Phospho-specific Smad3 signaling: Impact on breast oncogenesis

Cell Cycle

Volumn 11, Issue 13, 2012, Pages 2443-2451

  Tarasewicz, Elizabeth ^a   Jeruss, Jacqueline S ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

Breast cancer; Cell cycle; EMT; Smad3; TGF

Indexed keywords

CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE 6; EPIDERMAL GROWTH FACTOR RECEPTOR 2; FLAVOPIRIDOL; MATRIX METALLOPROTEINASE; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE 1; PEPTIDYLPROLYL ISOMERASE PIN1; PLASMINOGEN ACTIVATOR INHIBITOR; PROTEIN P15; PROTEIN P21; RAS PROTEIN; ROSCOVITINE; SMAD2 PROTEIN; SMAD3 PROTEIN; TISSUE INHIBITOR OF METALLOPROTEINASE 1; TISSUE INHIBITOR OF METALLOPROTEINASE 2; TRANSFORMING GROWTH FACTOR BETA; UBIQUITIN PROTEIN LIGASE;

BREAST CANCER; BREAST CARCINOGENESIS; CANCER GROWTH; CANCER PATIENT; CELL CYCLE; CELL CYCLE G1 PHASE; CELL CYCLE PROGRESSION; CLINICAL TRIAL (TOPIC); COLON CANCER; ENZYME INHIBITION; GENE EXPRESSION; GENE MUTATION; HEPATITIS B; HUMAN; LIVER CELL CARCINOMA; METASTASIS; ONCOGENE C MYC; ORGANOGENESIS; PANCREAS CANCER; PROSTATE CANCER; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; THYROID CANCER; TRANSCRIPTION REGULATION; UBIQUITINATION; WNT SIGNALING PATHWAY;

EID: 84863798396     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.20546     Document Type: Review

References (86)

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J Clin 2010; 60:277-300; PMID:20610543; http://dx.doi.org/10.3322/caac.20073.
2. Silberstein GB, Daniel CW. Reversible inhibition of mammary gland growth by transforming growth factorbeta. Science 1987; 237:291-3; PMID:3474783; http://dx.doi.org/10.1126/science.3474783.
3. Robinson SD, Silberstein GB, Roberts AB, Flanders KC, Daniel CW. Regulated expression and growth inhibitory effects of transforming growth factor-beta isoforms in mouse mammary gland development. Development 1991; 113:867-78; PMID:1821856.
4. Nguyen AV, Pollard JW. Transforming growth factor-beta3 induces cell death during the first stage of mammary gland involution. Development 2000; 127:3107-18; PMID:10862748.
5. Gorska AE, Joseph H, Derynck R, Moses HL, Serra R. Dominant-negative interference of the transforming growth factorbeta type II receptor in mammary gland epithelium results in alveolar hyperplasia and differentiation in virgin mice. Cell Growth Differ 1998; 9:229-38; PMID:9543389.
6. Jhappan C, Geiser AG, Kordon EC, Bagheri D, Hennighausen L, Roberts AB, et al. Targeting expression of a transforming growth factor-beta1 transgene to the pregnant mammary gland inhibits alveolar development and lactation. EMBO J 1993; 12:1835-45; PMID:8491177.
7. Daniel CW, Robinson S, Silberstein GB. The role of TGFbeta in patterning and growth of the mammary ductal tree. J Mammary Gland Biol Neoplasia 1996; 1:331-41; PMID:10887507; http://dx.doi.org/10.1007/BF02017389.
8. Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 2004; 430:226-31; PMID:15241418; http://dx.doi.org/10.1038/nature02650.
9. Cooley A, Zelivianski S, Jeruss JS. Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines. Cell Cycle 2010; 9:4900-7; PMID:21150326; http://dx.doi.org/10.4161/cc.9.24.14158.
10. Zelivianski S, Cooley A, Kall R, Jeruss JS. Cyclin-dependent kinase 4-mediated phosphorylation inhibits Smad3 activity in cyclin D-overexpressing breast cancer cells. Mol Cancer Res 2010; 8:1375-87; PMID:20736297; http://dx.doi.org/10.1158/1541-7786.MCR-09-0537.
11. Sekimoto G, Matsuzaki K, Yoshida K, Mori S, Murata M, Seki T, et al. Reversible Smad-dependent signaling between tumor suppression and oncogenesis. Cancer Res 2007; 67:5090-6; PMID:17545585; http://dx.doi.org/10.1158/0008-5472. CAN-06-4629.
12. Yue J, Mulder KM. Transforming growth factor-beta signal transduction in epithelial cells. Pharmacol Ther 2001; 91:1-34; PMID:11707292; http://dx.doi.org/10.1016/S0163-7258(01)00143-7.
13. Massagué J. TGFbeta signal transduction. Annu Rev Biochem 1998; 67:753-91; PMID:9759503; http://dx.doi.org/10.1146/annurev.biochem.67.1.753.
14. Lebrun JJ, Vale WW. Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation. Mol Cell Biol 1997; 17:1682-91; PMID:9032295.
15. Attisano L, Lee-Hoeflich ST. The Smads. Genome Biol 2001; 2:3010-8; http://dx.doi.org/10.1186/gb-2001-2-8-reviews3010.
16. Dennler S, Huet S, Gauthier JM. A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3. Oncogene 1999; 18:1643-8; PMID:10102636; http://dx.doi.org/10.1038/sj.onc.1202729.
17. Ross S, Hill CS. How the Smads regulate transcription. Int J Biochem Cell Biol 2008; 40:383-408; PMID:18061509; http://dx.doi.org/10.1016/j.biocel.2007. 09.006.
18. Kohn EA, Du Z, Sato M, Van Schyndle CM, Welsh MA, Yang YA, et al. A novel approach for the generation of genetically modified mammary epithelial cell cultures yields new insights into TGFβ signaling in the mammary gland. Breast Cancer Res 2010; 12:83; PMID:20942910; http://dx.doi.org/10.1186/bcr2728.
19. Dzwonek J, Preobrazhenska O, Cazzola S, Conidi A, Schellens A, van Dinther M, et al. Smad3 is a key nonredundant mediator of transforming growth factor-beta signaling in Nme mouse mammary epithelial cells. Mol Cancer Res 2009; 7:1342-53; PMID:19671686; http://dx.doi.org/10.1158/1541-7786.MCR-08-0558.
20. Chen CR, Kang Y, Siegel PM, Massagué J. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 2002; 110:19-32; PMID:12150994; http://dx.doi.org/10.1016/S0092-8674(02)00801-2.
21. Feng XH, Liang YY, Liang M, Zhai W, Lin X. Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGFbeta-mediated induction of the CDK inhibitor p15(Ink4B). Mol Cell 2002; 9:133-43; PMID:11804592; http://dx.doi.org/10.1016/ S1097-2765(01)00430-0.
22. Pardali K, Kurisaki A, Morén A, ten Dijke P, Kardassis D, Moustakas A. Role of Smad proteins and transcription factor Sp1 in p21(Waf1/Cip1) regulation by transforming growth factor-beta. J Biol Chem 2000; 275:29244-56; PMID:10878024; http://dx.doi.org/10.1074/jbc.M909467199.
23. INK4B-cdk4complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells. Mol Cell Biol 1997; 17:2458-67; PMID:9111314.
24. Reynisdóttir I, Polyak K, Iavarone A, Massagué J. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGFbeta. Genes Dev 1995; 9:1831-45; PMID:7649471; http://dx.doi.org/10.1101/gad. 9.15.1831.
25. Moustakas A, Pardali K, Gaal A, Heldin CH. Mechanisms of TGFbeta signaling in regulation of cell growth and differentiation. Immunol Lett 2002; 82:85-91; PMID:12008039; http://dx.doi.org/10.1016/S0165-2478(02)00023-8.
26. Iavarone A, Massagué J. Repression of the CDK activator Cdc25A and cell cycle arrest by cytokine TGFbeta in cells lacking the CDK inhibitor p15. Nature 1997; 387:417-22; PMID:9163429; http://dx.doi.org/10.1038/387417a0.
27. Jeruss JS, Sturgis CD, Rademaker AW, Woodruff TK. Downregulation of activin, activin receptors and Smads in high-grade breast cancer. Cancer Res 2003; 63:3783-90; PMID:12839974.
28. Kretzschmar M, Doody J, Timokhina I, Massagué J. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev 1999; 13:804-16; PMID:10197981; http://dx.doi.org/10.1101/gad.13.7.804.
29. Mori S, Matsuzaki K, Yoshida K, Furukawa F, Tahashi Y, Yamagata H, et al. TGFbeta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions. Oncogene 2004; 23:7416-29; PMID:15326485; http://dx.doi.org/10.1038/sj.onc.1207981.
30. Furukawa F, Matsuzaki K, Mori S, Tahashi Y, Yoshida K, Sugano Y, et al. p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts. Hepatology 2003; 38:879-89; PMID:14512875.
31. Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene 1993; 8:2127-33; PMID:8336939.
32. Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases and Cdk inhibitors in human cancer. Adv Cancer Res 1996; 68:67-108; PMID:8712071; http://dx.doi.org/10.1016/S0065-230X(08)60352-8.
33. Lin DI, Lessie MD, Gladden AB, Bassing CH, Wagner KU, Diehl JA. Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis. Oncogene 2008; 27:1231-42; PMID:17724472; http://dx.doi.org/10. 1038/sj.onc.1210738.
34. Kim JK, Diehl JA. Nuclear cyclin D1: an oncogenic driver in human cancer. J Cell Physiol 2009; 220:292-6; PMID:19415697; http://dx.doi.org/10.1002/jcp. 21791.
35. Satyanarayana A, Kaldis P. Mammalian cell cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene 2009; 28:2925-39; PMID:19561645; http://dx.doi.org/10.1038/onc.2009.170.
36. Boström P, Söderström M, Palokangas T, Vahlberg T, Collan Y, Carpen O, et al. Analysis of cyclins A, B1, D1 and E in breast cancer in relation to tumour grade and other prognostic factors. BMC Res Notes 2009; 2:140; PMID:19615042; http://dx.doi.org/10.1186/1756-0500-2-140.
37. Keyomarsi K, Tucker SL, Buchholz TA, Callister M, Ding Y, Hortobagyi GN, et al. Cyclin E and survival in patients with breast cancer. N Engl J Med 2002; 347:1566-75; PMID:12432043; http://dx.doi.org/10.1056/NEJMoa021153.
38. Fadare O, Tavassoli FA. Clinical and pathologic aspects of basal-like breast cancers. Nat Clin Pract Oncol 2008; 5:149-59; PMID:18212769; http://dx.doi.org/10.1038/ncponc1038.
39. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature 2000; 406:747-52; PMID:10963602; http://dx.doi.org/10.1038/35021093.
40. Matsuzaki K, Kitano C, Murata M, Sekimoto G, Yoshida K, Uemura Y, et al. Smad2 and Smad3 phosphorylated at both linker and COOH-terminal regions transmit malignant TGFbeta signal in later stages of human colorectal cancer. Cancer Res 2009; 69:5321-30; PMID:19531654; http://dx.doi.org/10.1158/0008-5472.CAN-08- 4203.
41. Liu F. Smad3 phosphorylation by cyclin-dependent kinases. Cytokine Growth Factor Rev 2006; 17:9-17; PMID:16289004; http://dx.doi.org/10.1016/j.cytogfr. 2005.09.010.
42. Matsuzaki K. Smad phosphoisoform signaling specificity: the right place at the right time. Carcinogenesis 2011; 32:1578-88; PMID:21798854; http://dx.doi.org/10.1093/carcin/bgr172.
43. Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989; 49:4682-9; PMID:2547513.
44. von Lintig FC, Dreilinger AD, Varki NM, Wallace AM, Casteel DE, Boss GR. Ras activation in human breast cancer. Breast Cancer Res Treat 2000; 62:51-62; PMID:10989985; http://dx.doi.org/10.1023/A:1006491619920.
45. Matsuzaki K. Modulation of TGFbeta signaling during progression of chronic liver diseases. Front Biosci 2009; 14:2923-34; PMID:19273245; http://dx.doi.org/10.2741/3423.
46. Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 1995; 80:179-85; PMID:7834738; http://dx.doi.org/10.1016/0092-8674(95)90401-8.
47. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature 2001; 410:37-40; PMID:11242034; http://dx.doi.org/10.1038/35065000.
48. 1 phase in BALB/c 3T3 cells. Mol Cell Biol 1994; 14:5441-9; PMID:8035821.
49. Mulcahy LS, Smith MR, Stacey DW. Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 1985; 313:241-3; PMID:3918269; http://dx.doi.org/10.1038/313241a0.
50. Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, et al. Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 1995; 270:23589-97; PMID:7559524; http://dx.doi.org/10.1074/jbc.270.40.23589.
51. Arber N, Sutter T, Miyake M, Kahn SM, Venkatraj VS, Sobrino A, et al. Increased expression of cyclin D1 and the Rb tumor suppressor gene in c-K-ras transformed rat enterocytes. Oncogene 1996; 12:1903-8; PMID:8649851.
52. 1 progression in NIH 3T3 cells. Mol Cell Biol 1995; 15:3654-63; PMID:7791772.
53. Winston JT, Coats SR, Wang YZ, Pledger WJ. Regulation of the cell cycle machinery by oncogenic ras. Oncogene 1996; 12:127-34; PMID:8552383.
54. 1 phase of the cell cycle. Cell 1991; 65:701-13; PMID:1827757; http://dx.doi.org/10.1016/0092-8674(91)90101-4.
55. Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature 2001; 411:1017-21; PMID:11429595; http://dx.doi.org/10.1038/35082500.
56. Liu F, Matsuura I. Inhibition of Smad antiproliferative function by CDK phosphorylation. Cell Cycle 2005; 4:63-6; PMID:15611645; http://dx.doi.org/10. 4161/cc.4.1.1366.
57. Lee EK, Diehl JA. Breast cancer go sMAD: cyclin towards aggressive phenotypes. Cell Cycle 2011; 10:187; PMID:21239879; http://dx.doi.org/10.4161/ cc.10.2.14480.
58. Ikushima H, Miyazono K. TGFβ signal transduction spreading to a wider field: a broad variety of mechanisms for context-dependent effects of TGFβ. Cell Tissue Res 2012; 347:37-49; PMID:21618142; http://dx.doi.org/10. 1007/s00441-011-1179-5.
59. Heldin CH, Moustakas A. Role of Smads in TGFβ signaling. Cell Tissue Res 2012; 347:21-36; PMID:21643690; http://dx.doi.org/10.1007/s00441-011-1190- x.
60. Sundqvist A, Ten Dijke P, van Dam H. Key signaling nodes in mammary gland development and cancer: Smad signal integration in epithelial cell plasticity. Breast Cancer Res 2012; 14:204; PMID:22315972; http://dx.doi.org/10.1186/ bcr3066.
61. Gao S, Alarcón C, Sapkota G, Rahman S, Chen PY, Goerner N, et al. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGFbeta signaling. Mol Cell 2009; 36:457-68; PMID:19917253; http://dx.doi.org/10.1016/j.molcel. 2009.09.043.
62. Lin X, Duan X, Liang YY, Su Y, Wrighton KH, Long J, et al. PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Cell 2006; 125:915-28; PMID:16751101; http://dx.doi.org/10.1016/j.cell.2006.03.044.
63. Sapkota G, Knockaert M, Alarcón C, Montalvo E, Brivanlou AH, Massagué J. Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways. J Biol Chem 2006; 281:40412-9; PMID:17085434; http://dx.doi.org/10.1074/jbc.M610172200.
64. Wrighton KH, Willis D, Long J, Liu F, Lin X, Feng XH. Small C-terminal domain phosphatases dephosphorylate the regulatory linker regions of Smad2 and Smad3 to enhance transforming growth factor-beta signaling. J Biol Chem 2006; 281:38365-75; PMID:17035229; http://dx.doi.org/10.1074/jbc.M607246200.
65. Kang JM, Park S, Kim SJ, Hong HY, Jeong J, Kim HS, et al. CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGFβ signaling. Oncogene 2012; PMID:22310290; http://dx.doi.org/10.1038/onc.2012.18.
66. Lin Q, Chen D, Timchenko NA, Medrano EE. SKI promotes Smad3 linker phosphorylations associated with the tumor-promoting trait of TGFbeta. Cell Cycle 2010; 9:1684-9; PMID:20404506; http://dx.doi.org/10.4161/cc.9.9.11292.
67. Theohari I, Giannopoulou I, Magkou C, Nomikos A, Melissaris S, Nakopoulou L. Differential effect of the expression of TGFβ pathway inhibitors, Smad-7 and Ski, on invasive breast carcinomas: relation to biologic behavior. APMIS 2012; 120:92-100; PMID:22229264; http://dx.doi.org/10.1111/j.1600-0463. 2011.02814.x.
68. Wulf GM, Ryo A, Wulf GG, Lee SW, Niu T, Petkova V, et al. Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1. EMBO J 2001; 20:3459-72; PMID:11432833; http://dx.doi.org/10.1093/emboj/20.13.3459.
69. Wulf G, Ryo A, Liou YC, Lu KP. The prolyl isomerase Pin1 in breast development and cancer. Breast Cancer Res 2003; 5:76-82; PMID:12631385; http://dx.doi.org/10.1186/bcr572.
70. Matsuura I, Chiang KN, Lai CY, He D, Wang G, Ramkumar R, et al. Pin1 promotes transforming growth factorbeta-induced migration and invasion. J Biol Chem 2010; 285:1754-64; PMID:19920136; http://dx.doi.org/10.1074/jbc.M109. 063826.
71. Fuxe J, Vincent T, Garcia de Herreros A. Transcriptional crosstalk between TGFβ and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell Cycle 2010; 9:2363-74; PMID:20519943; http://dx.doi.org/10.4161/cc.9.12.12050.
72. Moustakas A, Heldin CH. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci 2007; 98:1512-20; PMID:17645776; http://dx.doi.org/10.1111/j.1349-7006.2007.00550.x.
73. Nawshad A, Lagamba D, Polad A, Hay ED. Transforming growth factor-beta signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs 2005; 179:11-23; PMID:15942189; http://dx.doi.org/10.1159/000084505.
74. Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 1995; 154:8-20; PMID:8714286; http://dx.doi.org/10.1159/000147748.
75. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 2011; 145:926-40; PMID:21663795; http://dx.doi.org/ 10.1016/j.cell.2011.04.029.
76. Teicher BA. Malignant cells, directors of the malignant process: role of transforming growth factorbeta. Cancer Metastasis Rev 2001; 20:133-43; PMID:11831642; http://dx.doi.org/10.1023/A:1013177011767.
77. Matsuzaki K, Murata M, Yoshida K, Sekimoto G, Uemura Y, Sakaida N, et al. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factorbeta signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 2007; 46:48-57; PMID:17596875; http://dx.doi.org/10.1002/hep.21672.
78. Murata M, Matsuzaki K, Yoshida K, Sekimoto G, Tahashi Y, Mori S, et al. Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B. Hepatology 2009; 49:1203-17; PMID:19263472; http://dx.doi.org/10. 1002/hep.22765.
79. Matsuzaki K, Okazaki K. Transforming growth factorbeta during carcinogenesis: the shift from epithelial to mesenchymal signaling. J Gastroenterol 2006; 41:295-303; PMID:16741607; http://dx.doi.org/10.1007/s00535- 006-1795-0.
80. Wolfraim LA, Fernandez TM, Mamura M, Fuller WL, Kumar R, Cole DE, et al. Loss of Smad3 in acute T-cell lymphoblastic leukemia. N Engl J Med 2004; 351:552-9; PMID:15295048; http://dx.doi.org/10.1056/NEJMoa031197.
81. Ungefroren H, Groth S, Sebens S, Lehnert H, Gieseler F, Fändrich F. Differential roles of Smad2 and Smad3 in the regulation of TGF-β1-mediated growth inhibition and cell migration in pancreatic ductal adenocarcinoma cells: control by Rac1. Mol Cancer 2011; 10:67; PMID:21624123; http://dx.doi.org/10. 1186/1476-4598-10-67.
82. Bello-DeOcampo D, Tindall DJ. TGF-betal/Smad signaling in prostate cancer. Curr Drug Targets 2003; 4:197-207; PMID:12643470; http://dx.doi.org/10. 2174/1389450033491118.
83. Tian F, DaCosta Byfield S, Parks WT, Yoo S, Felici A, Tang B, et al. Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res 2003; 63:8284-92; PMID:14678987.
84. Kim SH, Ahn S, Park CK. Smad3 and its phosphoisoforms are prognostic predictors of hepatocellular carcinoma after curative hepatectomy. Hepatobiliary Pancreat Dis Int 2012; 11:51-9; PMID:22251470; http://dx.doi.org/10.1016/S1499- 3872(11)60125-2.
85. Pennison M, Pasche B. Targeting transforming growth factorbeta signaling. Curr Opin Oncol 2007; 19:579-85; PMID:17906455; http://dx.doi.org/10.1097/CCO. 0b013e3282f0ad0e.
86. Mullen AC, Orlando DA, Newman JJ, Lovén J, Kumar RM, Bilodeau S, et al. Master transcription factors determine cell-type-specific responses to TGFβ signaling. Cell 2011; 147:565-76; PMID:22036565; http://dx.doi.org/10. 1016/j.cell.2011.08.050.