cancer cells. Heregulin is a potent ligand that activates HER3 and HER4 receptors, and overexpression of this ligand is associated with the development of chemotherapy resistance. Exosomes released from cancer cells are small vesicles originating from the outward budding of lipid rafts that carry various mitogenic proteins that then act locally in an autocrine/paracrine manner to stimulate cancer cell growth. However, exosomes isolated from the culture media of breast cancer cells treated with γ-tocotrienol contain significantly less heregulin content and are significantly less potent in stimulating HER3/HER4 heterodimerization, activation, and mitogenic signaling, as compared to exosomes isolated from the culture media of breast cancer cells grown in control media. These findings provide strong evidence that the anticancer effects of γ-tocotrienol result, at least in part, by directly disrupting lipid raft integrity by directly interfering with HER receptor dimerization and signaling within the lipid rafts and indirectly by reducing exosome heregulin content and subsequent autocrine/paracrine mitogenic stimulation.

Keywords

γ-Tocotrienol Lipid rafts Exosomes Breast cancer HER Heregulin 

References

  1. 1.
    Shklar G. Oral mucosal carcinogenesis in hamsters: inhibition by vitamin E. J Natl Cancer Inst. 1982;68:791–7.PubMedGoogle Scholar
  2. 2.
    Wattenberg LW. Inhibition of carcinogenic and toxic effects of polycyclic hydrocarbons by phenolic antioxidants and ethoxyquin. J Natl Cancer Inst. 1972;48:1425–30.PubMedGoogle Scholar
  3. 3.
    Ip C. Dietary vitamin E intake and mammary carcinogenesis in rats. Carcinogenesis. 1982;3:1453–6.PubMedCrossRefGoogle Scholar
  4. 4.
    King MM, McCay PB. Modulation of tumor incidence and possible mechanisms of inhibition of mammary carcinogenesis by dietary antioxidants. Cancer Res. 1983;43:2485s–90s.PubMedGoogle Scholar
  5. 5.
    Horvath PM, Ip C. Synergistic effect of vitamin E and selenium in the chemoprevention of mammary carcinogenesis in rats. Cancer Res. 1983;43:5335–41.PubMedGoogle Scholar
  6. 6.
    Hunter DJ, Manson JE, Colditz GA, Stampfer MJ, Rosner B, Hennekens CH, Speizer FE, Willett WC. A prospective study of the intake of vitamins C, E, and A and the risk of breast cancer. N Engl J Med. 1993;329:234–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Goh SH, Hew NF, Norhanom AW, Yadav M. Inhibition of tumour promotion by various palm-oil tocotrienols. Int J Cancer. 1994;57:529–31.PubMedCrossRefGoogle Scholar
  8. 8.
    Gould MN, Haag JD, Kennan WS, Tanner MA, Elson CE. A comparison of tocopherol and tocotrienol for the chemoprevention of chemically induced rat mammary tumors. Am J Clin Nutr. 1991;53:1068S–70S.PubMedCrossRefGoogle Scholar
  9. 9.
    Kline K, Yu W, Sanders BG. Vitamin E: mechanisms of action as tumor cell growth inhibitors. J Nutr. 2001;131:161S–3S.PubMedCrossRefGoogle Scholar
  10. 10.
    McIntyre BS, Briski KP, Gapor A, Sylvester PW. Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. Proc Soc Exp Biol Med. 2000;224:292–301.PubMedCrossRefGoogle Scholar
  11. 11.
    Sylvester PW, Theriault A. Role of tocotrienols in the prevention of cardiovascular disease and breast cancer. Curr Top Nutraceutical Res. 2003;1:121–36.Google Scholar
  12. 12.
    Sylvester PW. Role of acute caloric-restriction in murine tumorigenesis. Prog Clin Biol Res. 1986;222:517–28.PubMedGoogle Scholar
  13. 13.
    Nesaretnam K, Khor HT, Ganeson J, Chong YH, Sundram K, Gapor A. The effects of vitamin E tocotrienols from palm oil on chemically induced mammary carcinogenesis in female rats. Nutr Res. 1992;12:879–92.CrossRefGoogle Scholar
  14. 14.
    McIntyre BS, Briski KP, Tirmenstein MA, Fariss MW, Gapor A, Sylvester PW. Antiproliferative and apoptotic effects of tocopherols and tocotrienols on normal mouse mammary epithelial cells. Lipids. 2000;35:171–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Tiwari RV, Parajuli P, Sylvester PW. gamma-Tocotrienol-induced autophagy in malignant mammary cancer cells. Exp Biol Med (Maywood). 2014;239:33–44.CrossRefGoogle Scholar
  16. 16.
    Kline K, Lawson KA, Yu W, Sanders BG. Vitamin E and breast cancer prevention: current status and future potential. J Mammary Gland Biol Neoplasia. 2003;8:91–102.PubMedCrossRefGoogle Scholar
  17. 17.
    Neuzil J, Weber T, Terman A, Weber C, Brunk UT. Vitamin E analogues as inducers of apoptosis: implications for their potential antineoplastic role. Redox Rep. 2001;6:143–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Elnagar AY, Wali VB, Sylvester PW, El Sayed KA. Design and preliminary structure-activity relationship of redox-silent semisynthetic tocotrienol analogues as inhibitors for breast cancer proliferation and invasion. Bioorg Med Chem. 2010;18:755–68.PubMedCrossRefGoogle Scholar
  19. 19.
    Ananthula S, Parajuli P, Behery FA, Alayoubi AY, El Sayed KA, Nazzal S, Sylvester PW. Oxazine derivatives of gamma- and delta-tocotrienol display enhanced anticancer activity in vivo. Anticancer Res. 2014;34:2715–26.PubMedGoogle Scholar
  20. 20.
    Fischgrabe J, Wulfing P. Targeted therapies in breast cancer: established drugs and recent developments. Curr Clin Pharmacol. 2008;3:85–98.PubMedCrossRefGoogle Scholar
  21. 21.
    Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006;3:269–80.PubMedCrossRefGoogle Scholar
  22. 22.
    Shah SJ, Sylvester PW. gamma-tocotrienol inhibits neoplastic mammary epithelial cell proliferation by decreasing Akt and nuclear factor kappaB activity. Exp Biol Med (Maywood). 2005;230:235–41.CrossRefGoogle Scholar
  23. 23.
    Sylvester PW, Ayoub NM. Tocotrienols target PI3K/Akt signaling in anti-breast cancer therapy. Anti Cancer Agents Med Chem. 2013;13:1039–47.CrossRefGoogle Scholar
  24. 24.
    Bachawal SV, Wali VB, Sylvester PW. Combined gamma-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells. Anticancer Res. 2010;30:429–37.PubMedGoogle Scholar
  25. 25.
    Wali VB, Sylvester PW. Synergistic antiproliferative effects of gamma-tocotrienol and statin treatment on mammary tumor cells. Lipids. 2007;42:1113–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Duhon D, Bigelow RL, Coleman DT, Steffan JJ, Yu C, Langston W, Kevil CG, Cardelli JA. The polyphenol epigallocatechin-3-gallate affects lipid rafts to block activation of the c-Met receptor in prostate cancer cells. Mol Carcinog. 2010;49:739–49.PubMedGoogle Scholar
  27. 27.
    Pike LJ. Growth factor receptors, lipid rafts and caveolae: an evolving story. Biochim Biophys Acta. 2005;1746:260–73.PubMedCrossRefGoogle Scholar
  28. 28.
    Chamberlain LH. Detergents as tools for the purification and classification of lipid rafts. FEBS Lett. 2004;559:1–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Pike LJ. Lipid rafts: bringing order to chaos. J Lipid Res. 2003;44:655–67.PubMedCrossRefGoogle Scholar
  30. 30.
    Park JH, Han HJ. Caveolin-1 plays important role in EGF-induced migration and proliferation of mouse embryonic stem cells: involvement of PI3K/Akt and ERK. Am J Physiol Cell Physiol. 2009;297:C935–44.PubMedCrossRefGoogle Scholar
  31. 31.
    Pike LJ. The challenge of lipid rafts. J Lipid Res. 2009;50(Suppl):S323–8.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Staubach S, Hanisch FG. Lipid rafts: signaling and sorting platforms of cells and their roles in cancer. Expert Rev Proteomics. 2011;8:263–77.PubMedCrossRefGoogle Scholar
  33. 33.
    Braicu C, Tomuleasa C, Monroig P, Cucuianu A, Berindan-Neagoe I, Calin GA. Exosomes as divine messengers: are they the Hermes of modern molecular oncology? Cell Death Differ. 2015;22:34–45.PubMedCrossRefGoogle Scholar
  34. 34.
    Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, Baran J, Urbanowicz B, Branski P, Ratajczak MZ, Zembala M. Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother. 2006;55:808–18.PubMedCrossRefGoogle Scholar
  35. 35.
    Hayes NV, Gullick WJ. The neuregulin family of genes and their multiple splice variants in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:205–14.PubMedCrossRefGoogle Scholar
  36. 36.
    Higginbotham JN, Demory Beckler M, Gephart JD, Franklin JL, Bogatcheva G, Kremers GJ, Piston DW, Ayers GD, McConnell RE, Tyska MJ, Coffey RJ. Amphiregulin exosomes increase cancer cell invasion. Curr Biol. 2011;21:779–86.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183–232.PubMedCrossRefGoogle Scholar
  38. 38.
    Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141:1117–34.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol. 2007;19:124–34.PubMedCrossRefGoogle Scholar
  40. 40.
    Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, Seger R, Hynes NE, Yarden Y. ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J. 1996;15:254–64.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Kim HH, Sierke SL, Koland JG. Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. J Biol Chem. 1994;269:24747–55.PubMedGoogle Scholar
  42. 42.
    Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, Stern HM. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878–87.PubMedCrossRefGoogle Scholar
  43. 43.
    Hubbard SR, Miller WT. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol. 2007;19:117–23.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.PubMedCrossRefGoogle Scholar
  45. 45.
    Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer. 2012;12:553–63.PubMedCrossRefGoogle Scholar
  46. 46.
    Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:15–31.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Lingwood D, Simons K. Lipid rafts as a membrane-organizing principle. Science. 2010;327:46–50.PubMedCrossRefGoogle Scholar
  48. 48.
    Browman DT, Hoegg MB, Robbins SM. The SPFH domain-containing proteins: more than lipid raft markers. Trends Cell Biol. 2007;17:394–402.PubMedCrossRefGoogle Scholar
  49. 49.
    Stuermer CA. The reggie/flotillin connection to growth. Trends Cell Biol. 2010;20:6–13.PubMedCrossRefGoogle Scholar
  50. 50.
    Staubach S, Razawi H, Hanisch FG. Proteomics of MUC1-containing lipid rafts from plasma membranes and exosomes of human breast carcinoma cells MCF-7. Proteomics. 2009;9:2820–35.PubMedCrossRefGoogle Scholar
  51. 51.
    Patel HH, Murray F, Insel PA. G-protein-coupled receptor-signaling components in membrane raft and caveolae microdomains. Handb Exp Pharmacol. 2008;186:167–84.CrossRefGoogle Scholar
  52. 52.
    Patel HH, Murray F, Insel PA. Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol. 2008;48:359–91.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Li L, Ren CH, Tahir SA, Ren C, Thompson TC. Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Mol Cell Biol. 2003;23:9389–404.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Kitano H. Cancer robustness: tumour tactics. Nature. 2003;426:125.PubMedCrossRefGoogle Scholar
  55. 55.
    Kitano H. Cancer as a robust system: implications for anticancer therapy. Nat Rev Cancer. 2004;4:227–35.PubMedCrossRefGoogle Scholar
  56. 56.
    Fevrier B, Raposo G. Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr Opin Cell Biol. 2004;16:415–21.PubMedCrossRefGoogle Scholar
  57. 57.
    Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci. 2000;113(Pt 19):3365–74.PubMedGoogle Scholar
  58. 58.
    Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 2012;40:D1241–4.PubMedCrossRefGoogle Scholar
  59. 59.
    van den Boorn JG, Dassler J, Coch C, Schlee M, Hartmann G. Exosomes as nucleic acid nanocarriers. Adv Drug Deliv Rev. 2013;65:331–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brugger B, Simons M. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008;10:619–24.PubMedCrossRefGoogle Scholar
  63. 63.
    Demory Beckler M, Higginbotham JN, Franklin JL, Ham AJ, Halvey PJ, Imasuen IE, Whitwell C, Li M, Liebler DC, Coffey RJ. Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol Cell Proteomics. 2013;12:343–55.PubMedCrossRefGoogle Scholar
  64. 64.
    Ananthula S, Parajuli P, Behery FA, Alayoubi AY, Nazzal S, El Sayed K, Sylvester PW. delta-Tocotrienol oxazine derivative antagonizes mammary tumor cell compensatory response to CoCl2-induced hypoxia. Biomed Res Int. 2014;2014:285752.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Dong D, Ni M, Li J, Xiong S, Ye W, Virrey JJ, Mao C, Ye R, Wang M, Pen L, Dubeau L, Groshen S, Hofman FM, Lee AS. Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res. 2008;68:498–505.PubMedCrossRefGoogle Scholar
  66. 66.
    Samant GV, Sylvester PW. gamma-Tocotrienol inhibits ErbB3-dependent PI3K/Akt mitogenic signalling in neoplastic mammary epithelial cells. Cell Prolif. 2006;39:563–74.PubMedCrossRefGoogle Scholar
  67. 67.
    Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Oikawa S, Miyazawa T. delta-Tocotrienol suppresses VEGF induced angiogenesis whereas alpha-tocopherol does not. J Agric Food Chem. 2009;57:8696–704.PubMedCrossRefGoogle Scholar
  68. 68.
    Bachawal SV, Wali VB, Sylvester PW. Enhanced antiproliferative and apoptotic response to combined treatment of gamma-tocotrienol with erlotinib or gefitinib in mammary tumor cells. BMC Cancer. 2010;10:84.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Shin-Kang S, Ramsauer VP, Lightner J, Chakraborty K, Stone W, Campbell S, Reddy SA, Krishnan K. Tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway. Free Radic Biol Med. 2011;51:1164–74.PubMedCrossRefGoogle Scholar
  70. 70.
    Ayoub NM, Akl MR, Sylvester PW. Combined gamma-tocotrienol and Met inhibitor treatment suppresses mammary cancer cell proliferation, epithelial-to-mesenchymal transition and migration. Cell Prolif. 2013;46:538–53.PubMedGoogle Scholar
  71. 71.
    Ayoub NM, Bachawal SV, Sylvester PW. gamma-Tocotrienol inhibits HGF-dependent mitogenesis and Met activation in highly malignant mammary tumour cells. Cell Prolif. 2011;44:516–26.PubMedCrossRefGoogle Scholar
  72. 72.
    Ahmed RA, Alawin OA, Sylvester PW. gamma-Tocotrienol reversal of epithelial-to-mesenchymal transition in human breast cancer cells is associated with inhibition of canonical Wnt signalling. Cell Prolif. 2016;49:460–70.PubMedCrossRefGoogle Scholar
  73. 73.
    Akl MR, Ayoub NM, Sylvester PW. Mechanisms mediating the synergistic anticancer effects of combined gamma-tocotrienol and sesamin treatment. Planta Med. 2012;78:1731–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Malaviya A, Sylvester PW. Mechanisms mediating the effects of gamma-tocotrienol when used in combination with PPARgamma agonists or antagonists on MCF-7 and MDA-MB-231 breast cancer cells. Int J Breast Cancer. 2013;2013:101705.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Shirode AB, Sylvester PW. Synergistic anticancer effects of combined gamma-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFkappaB signaling. Biomed Pharmacother. 2010;64:327–32.PubMedCrossRefGoogle Scholar
  76. 76.
    Shah S, Gapor A, Sylvester PW. Role of caspase-8 activation in mediating vitamin E-induced apoptosis in murine mammary cancer cells. Nutr Cancer. 2003;45:236–46.PubMedCrossRefGoogle Scholar
  77. 77.
    Wali VB, Bachawal SV, Sylvester PW. Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells. Apoptosis. 2009;14:1366–77.PubMedCrossRefGoogle Scholar
  78. 78.
    Sylvester PW, McIntyre BS, Gapor A, Briski KP. Vitamin E inhibition of normal mammary epithelial cell growth is associated with a reduction in protein kinase C(alpha) activation. Cell Prolif. 2001;34:347–57.PubMedCrossRefGoogle Scholar
  79. 79.
    Sylvester PW, Shah S. Antioxidants in dietary oils: their potential role in breast cancer prevention. Malays J Nutr. 2002;8:1–11.PubMedGoogle Scholar
  80. 80.
    Samant GV, Wali VB, Sylvester PW. Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression. Cell Prolif. 2010;43:77–83.PubMedCrossRefGoogle Scholar
  81. 81.
    Wali VB, Bachawal SV, Sylvester PW. Suppression in mevalonate synthesis mediates antitumor effects of combined statin and gamma-tocotrienol treatment. Lipids. 2009;44:925–34.PubMedCrossRefGoogle Scholar
  82. 82.
    Malaviya A, Parajuli P, Sylvester PW. Anticancer effects of combined γ-tocotrienol and PPARγ antagonist treatment are associated with a suppression in adipogenic factor expression. J Pharm Nutr Sci. 2014;4:43–56.Google Scholar
  83. 83.
    Parajuli P, Tiwari RV, Sylvester PW. Anticancer effects of gamma-tocotrienol are associated with a suppression in aerobic glycolysis. Biol Pharm Bull. 2015;38:1352–60.PubMedCrossRefGoogle Scholar
  84. 84.
    Alawin OA, Ahmed RA, Ibrahim BA, Briski KP, Sylvester PW. Antiproliferative effects of gamma-tocotrienol are associated with lipid raft disruption in HER2-positive human breast cancer cells. J Nutr Biochem. 2016;27:266–77.PubMedCrossRefGoogle Scholar
  85. 85.
    Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182:311–22.PubMedCrossRefGoogle Scholar
  86. 86.
    Nagy P, Vereb G, Sebestyen Z, Horvath G, Lockett SJ, Damjanovich S, Park JW, Jovin TM, Szollosi J. Lipid rafts and the local density of ErbB proteins influence the biological role of homo- and heteroassociations of ErbB2. J Cell Sci. 2002;115:4251–62.PubMedCrossRefGoogle Scholar
  87. 87.
    Sottocornola E, Misasi R, Mattei V, Ciarlo L, Gradini R, Garofalo T, Berra B, Colombo I, Sorice M. Role of gangliosides in the association of ErbB2 with lipid rafts in mammary epithelial HC11 cells. FEBS J. 2006;273:1821–30.PubMedCrossRefGoogle Scholar
  88. 88.
    Mukherjee S, Soe TT, Maxfield FR. Endocytic sorting of lipid analogues differing solely in the chemistry of their hydrophobic tails. J Cell Biol. 1999;144:1271–84.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Alawin OA, Ahmed RA, Dronamraju V, Briski KP, Sylvester PW. gamma-Tocotrienol-induced disruption of lipid rafts in human breast cancer cells is associated with a reduction in exosome heregulin content. J Nutr Biochem. 2017;48:83–93.PubMedCrossRefGoogle Scholar
  90. 90.
    Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol . Chapter 3: Unit. 2006;3:22.PubMedGoogle Scholar
  91. 91.
    Tan SS, Yin Y, Lee T, Lai RC, Yeo RW, Zhang B, Choo A, Lim SK. Therapeutic MSC exosomes are derived from lipid raft microdomains in the plasma membrane. J Extracell Vesicles. 2013;2.  https://doi.org/10.3402/jev.v2i0.22614
  92. 92.
    Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159–67.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445:437–41.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    She QB, Solit D, Basso A, Moasser MM. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3′-kinase/Akt pathway signaling. Clin Cancer Res. 2003;9:4340–6.PubMedGoogle Scholar
  95. 95.
    Carraway KL, Cantley LC. A neu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell. 1994;78:5–8.PubMedCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.College of PharmacyUniversity of Louisiana at MonroeMonroeUSA

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