An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer

Breast Cancer Research

Volumn 16, Issue 3, 2014, Pages

  Sato, Misako ^a,b   Kadota, Mitsutaka ^a,c   Tang, Binwu ^a   Yang, Howard H ^a   Yang, Yu an ^a   Shan, Mengge ^a   Weng, Jia ^a   Welsh, Michael A ^a   Flanders, Kathleen C ^a   Nagano, Yoshiko ^a,d   Michalowski, Aleksandra M ^a   Clifford, Robert J ^a,e   Lee, Maxwell P ^a   Wakefield, Lalage M ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

^b OSAKA CITY UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^c RIKEN Center for Biosystems Dynamics Research   (Japan)

^d TOKYO MEDICAL AND DENTAL UNIVERSITY   (Japan)

^e WALTER REED ARMY INSTITUTE OF RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EPHRIN A1; SMAD3 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; EPHRIN; EPHRIN RECEPTOR A2; SMAD2 PROTEIN; SMAD2 PROTEIN, HUMAN; SMAD3 PROTEIN, HUMAN; SMALL INTERFERING RNA; TUMOR SUPPRESSOR PROTEIN;

ARTICLE; BREAST CANCER CELL LINE; CANCER GRADING; CANCER GROWTH; CANCER INHIBITION; CANCER STAGING; CANCER SURGERY; CANCER SURVIVAL; CELL DIFFERENTIATION; CELL PROLIFERATION; CHROMATIN IMMUNOPRECIPITATION; CONTROLLED STUDY; DISTANT METASTASIS FREE SURVIVAL; DNA METHYLATION; ESTROGEN RECEPTOR POSITIVE BREAST CANCER; FEMALE; GENE CONTROL; GENE EXPRESSION; GENE IDENTIFICATION; GENE SILENCING; GENE TARGETING; GENOMICS; HUMAN; HUMAN TISSUE; IN VITRO STUDY; IN VIVO STUDY; OVERALL SURVIVAL; PROMOTER REGION; SIGNAL TRANSDUCTION; TRANSCRIPTOMICS; TUMOR SUPPRESSOR GENE; TUMOR XENOGRAFT; UPREGULATION; WESTERN BLOTTING; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; BINDING AFFINITY; BREAST CANCER; CANCER GENETICS; COHORT ANALYSIS; GENE OVEREXPRESSION; GENETIC TRANSCRIPTION; HUMAN CELL; MAJOR CLINICAL STUDY; MOLECULAR MECHANICS; MOUSE; NONHUMAN; PROTEIN FUNCTION; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; BREAST TUMOR; GENETICS; METABOLISM; PATHOLOGY; RNA INTERFERENCE; TUMOR CELL LINE;

BREAST NEOPLASMS; CELL DIFFERENTIATION; CELL LINE, TUMOR; CELL PROLIFERATION; EPHRINS; FEMALE; HUMANS; PROMOTER REGIONS, GENETIC; RECEPTOR, EPHA2; RNA INTERFERENCE; RNA, SMALL INTERFERING; SMAD2 PROTEIN; SMAD3 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; TUMOR SUPPRESSOR PROTEINS;

EID: 84903898814     PISSN: 14655411     EISSN: 1465542X     Source Type: Journal    
DOI: 10.1186/bcr3668     Document Type: Article

References (92)

1. Reis-Filho JS, Weigelt B, Fumagalli D, Sotiriou C. Molecular profiling: moving away from tumor philately. Sci Transl Med 2010, 2:ps43.
2. Gatza ML, Lucas JE, Barry WT, Kim JW, Wang Q, Crawford MD, Datto MB, Kelley M, Mathey-Prevot B, Potti A, Nevins JR. A pathway-based classification of human breast cancer. Proc Natl Acad Sci U S A 2010, 107:6994-6999.
3. Massague J. TGFβ in cancer. Cell 2008, 134:215-230.
4. Ikushima H, Miyazono K. TGFβ signalling: a complex web in cancer progression. Nat Rev Cancer 2010, 10:415-424.
5. Pardali K, Moustakas A. Actions of TGF-β as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 2007, 1775:21-62.
6. Akhurst RJ, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov 2012, 11:790-811.
7. Glick AB, Weinberg WC, Wu IH, Quan W, Yuspa SH. Transforming growth factor β1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. Cancer Res 1996, 56:3645-3650.
8. Tremain R, Marko M, Kinnimulki V, Ueno H, Bottinger E, Glick A. Defects in TGF-β signaling overcome senescence of mouse keratinocytes expressing v-Ha-ras. Oncogene 2000, 19:1698-1709.
9. Guasch G, Schober M, Pasolli HA, Conn EB, Polak L, Fuchs E. Loss of TGFβ signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia. Cancer Cell 2007, 12:313-327.
10. Kiyono K, Suzuki HI, Matsuyama H, Morishita Y, Komuro A, Kano MR, Sugimoto K, Miyazono K. Autophagy is activated by TGF-β and potentiates TGF-β-mediated growth inhibition in human hepatocellular carcinoma cells. Cancer Res 2009, 69:8844-8852.
11. Bierie B, Chung CH, Parker JS, Stover DG, Cheng N, Chytil A, Aakre M, Shyr Y, Moses HL. Abrogation of TGF-β signaling enhances chemokine production and correlates with prognosis in human breast cancer. J Clin Invest 2009, 119:1571-1582.
12. Novitskiy SV, Pickup MW, Gorska AE, Owens P, Chytil A, Aakre M, Wu H, Shyr Y, Moses HL. TGF-β receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms. Cancer Discov 2011, 1:430-441.
13. Cheng N, Bhowmick NA, Chytil A, Gorksa AE, Brown KA, Muraoka R, Arteaga CL, Neilson EG, Hayward SW, Moses HL. Loss of TGF-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene 2005, 24:5053-5068.
14. Lehmann K, Janda E, Pierreux CE, Rytomaa M, Schulze A, McMahon M, Hill CS, Beug H, Downward J. Raf induces TGFβ production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev 2000, 14:2610-2622.
15. Oft M, Peli J, Rudaz C, Schwarz H, Beug H, Reichmann E. TGF-β1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes Dev 1996, 10:2462-2477.
16. Seton-Rogers SE, Lu Y, Hines LM, Koundinya M, LaBaer J, Muthuswamy SK, Brugge JS. Cooperation of the ErbB2 receptor and transforming growth factor β in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci U S A 2004, 101:1257-1262.
17. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, Bell G, Guo W, Rubin J, Richardson AL, Weinberg RA. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 2011, 145:926-940.
18. Bruna A, Greenwood W, Le QJ, Teschendorff A, Miranda-Saavedra D, Rueda OM, Sandoval JL, Vidakovic AT, Saadi A, Pharoah P, Singl J, Caldas C. TGFβ induces the formation of tumour-initiating cells in claudin-low breast cancer. Nat Commun 2012, 3:1055.
19. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-β signaling in T cells. Nat Med 2001, 7:1118-1122.
20. Pardali E, ten Dijke P. Transforming growth factor-β signaling and tumor angiogenesis. Front Biosci 2009, 14:4848-4861.
21. Lewis MP, Lygoe KA, Nystrom ML, Anderson WP, Speight PM, Marshall JF, Thomas GJ. Tumour-derived TGF-β1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br J Cancer 2004, 90:822-832.
22. Moses H, Barcellos-Hoff MH. TGF-β biology in mammary development and breast cancer. Cold Spring Harb Perspect Biol 2011, 3:a003277.
23. Bierie B, Moses HL. Gain or loss of TGFβ signaling in mammary carcinoma cells can promote metastasis. Cell Cycle 2009, 8:3319-3327.
24. Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J. Transforming growth factor β signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A 2003, 100:8430-8435.
25. Tang B, Vu M, Booker T, Santner SJ, Miller FR, Anver MR, Wakefield LM. TGF-β switches from tumor suppressor to prometastatic factor in a model of breast cancer progression. J Clin Invest 2003, 112:1116-1124.
26. Bierie B, Stover DG, Abel TW, Chytil A, Gorska AE, Aakre M, Forrester E, Yang L, Wagner KU, Moses HL. Transforming growth factor-β regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. Cancer Res 2008, 68:1809-1819.
27. Forrester E, Chytil A, Bierie B, Aakre M, Gorska AE, Sharif-Afshar AR, Muller WJ, Moses HL. Effect of conditional knockout of the type II TGF-β receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res 2005, 65:2296-2302.
28. Kohn EA, Yang YA, Du Z, Nagano Y, Van Schyndle CM, Herrmann MA, Heldman M, Chen JQ, Stuelten CH, Flanders KC, Wakefield LM. Biological responses to TGF-β in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression. Mol Cancer Res 2012, 10:1389-1399.
29. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikoskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, et al. The genomic landscapes of human breast and colorectal cancers. Science 2007, 318:1108-1113.
30. Brown KA, Aakre ME, Gorska AE, Price JO, Eltom SE, Pietenpol JA, Moses HL. Induction by transforming growth factor-β1 of epithelial to mesenchymal transition is a rare event in vitro. Breast Cancer Res 2004, 6:R215-R231.
31. Gobbi H, Dupont WD, Simpson JF, Plummer WD, Schuyler PA, Olson SJ, Arteaga CL, Page DL. Transforming growth factor-β and breast cancer risk in women with mammary epithelial hyperplasia. J Natl Cancer Inst 1999, 91:2096-2101.
32. Wang SE, Xiang B, Guix M, Olivares MG, Parker J, Chung CH, Pandiella A, Arteaga CL. Transforming growth factor β engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab. Mol Cell Biol 2008, 28:5605-5620.
33. Coulouarn C, Factor VM, Thorgeirsson SS. Transforming growth factor-β gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 2008, 47:2059-2067.
34. Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massague J. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008, 133:66-77.
35. Xu XL, Kapoun AM. Heterogeneous activation of the TGFβ pathway in glioblastomas identified by gene expression-based classification using TGFβ-responsive genes. J Transl Med 2009, 7:12.
36. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K. Molecular definition of breast tumor heterogeneity. Cancer Cell 2007, 11:259-273.
37. Santner SJ, Dawson PJ, Tait L, Soule HD, Eliason J, Mohamed AN, Wolman SR, Heppner GH, Miller FR. Malignant MCF10CA1 cell lines derived from premalignant human breast epithelial MCF10AT cells. Breast Cancer Res Treat 2001, 65:101-110.
38. Strickland LB, Dawson PJ, Santner SJ, Miller FR. Progression of premalignant MCF10AT generates heterogeneous malignant variants with characteristic histologic types and immunohistochemical markers. Breast Cancer Res Treat 2000, 64:235-240.
39. Soule HD, Maloney TM, Wolman SR, Peterson WD, Brenz R, McGrath CM, Russo J, Pauley RJ, Jones RF, Brooks SC. Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res 1990, 50:6075-6086.
40. Visscher DW, Nanjia-Makker P, Heppner G, Shekhar PV. Tamoxifen suppresses histologic progression to atypia and DCIS in MCFIOAT xenografts, a model of early human breast cancer. Breast Cancer Res Treat 2001, 65:41-47.
41. Shekhar PV, Chen ML, Werdell J, Heppner GH, Miller FR, Christman JK. Transcriptional activation of functional endogenous estrogen receptor gene expression in MCF10AT cells: a model for early breast cancer. Int J Oncol 1998, 13:907-915.
42. Shekhar MP, Werdell J, Santner SJ, Pauley RJ, Tait L. Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression. Cancer Res 2001, 61:1320-1326.
43. Shekhar MP, Nangia-Makker P, Wolman SR, Tait L, Heppner GH, Visscher DW. Direct action of estrogen on sequence of progression of human preneoplastic breast disease. Am J Pathol 1998, 152:1129-1132.
44. Kadota M, Yang HH, Gomez B, Sato M, Clifford RJ, Meerzaman D, Dunn BK, Wakefield LM, Lee MP. Delineating genetic alterations for tumor progression in the MCF10A series of breast cancer cell lines. PLoS One 2010, 5:e9201.
45. Michelucci A, Di CC, Lami A, Collecchi P, Caligo A, Decarli N, Leopizzi M, Aretini P, Bertacca G, Porta RP, Ricci S, Della Rocca C, Stanta G, Bevilacqua G, Cazzana A. PIK3CA in breast carcinoma: a mutational analysis of sporadic and hereditary cases. Diagn Mol Pathol 2009, 18:200-205.
46. Bild AH, Parker JS, Gustafson AM, Acharya CR, Hoadley KA, Anders C, Marcom PK, Carey LA, Potti A, Nevins JR, Perou CM. An integration of complementary strategies for gene-expression analysis to reveal novel therapeutic opportunities for breast cancer. Breast Cancer Res 2009, 11:R55.
47. Kohn EA, Du Z, Sato M, Van Schyndle CM, Welsh MA, Yang YA, Stuelten CH, Tang B, Ju W, Bottinger EP, Wakefield LM. 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:R83.
48. Liang G, Lin JC, Wei V, Yoo C, Cheng JC, Nguyen CT, Weisenberger DJ, Egger G, Takai D, Gonzales FA, Jones PA. Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. Proc Natl Acad Sci U S A 2004, 101:7357-7362.
49. Karmodiya K, Krebs AR, Oulad-Abdelghani M, Kimura H, Tora L. H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells. BMC Genomics 2012, 13:424.
50. Kadota M, Yang HH, Hu N, Wang C, Hu Y, Taylor PR, Buetow KH, Lee MP. Allele-specific chromatin immunoprecipitation studies show genetic influence on chromatin state in human genome. PLoS Genet 2007, 3:e81.
51. Nicol JW, Helt GA, Blanchard SG, Raja A, Loraine AE. The Integrated Genome Browser: free software for distribution and exploration of genome-scale datasets. Bioinformatics 2009, 25:2730-2731.
52. The Galaxy Project. [https://usegalaxy.org].
53. Silverman BW. Density Estimation 1986, London, UK: Chapman and Hall.
54. The R Project for Statistical Computing. [http://www.R-project.org].
55. Genomatix Software Tools. [https://www.genomatix.de].
56. Ringner M, Fredlund E, Hakkinen J, Borg A, Staaf J. GOBO: gene expression-based outcome for breast cancer online. PLoS One 2011, 6:e17911.
57. GOBO: gene expression-based outcome for breast cancer online. [http://co.bmc.lu.se/gobo/].
58. van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsam D, Witteveen A, Glas A, Delahaye L, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002, 347:1999-2009.
59. Broad Institute Genome Data Analysis Center. [http://gdac.broadinstitute.org/].
60. Venet D, Dumont JE, Detours V. Most random gene expression signatures are significantly associated with breast cancer outcome. PLoS Comput Biol 2011, 7:e1002240.
61. Ge X, Yamamoto S, Tsutsumi S, Midorikawa Y, Ihara S, Wang SM, Aburatani H. Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005, 86:127-141.
62. Lim E, Wu D, Pa B, Bouras T, Asselin-Labat ML, Vaillant F, Yagita H, Lindeman GJ, Smyth GK, Visvader JE. Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways. Breast Cancer Res 2010, 12:R21.
63. Kim J, Villadsen R, Sorlie T, Fogh L, Gronlund SZ, Fridriksdottir AJ, Kuhn I, Rank F, Wielenga VT, Solvang H, Edwards PA, Borresen-Dale AL, Ronnov-Jessen L, Bissell MJ, Petersen OW. Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity. Proc Natl Acad Sci U S A 2012, 109:6124-6129.
64. Gao H, Chakraborty G, Lee-Lim AP, Mo Q, Decker M, Vonica A, Shen R, Brogi E, Brivanlou AH, Giancotti FG. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 2012, 150:764-779.
65. Tang B, Yoo N, Vu M, Mamura M, Nam JS, Ooshima A, Du Z, Desprez PY, Anver MR, Michalowska AM, Shih J, Parks WT, Wakefield LM. Transforming growth factor-β can suppress tumorigenesis through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model. Cancer Res 2007, 67:8643-8652.
66. Schmierer B, Hill CS. TGFβ-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 2007, 8:970-982.
67. Brown KA, Pietenpol JA, Moses HL. A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-β signaling. J Cell Biochem 2007, 101:9-33.
68. Matsuzaki K, Okazaki K. Transforming growth factor-β during carcinogenesis: the shift from epithelial to mesenchymal signaling. J Gastroenterol 2006, 41:295-303.
69. Zhu S, Wang W, Clarke DC, Liu X. Activation of Mps1 promotes transforming growth factor-β-independent Smad signaling. J Biol Chem 2007, 282:18327-18338.
70. Lee BH, Chen W, Stippec S, Cobb MH. Biological cross-talk between WNK1 and the transforming growth factor β-Smad signaling pathway. J Biol Chem 2007, 282:17985-17996.
71. Seong HA, Jung H, Ha H. Murine protein serine/threonine kinase 38 stimulates TGF-β signaling in a kinase-dependent manner via direct phosphorylation of Smad proteins. J Biol Chem 2010, 285:30959-30970.
72. Chung AC, Zhang H, Kong YZ, Tan JJ, Huang XR, Kopp JB, Lan HY. Advanced glycation end-products induce tubular CTGF via TGF-β-independent Smad3 signaling. J Am Soc Nephrol 2010, 21:249-260.
73. Koinuma D, Tsutsumi S, Kamimura N, Taniguchi H, Miyazawa K, Sunamura M, Imamura T, Miyazono K, Aburatani H. Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor β signaling. Mol Cell Biol 2009, 29:172-186.
74. Mizutani A, Koinuma D, Tsutsumi S, Kamimura N, Morikawa M, Suzuki HI, Imamura T, Miyazono K, Aburatani H. Cell-type specific target selection by combinatorial binding of Smad2/3 and hepatocyte nuclear factor 4{alpha} in HepG2 cells. J Biol Chem 2011, 286:29848-29860.
75. Zhang Y, Handley D, Kaplan T, Yu H, Bais AS, Richards T, Pandit KV, Zeng Q, Benos PV, Friedman N, Eickelberg O, Kaminski N. High throughput determination of TGFβ1/SMAD3 targets in A549 lung epithelial cells. PLoS One 2011, 6:e20319.
76. Zhang Y, Feng XH, Derynck R. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-β-induced transcription. Nature 1998, 394:909-913.
77. Sundqvist A, Zieba A, Vasilaki E, Herrera HC, Soderberg O, Koinuma D, Miyazono K, Heldin CH, Landegren U, ten Dijke P, van Dam H. Specific interactions between Smad proteins and AP-1 components determine TGFβ-induced breast cancer cell invasion. Oncogene 2013, 32:3606-3615.
78. The Cancer Genome Atlas. [http://cancergenome.nih.gov/].
79. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 2012, 486:346-352.
80. Mosley JD, Keri RA. Cell cycle correlated genes dictate the prognostic power of breast cancer gene lists. BMC Med Genomics 2008, 1:11.
81. Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR, Palacios J, Richardson AL, Schnitt SJ, Schmitt FC, Tan PH, Tse GM, Badve S, Ellis IO. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res 2010, 12:207.
82. Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 2010, 10:165-180.
83. Vaught D, Brantley-Sieders DM, Chen J. Eph receptors in breast cancer: roles in tumor promotion and tumor suppression. Breast Cancer Res 2008, 10:217.
84. Miao H, Wang B. EphA receptor signaling-complexity and emerging themes. Semin Cell Dev Biol 2012, 23:16-25.
85. Kennedy BA, Deatherage DE, Gu F, Tang B, Chan MW, Nephew KP, Huang TH, Jin VX. ChIP-seq defined genome-wide map of TGFβ/SMAD4 targets: implications with clinical outcome of ovarian cancer. PLoS One 2011, 6:e22606.
86. Mullen AC, Orlando DA, Newman JJ, Loven J, Kumar RM, Bilodeau S, Reddy J, Guenther MG, Dekoter RP, Young RA. Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell 2011, 147:565-576.
87. Kendrick H, Regan JL, Magnay FA, Grigoriadis A, Mitsopoulos C, Zvelebil M, Smalley MJ. Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate. BMC Genomics 2008, 9:591.
88. Ewan KB, Oketch-Rabah HA, Ravani SA, Shyamala G, Moses HL, Barcellos-Hoff MH. Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-β1 in adult mice. Am J Pathol 2005, 167:409-417.
89. Noblitt LW, Bangari DS, Shukla S, Knapp DW, Mohammed S, Kinch MS, Mittal SK. Decreased tumorigenic potential of EphA2-overexpressing breast cancer cells following treatment with adenoviral vectors that express EphrinA1. Cancer Gene Ther 2004, 11:757-766.
90. Brantley-Sieders DM, Zhuang G, Hicks D, Fang WB, Hwang Y, Cates JM, Coffman K, Jackson D, Bruckheimer E, Muraoka-Cook RS, Chen J. The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling. J Clin Invest 2008, 118:64-78.
91. Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res 2001, 61:2301-2306.
92. Brantley-Sieders DM, Fang WB, Hwang Y, Hicks D, Chen J. Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice. Cancer Res 2006, 66:10315-10324.