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Cancer statistics, 2015. CA Cancer J. Clin.<\/i>, 65<\/b>, 5\u201329 (2015).","DOI":"10.3322\/caac.21254"},{"key":"2","doi-asserted-by":"crossref","unstructured":"2) Taylor MA, Davuluri G, Parvani JG, Schiemann BJ, Wendt MK, Plow EF, Schiemann WP, Sossey-Alaoui K. Upregulated WAVE3 expression is essential for TGF-\u03b2-mediated EMT and metastasis of triple-negative breast cancer cells. Breast Cancer Res. Treat.<\/i>, 142<\/b>, 341\u2013353 (2013).","DOI":"10.1007\/s10549-013-2753-1"},{"key":"3","doi-asserted-by":"crossref","unstructured":"3) Escudero-Esparza A, Jiang WG, Martin TA. Claudin-5 is involved in breast cancer cell motility through the N-WASP and ROCK signalling pathways. J. Exp. Clin. Cancer Res.<\/i>, 31<\/b>, 43 (2012).","DOI":"10.1186\/1756-9966-31-43"},{"key":"4","doi-asserted-by":"crossref","unstructured":"4) Ishihara D, Dovas A, Hernandez L, Pozzuto M, Wyckoff J, Segall JE, Condeelis JS, Bresnick AR, Cox D. Wiskott\u2013Aldrich syndrome protein regulates leukocyte-dependent breast cancer metastasis. Cell Reports<\/i>, 4<\/b>, 429\u2013436 (2013).","DOI":"10.1016\/j.celrep.2013.07.007"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5) Ko HS, Kim JS, Cho SM, Lee H-J, Ahn KS, Kim S-H, Lee E-O. Urokinase-type plasminogen activator expression and Rac1\/WAVE-2\/Arp2\/3 pathway are blocked by pterostilbene to suppress cell migration and invasion in MDA-MB-231 cells. Bioorg. Med. Chem. Lett.<\/i>, 24<\/b>, 1176\u20131179 (2014).","DOI":"10.1016\/j.bmcl.2013.12.115"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6) Yamaguchi H, Condeelis J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim. Biophys. Acta (BBA)-Molecular Cell Research<\/i>, 1773<\/b>, 642\u2013652 (2007).","DOI":"10.1016\/j.bbamcr.2006.07.001"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7) Kim JS, Kang CG, Kim S-H, Lee E-O. Rhapontigenin suppresses cell migration and invasion by inhibiting the PI3K-dependent Rac1 signaling pathway in MDA-MB-231 human breast cancer cells. J. Nat. Prod.<\/i>, 77<\/b>, 1135\u20131139 (2014).","DOI":"10.1021\/np401078g"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8) Ikenouchi J, Matsuda M, Furuse M, Tsukita S. Regulation of tight junctions during the epithelium\u2013mesenchyme transition: direct repression of the gene expression of claudins\/occludin by Snail. J. Cell Sci.<\/i>, 116<\/b>, 1959\u20131967 (2003).","DOI":"10.1242\/jcs.00389"},{"key":"9","doi-asserted-by":"crossref","unstructured":"9) Kalluri R, Weinberg RA. The basics of epithelial\u2013mesenchymal transition. J. Clin. Invest.<\/i>, 119<\/b>, 1420\u20131428 (2009).","DOI":"10.1172\/JCI39104"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10) Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science<\/i>, 307<\/b>, 1603\u20131609 (2005).","DOI":"10.1126\/science.1105718"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11) Savagner P. The epithelial\u2013mesenchymal transition (EMT) phenomenon. Ann. Oncol.<\/i>, 21<\/b> (Suppl. 7), vii89\u2013vii92 (2010).","DOI":"10.1093\/annonc\/mdq292"},{"key":"12","doi-asserted-by":"crossref","unstructured":"12) Foerster F, Braig S, Moser C, Kubisch R, Busse J, Wagner E, Schmoeckel E, Mayr D, Schmitt S, Huettel S, Zischka H, Mueller R, Vollmar AM. Targeting the actin cytoskeleton: selective antitumor action via<\/i> trapping PKC\u03b5. Cell Death Dis.<\/i>, 5<\/b>, e1398 (2014).","DOI":"10.1038\/cddis.2014.363"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13) Higgs HN, Pollard TD. Regulation of actin polymerization by Arp2\/3 complex and WASp\/Scar proteins. J. Biol. Chem.<\/i>, 274<\/b>, 32531\u201332534 (1999).","DOI":"10.1074\/jbc.274.46.32531"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14) Upadhyaya A, van Oudenaarden A. Actin polymerization: forcing flat faces forward. Curr. Biol.<\/i>, 14<\/b>, R467\u2013R469 (2004).","DOI":"10.1016\/j.cub.2004.06.010"},{"key":"15","doi-asserted-by":"crossref","unstructured":"15) Yin C, Li H, Zhang B, Liu Y, Lu G, Lu S, Sun L, Qi Y, Li X, Chen W. RAGE-binding S100A8\/A9 promotes the migration and invasion of human breast cancer cells through actin polymerization and epithelial\u2013mesenchymal transition. Breast Cancer Res. Treat.<\/i>, 142<\/b>, 297\u2013309 (2013).","DOI":"10.1007\/s10549-013-2737-1"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16) Zhang J, Shen Y, Liu J, Wei D. Antimetastatic effect of prodigiosin through inhibition of tumor invasion. Biochem. Pharmacol.<\/i>, 69<\/b>, 407\u2013414 (2005).","DOI":"10.1016\/j.bcp.2004.08.037"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17) Kurisu S, Suetsugu S, Yamazaki D, Yamaguchi H, Takenawa T. Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells. Oncogene<\/i>, 24<\/b>, 1309\u20131319 (2005).","DOI":"10.1038\/sj.onc.1208177"},{"key":"18","doi-asserted-by":"crossref","unstructured":"18) Kurisu S, Takenawa T. The WASP and WAVE family proteins. Genome Biol.<\/i>, 10<\/b>, 226 (2009).","DOI":"10.1186\/gb-2009-10-6-226"},{"key":"19","doi-asserted-by":"crossref","unstructured":"19) Kurisu S, Takenawa T. WASP and WAVE family proteins: friends or foes in cancer invasion? Cancer Sci.<\/i>, 101<\/b>, 2093\u20132104 (2010).","DOI":"10.1111\/j.1349-7006.2010.01654.x"},{"key":"20","doi-asserted-by":"crossref","unstructured":"20) Yokotsuka M, Iwaya K, Saito T, Pandiella A, Tsuboi R, Kohno N, Matsubara O, Mukai K. Overexpression of HER2 signaling to WAVE2\u2013Arp2\/3 complex activates MMP-independent migration in breast cancer. Breast Cancer Res. Treat.<\/i>, 126<\/b>, 311\u2013318 (2011).","DOI":"10.1007\/s10549-010-0896-x"},{"key":"21","unstructured":"21) Frugtniet B, Jiang WG, Martin TA. Role of the WASP and WAVE family proteins in breast cancer invasion and metastasis. Breast Cancer: Targets and Therapy<\/i>, 7<\/b>, 99\u2013109 (2015)."},{"key":"22","doi-asserted-by":"crossref","unstructured":"22) Machesky LM, Insall RH. Scar1 and the related Wiskott\u2013Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2\/3 complex. Curr. Biol.<\/i>, 8<\/b>, 1347\u20131356 (1998).","DOI":"10.1016\/S0960-9822(98)00015-3"},{"key":"23","unstructured":"23) Takenawa T, Miki H. WASP and WAVE family proteins: key molecules for rapid rearrangement of cortical actin filaments and cell movement. J. Cell Sci.<\/i>, 114<\/b>, 1801\u20131809 (2001)."},{"key":"24","doi-asserted-by":"crossref","unstructured":"24) Yarar D, To W, Abo A, Welch MD. The Wiskott\u2013Aldrich syndrome protein directs actin-based motility by stimulating actin nucleation with the Arp2\/3 complex. Curr. Biol.<\/i>, 9<\/b>, 555\u2013558 (1999).","DOI":"10.1016\/S0960-9822(99)80243-7"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25) 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.<\/i>, 27<\/b>, 266\u2013277 (2016).","DOI":"10.1016\/j.jnutbio.2015.09.018"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26) Ayoub NM, Bachawal SV, Sylvester PW. \u03b3-Tocotrienol inhibits HGF-dependent mitogenesis and Met activation in highly malignant mammary tumour cells. Cell Prolif.<\/i>, 44<\/b>, 516\u2013526 (2011).","DOI":"10.1111\/j.1365-2184.2011.00785.x"},{"key":"27","doi-asserted-by":"crossref","unstructured":"27) 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<\/i>, 10<\/b>, 84 (2010).","DOI":"10.1186\/1471-2407-10-84"},{"key":"28","doi-asserted-by":"crossref","unstructured":"28) Sylvester PW. Targeting met mediated epithelial\u2013mesenchymal transition in the treatment of breast cancer. Clin. Transl. Med.<\/i>, 3<\/b>, 30 (2014).","DOI":"10.1186\/s40169-014-0030-5"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29) Sylvester PW, Ayoub NM. Tocotrienols target PI3K\/Akt signaling in anti-breast cancer therapy. Anticancer. Agents Med. Chem.<\/i>, 13<\/b>, 1039\u20131047 (2013).","DOI":"10.2174\/18715206113139990116"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30) Anderson LW, Danielson KG, Hosick HL. New cell line. Epithelial cell line and subline established from premalignant mouse mammary tissue. In Vitro<\/i>, 15<\/b>, 841\u2013843 (1979).","DOI":"10.1007\/BF02618037"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31) Anderson LW, Danielson KG, Hosick HL. Metastatic potential of hyperplastic alveolar nodule derived mouse mammary tumor cells following intravenous inoculation. Eur. J. Cancer Clin. Oncol.<\/i>, 17<\/b>, 1001\u20131008 (1981).","DOI":"10.1016\/S0277-5379(81)80005-3"},{"key":"32","unstructured":"32) Danielson KG, Anderson LW, Hosick HL. Selection and characterization in culture of mammary tumor cells with distinctive growth properties in vivo.<\/i> Cancer Res.<\/i>, 40<\/b>, 1812\u20131819 (1980)."},{"key":"33","doi-asserted-by":"crossref","unstructured":"33) 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.<\/i>, 224<\/b>, 292\u2013301 (2000).","DOI":"10.1046\/j.1525-1373.2000.22434.x"},{"key":"34","doi-asserted-by":"crossref","unstructured":"34) 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<\/i>, 35<\/b>, 171\u2013180 (2000).","DOI":"10.1007\/BF02664767"},{"key":"35","doi-asserted-by":"crossref","unstructured":"35) Tiwari RV, Parajuli P, Sylvester PW. \u03b3-Tocotrienol-induced autophagy in malignant mammary cancer cells. Exp. Biol. Med.<\/i> (Maywood), 239<\/b>, 33\u201344 (2014).","DOI":"10.1177\/1535370213511022"},{"key":"36","doi-asserted-by":"crossref","unstructured":"36) Parajuli P, Tiwari RV, Sylvester PW. Antiproliferative effects of \u03b3-tocotrienol are associated with a suppression in c-Myc expression in mammary tumor cells. Cell Prolif.<\/i>, 48<\/b>, 421\u2013435 (2015).","DOI":"10.1111\/cpr.12196"},{"key":"37","doi-asserted-by":"crossref","unstructured":"37) 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.<\/i>, 46<\/b>, 538\u2013553 (2013).","DOI":"10.1111\/cpr.12059"},{"key":"38","doi-asserted-by":"crossref","unstructured":"38) Aggarwal B, Nesaretnam K. Vitamin E tocotrienols: life beyond tocopherols. Genes Nutr.<\/i>, 7<\/b>, 1 (2012).","DOI":"10.1007\/s12263-011-0234-x"},{"key":"39","doi-asserted-by":"crossref","unstructured":"39) Sylvester PW, Akl MR, Malaviya A, Parajuli P, Ananthula S, Tiwari RV, Ayoub NM. Potential role of tocotrienols in the treatment and prevention of breast cancer. Biofactors<\/i>, 40<\/b>, 49\u201358 (2014).","DOI":"10.1002\/biof.1116"},{"key":"40","unstructured":"40) 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.<\/i>, 30<\/b>, 429\u2013437 (2010)."},{"key":"41","doi-asserted-by":"crossref","unstructured":"41) Samant GV, Sylvester PW. \u03b3-Tocotrienol inhibits ErbB3-dependent PI3K\/Akt mitogenic signalling in neoplastic mammary epithelial cells. Cell Prolif.<\/i>, 39<\/b>, 563\u2013574 (2006).","DOI":"10.1111\/j.1365-2184.2006.00412.x"},{"key":"42","doi-asserted-by":"crossref","unstructured":"42) 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.<\/i>, 43<\/b>, 77\u201383 (2010).","DOI":"10.1111\/j.1365-2184.2009.00657.x"},{"key":"43","doi-asserted-by":"crossref","unstructured":"43) Malaviya A, Sylvester PW. Mechanisms mediating the effects of gamma-tocotrienol when used in combination with PPAR\u03b3 agonists or antagonists on MCF-7 and MDA-MB-231 breast cancer cells. Int. J. Breast Cancer<\/i>, 2013<\/b>, 101705 (2013).","DOI":"10.1155\/2013\/101705"},{"key":"44","doi-asserted-by":"crossref","unstructured":"44) Shah SJ, Sylvester PW. \u03b3-Tocotrienol inhibits neoplastic mammary epithelial cell proliferation by decreasing Akt and nuclear factor kappaB activity. Exp. Biol. Med.<\/i> (Maywood), 230<\/b>, 235\u2013241 (2005).","DOI":"10.1177\/153537020523000402"},{"key":"45","doi-asserted-by":"crossref","unstructured":"45) Wali VB, Sylvester PW. Synergistic antiproliferative effects of gamma-tocotrienol and statin treatment on mammary tumor cells. Lipids<\/i>, 42<\/b>, 1113\u20131123 (2007).","DOI":"10.1007\/s11745-007-3102-0"},{"key":"46","doi-asserted-by":"crossref","unstructured":"46) Hanna S, El-Sibai M. Signaling networks of Rho GTPases in cell motility. Cell. Signal.<\/i>, 25<\/b>, 1955\u20131961 (2013).","DOI":"10.1016\/j.cellsig.2013.04.009"},{"key":"47","doi-asserted-by":"crossref","unstructured":"47) Nolz JC, Gomez TS, Zhu P, Li S, Medeiros RB, Shimizu Y, Burkhardt JK, Freedman BD, Billadeau DD. The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr. Biol.<\/i>, 16<\/b>, 24\u201334 (2006).","DOI":"10.1016\/j.cub.2005.11.036"},{"key":"48","doi-asserted-by":"crossref","unstructured":"48) Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, Lengyel E. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene<\/i>, 19<\/b>, 3013\u20133020 (2000).","DOI":"10.1038\/sj.onc.1203621"},{"key":"49","doi-asserted-by":"crossref","unstructured":"49) Zhang Y, Rivera Rosado LA, Moon SY, Zhang B. Silencing of D4-GDI inhibits growth and invasive behavior in MDA-MB-231 cells by activation of Rac-dependent p38 and JNK signaling. J. Biol. Chem.<\/i>, 284<\/b>, 12956\u201312965 (2009).","DOI":"10.1074\/jbc.M807845200"},{"key":"50","doi-asserted-by":"crossref","unstructured":"50) Fritz G, Just I, Kaina B. Rho GTPases are over-expressed in human tumors. Int. J. Cancer<\/i>, 81<\/b>, 682\u2013687 (1999).","DOI":"10.1002\/(SICI)1097-0215(19990531)81:5<682::AID-IJC2>3.0.CO;2-B"},{"key":"51","doi-asserted-by":"crossref","unstructured":"51) Iwaya K, Norio K, Mukai K. Coexpression of Arp2 and WAVE2 predicts poor outcome in invasive breast carcinoma. Mod. Pathol.<\/i>, 20<\/b>, 339\u2013343 (2007).","DOI":"10.1038\/modpathol.3800741"},{"key":"52","doi-asserted-by":"crossref","unstructured":"52) Kikuchi K, Li X, Zheng Y, Takano Y. Invasion of breast cancer cells into collagen matrix requires TGF-\u03b1 and Cdc42 signaling. 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