系統識別號 U0026-1301201120110800
論文名稱(中文) 雌激素誘導4T1乳癌細胞於小鼠體內擴散之細胞機制
論文名稱(英文) Cellular mechanisms of estrogen-induced 4T1 spreading in mice
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 99
學期 1
出版年 100
研究生(中文) 劉瑩一
研究生(英文) Ying-Yi Liu
學號 s3697401
學位類別 碩士
語文別 英文
論文頁數 92頁
口試委員 指導教授-蔡美玲
中文關鍵字 雌性激素  雌性激素受體  癌細胞擴散  微管蛋白 
英文關鍵字 17β-estradiol  ERβ  tumor spreading  α-tubulin 
中文摘要 流行病學及動物實驗數據顯示乳癌的生長及轉移受到雌性激素濃度的影響。已發現雌性激素受體有兩種(ERα和ERβ)。在乳癌細胞中已知雌激素活化ERα 並經由基因組和非基因組途徑增加細胞增生;而活化的ERβ 主要經由非基因組途徑,利用修飾ERα的活性而降低細胞增生。於4T1腫瘤小鼠模式中,雌激素增加腫瘤轉移至肺臟。因4T1乳癌細胞並沒有ERα 的表現且雌激素不會增加其增生,目前並不清楚雌激素如何誘導4T1乳癌細胞的轉移及其機制。已知腫瘤轉移需要腫瘤細胞本身的癌化以及腫瘤微環境中發生血管新生。癌化的過程包括腫瘤細胞增生、去分化及擴散。因此本篇論文的目的是研究雌激素誘導4T1乳癌細胞於小鼠體內擴散之細胞機制。長期暴露雌激素於4T1腫瘤小鼠增加腫瘤的擴散面積,但並不會影響腫瘤的總量,若施打ERβ 拮抗劑PHTPP則可減少由雌激素增加之腫瘤擴散面積。在細胞實驗中,雌激素不影響4T1細胞的存活率及細胞週期,但會促進細胞型態的改變且增加細胞爬行的能力。更進一步測量血管新生相關蛋白的表現量也發現,雌激素使得原位癌處的血管內皮細胞生長因子A以及血管內皮生細胞長因子受體2的表現量增加,但並不會直接影響4T1乳癌細胞的血管內皮細胞生長因子A和血管內皮生細胞長因子受體2表現量。數據顯示雌激素並不會導致ERβ 由細胞質轉移至細胞核內,利用鑑別性的蛋白質譜分析細胞質內蛋白的改變,發現雌激素降低細胞骨架微管蛋白及絲切蛋白的含量,並利用西方墨點轉漬法確認雌激素降低α-微管蛋白的表現量。而太平洋紫杉醇促進微管蛋白的聚合作用但不影響微管蛋白含量。在雌激素存在下,太平洋紫杉醇降低由雌激素增加之細胞爬行能力。我們的結果顯示毋須ERα存在,雌激素藉由調控微管蛋白加速4Τ1乳癌細胞擴散。
英文摘要 Both epidemiological and animal studies show a positive association of breast tumor growth and metastatic spread with circulating levels of 17β-estradiol (E2). Two estrogen receptors (ERα and ERβ) in various breast tumor cells have been identified. The binding of E2 to ERα induces cell proliferation via both genomic and non-genomic pathways. However, ERβ suppresses ERα -induced cell proliferation. In tumor bearing mice, E2 increase tumor metastasis to lung in 4T1-implanted mice. Because E2 does not induce cell proliferation in 4T1 which does not contain ERα, it is not clear how estrogens increase the metastasis of 4T1. It has been well recognized that tumor metastasis requires the tumorigenesis of tumor cell and angiogenesis in the microenvironment. Tumorigenesis includes tumor proliferation, dedifferentiatioin, and migration. The purpose of the study was to investigate the cellular mechanisms of estrogen-induced 4T1 spreading in mice. Our data showed that E2 did not affect tumor mass but increased the spreading areas in 4T1-implanted mice. An ERβ antagonist, PHTPP, prevented E2-induced increases of spreading areas. E2 did not directly increase cell viability and cell cycle but induced the morphological change and migration ability of 4T1 as shown in both Wound-Healing and chemotaxis assays. We further examined the effect of E2 on angiogenesis. E2 did not directly influence the expression of VEGFA and VEGFR2 in 4T1 cell, but increased VEGF in tumor tissues. Because E2 did not cause the translocation of ERβ from cytosol to nucleus in 4T1, cellular mechanisms in 4T1 which facilitate tumor migration was then explored after quantitative proteomic analyses. Functional annotation indicated that E2 decreased the abundance of cofilin (an actin-regulated protein), α- and β- tubulin. Western blot analysis confirmed the decreased expression of α-tubulin by E2. Paclitaxel which induces the polymerization of tubulin did not affect 4T1 migration and the abundance of α and β-tubulin. In the presence of E2, paclitaxel prevented E2-induced 4T1 migration examined by both wound healing and chemotaxis assay. In conclusion, activation of ERβ may facilitate the spreading of tumor cells mianly by inducing tumor cell spreading through tubulin-dependent pathways. The significance of this study is that E2 facilitate tumor spreading by altering the composition of microtubule in ERα(-)4T1 breast tumor cells.
論文目次 Abstract I
中文摘要 III
誌謝 V
Index VII
List of tables XI
List of figures XII

Chapter I. Introduction 1

I. Development of breast tumor 1
Epidemiological studies of breast cancer 1
Cell cycle progression and tumor proliferation growth 1
Epithelial–mesenchymal transition 2
Migration and tumor spreading 3
VEGF-induced angiogenesis and tumor expansion 4

II. Estrogen and breast tumor formation 4
Estrogen and reproductive function 4
Contribution of estrogen to breast tumor growth and metastasis 5

III. Current studies of ER isoforms (ERs) in tumorigenesis and angiogenesis 5
The effect of ERs on proliferation 6
The effect of ERs on EMT 7
The effect of ERs on migration 7
The effect of ERs on angiogenesis 8
Chapter II. Motive of this study 9
Controversial role of ERα and ERβ in breast tumor formation 9
Unsolved issues of estrogens on breast tumor formation 9
The purpose and design of this study 9

Chapter III. Materials and Methods 11
I. Establishment of tumor-bearing mice with E2 capsule implantation 11
1. Animals 11
2. Cell culture 11
3. Preparation of E2 capsule 12
4. Implantation of E2 capsule into tumor-bearing mice 13
5. In vivo image 14

II. Functional assays in 4T1 cell 15
1. MTT assay 15
2. Analysis of cell cycle by flow cytometry 15
3. Counting of elongated cell 16
4. Wound healing assay 16
5. Boyden chamber assay 17
6. Immunofluorescence staining 17

III. Sample preparation 18
1. Tumor tissue homogenate 18
2. Cell lysate 18
3. Subcellular fraction 18

IV. Western blot and Proteomic analysis 19
1. Western blot analysis 19
2. In solution digestion 20
3. Stable isotope dimethyl labeling 20
4. Mass spectrometry and protein identification 22
5. Quantitative analysis of dimethyl labeled peptides 24

V. Data analysis and statistical evaluation 24

Chapter IV. Results 25
1. The effect of E2 on the tumor area and tumor mass in the primary tumor site 25
2. The effect of E2 on the tumor mass in lungs 26
3. The effect of E2 on cell proliferation 26
4. The effect of E2 on EMT 26
5. The effect of E2 on cell migration 27
6. The expression of VEGFA and VEGFR2 in primary tumor site 27
7. The expression of VEGFA and VEGFR2 in 4T1 27
8. Subcellular localization and translocation of ERβ in 4T1 27
9. Quantitative proteome of cytosolic proteins in 4T1 28
10. Proposed hypothesis of estrogen-induced changes in cell phenotypes 29
11. To test the hypothesis that the increased production of tubulin isoforms enhances estrogen-induced migration in 4T1 29

Chapter V. Discussion 31
Summary of this study 31
E2-increased tumor spreading in mice 32
Acceleration of tumorigenesis by long-term treatment with E2 34
Increase of angiogenesis-related factors by long-term treatment of E2 37
E2-induced alterations in various cytoskeleton proteins in 4T1 38
Facilitation of cell migration by estrogen through tubulin-dependent pathways 40
Significance of this study 41

Chapter VI. Reference 43
Chapter VII. Tables 51
Chapter VIII. Figures 70
Curriculim Vitae 92
參考文獻 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin 2009, 59(4):225-249.
2. Fry WA, Phillips JL, Menck HR: Ten-year survey of lung cancer treatment and survival in hospitals in the United States: a national cancer data base report. Cancer 1999, 86(9):1867-1876.
3. Ceballos E, Munoz-Alonso MJ, Berwanger B, Acosta JC, Hernandez R, Krause M, Hartmann O, Eilers M, Leon J: Inhibitory effect of c-Myc on p53-induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of p53 target genes and upregulation of chaperone genes. Oncogene 2005, 24(28):4559-4571.
4. Freytag SO: Enforced expression of the c-myc oncogene inhibits cell differentiation by precluding entry into a distinct predifferentiation state in G0/G1. Mol Cell Biol 1988, 8(4):1614-1624.
5. Mauleon I, Lombard MN, Munoz-Alonso MJ, Canelles M, Leon J: Kinetics of myc-max-mad gene expression during hepatocyte proliferation in vivo: Differential regulation of mad family and stress-mediated induction of c-myc. Mol Carcinog 2004, 39(2):85-90.
6. Munoz-Alonso MJ, Acosta JC, Richard C, Delgado MD, Sedivy J, Leon J: p21Cip1 and p27Kip1 induce distinct cell cycle effects and differentiation programs in myeloid leukemia cells. J Biol Chem 2005, 280(18):18120-18129.
7. Wu S, Cetinkaya C, Munoz-Alonso MJ, von der Lehr N, Bahram F, Beuger V, Eilers M, Leon J, Larsson LG: Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene 2003, 22(3):351-360.
8. Birchmeier C, Birchmeier W, Brand-Saberi B: Epithelial-mesenchymal transitions in cancer progression. Acta Anat (Basel) 1996, 156(3):217-226.
9. Savagner P: Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays 2001, 23(10):912-923.
10. Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002, 2(6):442-454.
11. Vincent-Salomon A, Thiery JP: Host microenvironment in breast
cancer development: epithelial-mesenchymal transition in breast cancer development. Breast Cancer Res 2003, 5(2):101-106.
12. Xu J, Lamouille S, Derynck R: TGF-beta-induced epithelial to mesenchymal transition. Cell Res 2009, 19(2):156-172.
13. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, Thompson EW: Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression. J Cell Physiol 2007, 213(2):374-383.
14. Acconcia F, Barnes CJ, Kumar R: Estrogen and tamoxifen induce cytoskeletal remodeling and migration in endometrial cancer cells. Endocrinology 2006, 147(3):1203-1212.
15. Giretti MS, Simoncini T: Rapid regulatory actions of sex steroids on cell movement through the actin cytoskeleton. Steroids 2008, 73(9-10):895-900.
16. M A: The Croonian Lecture, 1978: The Crawling Movement of Metazoan Cells. . Proc Roy Soc Lond B 1980, 207:129-147.
17. Ananthakrishnan R, Ehrlicher A: The forces behind cell movement. Int J Biol Sci 2007, 3(5):303-317.
18. Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR: Cell migration: integrating signals from front to back. Science 2003, 302(5651):1704-1709.
19. Banka CL, Lund CV, Nguyen MT, Pakchoian AJ, Mueller BM, Eliceiri BP: Estrogen induces lung metastasis through a host compartment-specific response. Cancer Res 2006, 66(7):3667-3672.
20. Chambers AF, Matrisian LM: Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 1997, 89(17):1260-1270.
21. Lorusso G, Ruegg C: The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol 2008, 130(6):1091-1103.
22. Hunter KW, Crawford NP, Alsarraj J: Mechanisms of metastasis. Breast Cancer Res 2008, 10 Suppl 1:S2.
23. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN et al: Involvement of chemokine receptors in breast cancer metastasis. Nature 2001, 410(6824):50-56.
24. Miller WL: Molecular biology of steroid hormone synthesis. Endocr Rev 1988, 9(3):295-318.
25. Pike MC, Spicer DV, Dahmoush L, Press MF: Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 1993, 15(1):17-35.
26. Russo J, Russo IH: The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol 2006, 102(1-5):89-96.
27. Novelli F, Milella M, Melucci E, Di Benedetto A, Sperduti I, Perrone-Donnorso R, Perracchio L, Venturo I, Nistico C, Fabi A et al: A divergent role for estrogen receptor-beta in node-positive and node-negative breast cancer classified according to molecular subtypes: an observational prospective study. Breast Cancer Res 2008, 10(5):R74.
28. Song RX, Fan P, Yue W, Chen Y, Santen RJ: Role of receptor complexes in the extranuclear actions of estrogen receptor alpha in breast cancer. Endocr Relat Cancer 2006, 13 Suppl 1:S3-13.
29. Acconcia F, Totta P, Ogawa S, Cardillo I, Inoue S, Leone S, Trentalance A, Muramatsu M, Marino M: Survival versus apoptotic 17beta-estradiol effect: role of ER alpha and ER beta activated non-genomic signaling. J Cell Physiol 2005, 203(1):193-201.
30. Ahmad S, Singh N, Glazer RI: Role of AKT1 in 17beta-estradiol- and insulin-like growth factor I (IGF-I)-dependent proliferation and prevention of apoptosis in MCF-7 breast carcinoma cells. Biochem Pharmacol 1999, 58(3):425-430.
31. Planas-Silva MD, Waltz PK: Estrogen promotes reversible epithelial-to-mesenchymal-like transition and collective motility in MCF-7 breast cancer cells. J Steroid Biochem Mol Biol 2007, 104(1-2):11-21.
32. Ye Y, Xiao Y, Wang W, Yearsley K, Gao JX, Shetuni B, Barsky SH: ERalpha signaling through slug regulates E-cadherin and EMT. Oncogene 2010, 29(10):1451-1462.
33. Giretti MS, Fu XD, De Rosa G, Sarotto I, Baldacci C, Garibaldi S, Mannella P, Biglia N, Sismondi P, Genazzani AR et al: Extra-nuclear signalling of estrogen receptor to breast cancer cytoskeletal remodelling, migration and invasion. PLoS One 2008, 3(5):e2238.
34. Simoncini T, Scorticati C, Mannella P, Fadiel A, Giretti MS, Fu XD, Baldacci C, Garibaldi S, Caruso A, Fornari L et al: Estrogen receptor alpha interacts with Galpha13 to drive actin remodeling and endothelial cell migration via the RhoA/Rho kinase/moesin pathway. Mol Endocrinol 2006, 20(8):1756-1771.
35. Azios NG, Krishnamoorthy L, Harris M, Cubano LA, Cammer M, Dharmawardhane SF: Estrogen and resveratrol regulate Rac and Cdc42 signaling to the actin cytoskeleton of metastatic breast cancer cells. Neoplasia 2007, 9(2):147-158.
36. Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R, Santen RJ: Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation. Mol Endocrinol 2002, 16(1):116-127.
37. Wood PA, Bove K, You S, Chambers A, Hrushesky WJ: Cancer growth and spread are saltatory and phase-locked to the reproductive cycle through mediators of angiogenesis. Mol Cancer Ther 2005, 4(7):1065-1075.
38. Ruohola JK, Valve EM, Karkkainen MJ, Joukov V, Alitalo K, Harkonen PL: Vascular endothelial growth factors are differentially regulated by steroid hormones and antiestrogens in breast cancer cells. Mol Cell Endocrinol 1999, 149(1-2):29-40.
39. Liang Y, Brekken RA, Hyder SM: Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr Relat Cancer 2006, 13(3):905-919.
40. Lamote I, Meyer E, Massart-Leen AM, Burvenich C: Sex steroids and growth factors in the regulation of mammary gland proliferation, differentiation, and involution. Steroids 2004, 69(3):145-159.
41. Salih AK, Fentiman IS: Breast cancer prevention: present and future. Cancer Treat Rev 2001, 27(5):261-273.
42. Shen Q, Brown PH: Novel agents for the prevention of breast cancer: targeting transcription factors and signal transduction pathways. J Mammary Gland Biol Neoplasia 2003, 8(1):45-73.
43. Azios NG, Dharmawardhane SF: Resveratrol and estradiol exert disparate effects on cell migration, cell surface actin structures, and focal adhesion assembly in MDA-MB-231 human breast cancer cells. Neoplasia 2005, 7(2):128-140.
44. Tang MJ, Hu JJ, Lin HH, Chiu WT, Jiang ST: Collagen gel overlay induces apoptosis of polarized cells in cultures: disoriented cell death. Am J Physiol 1998, 275(4 Pt 1):C921-931.
45. Catts VS, Catts SV, McGrath JJ, Feron F, McLean D, Coulson EJ, Lutze-Mann LH: Apoptosis and schizophrenia: a pilot study based on dermal fibroblast cell lines. Schizophr Res 2006, 84(1):20-28.
46. Cox B, Emili A: Tissue subcellular fractionation and protein extraction for use in mass-spectrometry-based proteomics. Nat Protoc 2006, 1(4):1872-1878.
47. Vitorino R, Ferreira R, Neuparth M, Guedes S, Williams J, Tomer KB, Domingues PM, Appell HJ, Duarte JA, Amado FM: Subcellular proteomics of mice gastrocnemius and soleus muscles. Anal Biochem 2007, 366(2):156-169.
48. Guillemin I, Becker M, Ociepka K, Friauf E, Nothwang HG: A subcellular prefractionation protocol for minute amounts of mammalian cell cultures and tissue. Proteomics 2005, 5(1):35-45.
49. Platet N, Cathiard AM, Gleizes M, Garcia M: Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Crit Rev Oncol Hematol 2004, 51(1):55-67.
50. Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS: Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 1997, 277(5331):1508-1510.
51. Tao K, Fang M, Alroy J, Sahagian GG: Imagable 4T1 model for the study of late stage breast cancer. BMC Cancer 2008, 8:228.
52. Chambers AF, Groom AC, MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002, 2(8):563-572.
53. Johnson MD, Kenney N, Stoica A, Hilakivi-Clarke L, Singh B, Chepko G, Clarke R, Sholler PF, Lirio AA, Foss C et al: Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Nat Med 2003, 9(8):1081-1084.
54. Casey G: The BRCA1 and BRCA2 breast cancer genes. Curr Opin Oncol 1997, 9(1):88-93.
55. Dixon JM, Page DL, Anderson TJ, Lee D, Elton RA, Stewart HJ, Forrest AP: Long-term survivors after breast cancer. Br J Surg 1985, 72(6):445-448.
56. Polyak K: Breast cancer: origins and evolution. J Clin Invest 2007, 117(11):3155-3163.
57. Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ, Kaufmann M, Diebold J, Arnholdt H, Muller P et al: From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci U S A 2003, 100(13):7737-7742.
58. Kaiser BK, Zimmerman ZA, Charbonneau H, Jackson PK: Disruption of
centrosome structure, chromosome segregation, and cytokinesis by misexpression of human Cdc14A phosphatase. Mol Biol Cell 2002, 13(7):2289-2300.
59. Ou Y, Rattner JB: The centrosome in higher organisms: structure, composition, and duplication. Int Rev Cytol 2004, 238:119-182.
60. Azimzadeh J, Bornens M: Structure and duplication of the centrosome. J Cell Sci 2007, 120(Pt 13):2139-2142.
61. Yager JD, Davidson NE: Estrogen carcinogenesis in breast cancer. N Engl J Med 2006, 354(3):270-282.
62. Horner-Glister E, Maleki-Dizaji M, Guerin CJ, Johnson SM, Styles J, White IN: Influence of oestradiol and tamoxifen on oestrogen receptors-alpha and -beta protein degradation and non-genomic signalling pathways in uterine and breast carcinoma cells. J Mol Endocrinol 2005, 35(3):421-432.
63. Planas-Silva MD, Weinberg RA: Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Mol Cell Biol 1997, 17(7):4059-4069.
64. Wang W, Smith R, 3rd, Safe S: Aryl hydrocarbon receptor-mediated antiestrogenicity in MCF-7 cells: modulation of hormone-induced cell cycle enzymes. Arch Biochem Biophys 1998, 356(2):239-248.
65. Wang W, Dong L, Saville B, Safe S: Transcriptional activation of E2F1 gene expression by 17beta-estradiol in MCF-7 cells is regulated by NF-Y-Sp1/estrogen receptor interactions. Mol Endocrinol 1999, 13(8):1373-1387.
66. Sundar SN, Marconett CN, Doan VB, Willoughby JA, Sr., Firestone GL: Artemisinin selectively decreases functional levels of estrogen receptor-alpha and ablates estrogen-induced proliferation in human breast cancer cells. Carcinogenesis 2008, 29(12):2252-2258.
67. Hodges-Gallagher L, Valentine CD, El Bader S, Kushner PJ: Estrogen receptor beta increases the efficacy of antiestrogens by effects on apoptosis and cell cycling in breast cancer cells. Breast Cancer Res Treat 2008, 109(2):241-250.
68. Omoto Y, Eguchi H, Yamamoto-Yamaguchi Y, Hayashi S: Estrogen receptor (ER) beta1 and ERbetacx/beta2 inhibit ERalpha function differently in breast cancer cell line MCF7. Oncogene 2003, 22(32):5011-5020.
69. Behrens D, Gill JH, Fichtner I: Loss of tumourigenicity of stably ERbeta-transfected MCF-7 breast cancer cells. Mol Cell Endocrinol
2007, 274(1-2):19-29.
70. Etienne-Manneville S: Actin and microtubules in cell motility: which one is in control? Traffic 2004, 5(7):470-477.
71. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L: VEGF-receptor signal transduction. Trends Biochem Sci 2003, 28(9):488-494.
72. Carmeliet P, Collen D: Role of vascular endothelial growth factor and vascular endothelial growth factor receptors in vascular development. Curr Top Microbiol Immunol 1999, 237:133-158.
73. Donaldson SK: Breakthroughs in scientific research: the discipline of nursing, 1960-1999. Annu Rev Nurs Res 2000, 18:247-311.
74. Pollard TD, Borisy GG: Cellular motility driven by assembly and disassembly of actin filaments. Cell 2003, 112(4):453-465.
75. dos Remedios CG, Chhabra D, Kekic M, Dedova IV, Tsubakihara M, Berry DA, Nosworthy NJ: Actin binding proteins: regulation of cytoskeletal microfilaments. Physiol Rev 2003, 83(2):433-473.
76. Eiseler T, Doppler H, Yan IK, Kitatani K, Mizuno K, Storz P: Protein kinase D1 regulates cofilin-mediated F-actin reorganization and cell motility through slingshot. Nat Cell Biol 2009, 11(5):545-556.
77. Turner CE, West KA, Brown MC: Paxillin-ARF GAP signaling and the cytoskeleton. Curr Opin Cell Biol 2001, 13(5):593-599.
78. Jordan MA, Wilson L: Microtubules as a target for anticancer drugs. Nat Rev Cancer 2004, 4(4):253-265.
79. Nakaya Y, Sukowati EW, Wu Y, Sheng G: RhoA and microtubule dynamics control cell-basement membrane interaction in EMT during gastrulation. Nat Cell Biol 2008, 10(7):765-775.
80. Levayer R, Lecuit T: Breaking down EMT. Nat Cell Biol 2008, 10(7):757-759.
81. Bialkowska K, Zaffran Y, Meyer SC, Fox JE: 14-3-3 zeta mediates integrin-induced activation of Cdc42 and Rac. Platelet glycoprotein Ib-IX regulates integrin-induced signaling by sequestering 14-3-3 zeta. J Biol Chem 2003, 278(35):33342-33350.
82. Deakin NO, Bass MD, Warwood S, Schoelermann J, Mostafavi-Pour Z, Knight D, Ballestrem C, Humphries MJ: An integrin-alpha4-14-3-3zeta-paxillin ternary complex mediates localised Cdc42 activity and accelerates cell migration. J Cell Sci 2009, 122(Pt 10):1654-1664.
83. Hall A: The cytoskeleton and cancer. Cancer Metastasis Rev 2009, 28(1-2):5-14.
84. Chianale F, Rainero E, Cianflone C, Bettio V, Pighini A, Porporato PE, Filigheddu N, Serini G, Sinigaglia F, Baldanzi G et al: Diacylglycerol kinase alpha mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI. Proc Natl Acad Sci U S A 2010, 107(9):4182-4187.
85. Koivisto L, Hakkinen L, Matsumoto K, McCulloch CA, Yamada KM, Larjava H: Glycogen synthase kinase-3 regulates cytoskeleton and translocation of Rac1 in long cellular extensions of human keratinocytes. Exp Cell Res 2004, 293(1):68-80.
86. Von Hoff DD: The taxoids: same roots, different drugs. Semin Oncol 1997, 24(4 Suppl 13):S13-13-S13-10.
87. Markman M: Managing taxane toxicities. Support Care Cancer 2003, 11(3):144-147.
88. Schiff PB, Fant J, Horwitz SB: Promotion of microtubule assembly in vitro by taxol. Nature 1979, 277(5698):665-667.
89. Nogales E: Structural insight into microtubule function. Annu Rev Biophys Biomol Struct 2001, 30:397-420.
90. Bayet-Robert M, Morvan D, Chollet P, Barthomeuf C: Pharmacometabolomics of docetaxel-treated human MCF7 breast cancer cells provides evidence of varying cellular responses at high and low doses. Breast Cancer Res Treat 2010, 120(3):613-626.
91. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP: HDAC6 is a microtubule-associated deacetylase. Nature 2002, 417(6887):455-458.
92. Azuma K, Urano T, Horie-Inoue K, Hayashi S, Sakai R, Ouchi Y, Inoue S: Association of estrogen receptor alpha and histone deacetylase 6 causes rapid deacetylation of tubulin in breast cancer cells. Cancer Res 2009, 69(7):2935-2940.
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