Tumor microenvironment and breast cancer progression: A complex scenario

Cancer Biology and Therapy

Volumn 13, Issue 1, 2012, Pages 14-24

  Artacho Cordón, Antonia ^a   Artacho Cordón, Francisco ^a   Ríos Arrabal, Sandra ^a   Calvente, Irene ^a   Núñez, María Isabel ^a  

^a HOSPITAL UNIVERSITARIO SAN CECILIO   (Spain)

Author keywords

Angiogenesis; Breast cancer; Epigenetic; Inflammation; Matrix metalloproteinases; Tumor microenvironment; Tumor progression

Indexed keywords

ANGIOPOIETIN 1; ANGIOPOIETIN 2; ANGIOPOIETIN RECEPTOR; BRCA1 PROTEIN; BRCA2 PROTEIN; CAVEOLIN 1; EPIDERMAL GROWTH FACTOR RECEPTOR 2; FIBROBLAST GROWTH FACTOR RECEPTOR 1; GELATINASE A; GELATINASE B; MICRORNA; RNA; SMAD3 PROTEIN; STROMAL CELL DERIVED FACTOR 1ALPHA; STROMELYSIN 3; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; VASCULOTROPIN RECEPTOR 1; VASCULOTROPIN RECEPTOR 3;

ANGIOGENESIS; APOPTOSIS; BREAST CANCER; CANCER GROWTH; CANCER INVASION; CANCER MORTALITY; CANCER SURVIVAL; CARCINOGENESIS; COPY NUMBER VARIATION; DNA METHYLATION; DNA REPAIR; ENZYME ACTIVITY; EPIGENETICS; GENE EXPRESSION; GENE MUTATION; GENOMIC INSTABILITY; HISTONE MODIFICATION; HUMAN; LYMPHOCYTIC INFILTRATION; METASTASIS; NEUTROPHIL CHEMOTAXIS; NONHUMAN; OVERALL SURVIVAL; OXIDATIVE STRESS; PHENOTYPE; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; TUMOR CELL; TUMOR MICROENVIRONMENT; BREAST TUMOR; DISEASE COURSE; FEMALE; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; PATHOLOGY;

BREAST NEOPLASMS; DISEASE PROGRESSION; EPIGENOMICS; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; TUMOR MICROENVIRONMENT;

EID: 84856407789     PISSN: 15384047     EISSN: 15558576     Source Type: Journal    
DOI: 10.4161/cbt.13.1.18869     Document Type: Review

References (136)

1. Patocs A, Zhang L, Xu Y, Weber F, Caldes T, Mutter GL, et al. Breast-cancer stromal cells with TP53 mutations and nodal metastases. N Engl J Med 2007; 357:2543-51; PMID:18094375; http://dx.doi.org/10. 1056/NEJMoa071825
2. Hu M, Yao J, Cai L, Bachman KE, van den BrÛle F, Velculescu V, et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 2005; 37: 899-905; PMID:16007089; http://dx.doi.org/10. 1038/ng1596
3. Fiegl H, Millinger S, Goebel G, Müller-Holzner E, Marth C, Laird PW, et al. Breast cancer DNA methylation profiles in cancer cells and tumor stroma: association with HER-2/neu status in primary breast cancer. Cancer Res 2006; 66:29-33; PMID:16397211; http://dx.doi.org/10.1158/0008-5472.CAN-05-2508
4. Shekhar MP, Pauley R, Heppner G. Host microenvironment in breast cancer development: Extracellular matrix-stromal cell contribution to neoplastic phenotype of epithelial cells in the breast. Breast Cancer Res 2003; 5:130-5; PMID:12793893; http:// dx.doi.org/10.1186/bcr580
5. Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression? J Theor Biol 1982; 99:31-68; PMID:6892044; http://dx.doi. org/10.1016/0022-5193(82)90388-5
6. Bissell MJ, Ram TG. Regulation of functional cytodifferentiation and histogenesis in mammary epithelial cells: role of the extracellular matrix. Environ Health Perspect 1989; 80:61-70; PMID:2647485; http://dx. doi.org/10.1289/ehp.898061
7. Bissell MJ, Barcellos-Hoff MH. The influence of extracellularmatrix on gene expression: is structure the message? J Cell Sci Suppl 1987; 8:327-43; PMID: 3332665
8. Gehler S, Baldassarre M, Lad Y, Leight JL, Wozniak MA, Riching KM, et al. Filamin A-b1 integrin complex tunes epithelial cell response to matrix tension. Mol Biol Cell 2009; 20:3224-38; PMID:19458194; http://dx. doi.org/10.1091/mbc. E08-12-1186
9. Dvorak HF, Weaver VM, Tlsty T, Bergers G. Tumor microenvironment and progression. J Surg Oncol 2011; 103:468-74; PMID:21480238; http://dx.doi.org/10. 1002/jso.21709
10. Maffini MV, Calabro JM, Soto AM, Sonnenschein C. Stromal regulation of neoplastic development: age-dependent normalization of neoplastic mammary cells by mammary stroma. Am J Pathol 2005; 167:1405-10; PMID:16251424; http://dx.doi.org/10.1016/ S0002-9440(10)61227-8
11. Bussard KM, Boulanger CA, Booth BW, Bruno RD, Smith GH. Reprogramminghuman cancer cells in the mouse mammary gland. Cancer Res 2010; 70:6336-43; PMID:20647316; http://dx.doi.org/10.1158/0008-5472.CAN-10-0591
12. Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C. The stroma as a crucial target in ratmammary gland carcinogenesis. J Cell Sci 2004; 117:1495-502; PMID:14996910; http://dx.doi.org/10.1242/jcs.01000
13. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57-70; PMID:10647931; http://dx.doi.org/10.1016/S0092-8674(00)81683-9
14. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009; 30:1073-81; PMID:19468060; http://dx.doi.org/10.1093/ carcin/bgp127
15. Polyak K. Breast cancer: origins and evolution. J Clin Invest 2007; 117:3155-63; PMID:17975657; http:// dx.doi.org/10.1172/JCI33295
16. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea-a paradigm shift. Cancer Res 2006; 66:1883-90; PMID:16488983; http://dx.doi.org/10.1158/ 0008-5472.CAN-05-3153
17. Sgroi DC. Preinvasive breast cancer. Annu Rev Pathol 2010; 5:193-221; PMID:19824828; http://dx.doi.org/10.1146/annurev.pathol.4.110807.092306
18. Hunter KW. Host genetics and tumour metastasis. Br J Cancer 2004; 90:752-5; PMID:14970848; http://dx.doi.org/10.1038/sj.bjc.6601590
19. Weber F, Shen L, Fukino K, Patocs A, Mutter G, Caldés T, et al. Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am J Hum Genet 2006; 78:961-72; PMID:16685647; http://dx.doi.org/10.1086/504090
20. Allred DC, Mohsin SK, Fuqua SA. Histological and biological evolution of human premalignant breast disease. Endocr Relat Cancer 2001; 8:47-61; PMID: 11350726; http://dx.doi.org/10.1677/erc.0.0080047
21. Orimo A, Weinberg RA. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 2006; 5:1597-601; PMID:16880743; http://dx.doi.org/10.4161/cc.5.15.3112
22. Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends Genet 2009; 25:30-8; PMID:19054589; http://dx.doi.org/10.1016/j.tig.2008.10.012
23. Hu M, Polyak K. Microenvironmental regulation of cancer development. Curr Opin Genet Dev 2008; 18: 27-34; PMID:18282701; http://dx.doi.org/10.1016/j.gde. 2007.12.006
24. Nelson CM, Bissell MJ. Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2006; 22:287-309; PMID:16824016; http:// dx.doi.org/10.1146/ annurev.cellbio.22.010305.104315
25. Chin K, de Solorzano CO, Knowles D, Jones A, Chou W, Rodriguez EG, et al. In situ analyses of genome instability in breast cancer. Nat Genet 2004; 36:984-8; PMID:15300252; http://dx.doi.org/10.1038/ng1409
26. Maruyama R, Choudhury S, Kowalczyk A, Bessarabova M, Beresford-Smith B, Conway T, et al. Epigenetic regulation of cell type-specific expression patterns in the human mammary epithelium. PLoS Genet 2011; 7:e1001369; PMID:21533021; http:// dx.doi.org/10.1371/journal.pgen.1001369
27. Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 2002; 32:355-7; PMID: 12379854; http://dx.doi.org/10.1038/ng1013
28. Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH. Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum Mol Genet 2001; 10:1907-13; PMID:11555627; http://dx.doi.org/10.1093/hmg/10.18.1907
29. Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, Tavassoli FA. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res 2000; 60:2562-6; PMID:10811140
30. Qiu W, Hu M, Sridhar A, Opeskin K, Fox S, Shipitsin M, et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat Genet 2008; 40:650-5; PMID:18408720; http://dx.doi.org/10. 1038/ng.117
31. Fukino K, Shen L, Matsumoto S, Morrison CD, Mutter GL, Eng C. Combined Total Genome Loss of Heterozygosity Scan of Breast Cancer Stroma and Epithelium Reveals Multiplicity of Stromal Targets. Cancer Res 2004; 64:7231-6; PMID:15492239; http://dx.doi.org/10.1158/0008-5472.CAN-04-2866
32. Fukino K, Shen L, Patocs A, Mutter GL, Eng C. Genomic instability within tumor stroma and clinico-pathological characteristics of sporadic primary invasive breast carcinoma. JAMA 2007; 297:2103-11; PMID: 17507346; http://dx.doi.org/10.1001/jama.297.19.2103
33. Weber F, Fukino K, Sawada T, Williams N, Sweet K, Brena RM, et al. Variability in organ-specific EGFR mutational spectra in tumour epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors. Br J Cancer 2005; 92: 1922-6; PMID:15841079; http://dx.doi.org/10. 1038/sj.bjc.6602557
34. Weber F, Shen L, Fukino K, Patocs A, Mutter GL, Caldes T, et al. Total-genome analysis of BRCA1/2- related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am J Hum Genet 2006; 78:961-72; PMID: 16685647; http://dx.doi.org/10.1086/504090
35. Hu M, Yao J, Carroll DK, Weremowicz S, Chen H, Carrasco D, et al. Regulation of in situ to invasive breast carcinoma transition. Cancer Cell 2008; 13: 394-406; PMID:18455123; http://dx.doi.org/10.1016/j.ccr.2008.03.007
36. Cunha GR, Hayward SW, Wang YZ. Role of stroma in carcinogenesis of the prostate. Differentiation 2002; 70:473-85; PMID:12492490; http://dx.doi.org/10. 1046/j.1432-0436.2002.700902.x
37. Barcellos-Hoff MH. The potential influence of radiation-induced microenvironments in neoplastic progression. J Mammary Gland Biol Neoplasia 1998; 3:165-75; PMID:10819525; http://dx.doi.org/10.1023/A:1018794806635
38. Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao JH, et al. Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell 2011; 19:640-51; PMID:21575864; http://dx.doi.org/10. 1016/j.ccr.2011.03.011
39. Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 2004; 6:17-32; PMID:15261139; http:// dx.doi.org/10.1016/j.ccr.2004. 06.010
40. Ma XJ, Dahiya S, Richardson E, Erlander M, Sgroi D. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res 2009; 11:R7; PMID:19187537; http://dx.doi.org/10.1186/bcr2222
41. Ma XJ, Salunga R, Tuggle JT, Gaudet J, Enright EE, McQuary P, et al. Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci USA 2003; 100:5974-9; PMID:12714683; http://dx.doi.org/10.1073/pnas.0931261100
42. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 2008; 14:518-27; PMID:18438415; http:// dx.doi.org/10.1038/nm1764
43. Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 2009; 15:68-74; PMID:19122658; http://dx.doi.org/10. 1038/nm.1908
44. Lerwill MF. Current practical applications of diagnostic immunohistochemistry in breast pathology. Am J Surg Pathol 2004; 28:1076-91; PMID:15252316; http://dx.doi.org/10.1097/01.pas.0000126780.10029.f0
45. Schäfer M, Werner S. Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol 2008; 9:628-38; PMID:18628784; http:// dx.doi.org/10.1038/nrm2455
46. Hunter KW, Crawford N, Alsarraj J. Mechanisms of metastasis. Breast Cancer Res 2008; 10:S2; PMID: 19091006; http://dx.doi.org/10.1186/bcr1988
47. Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med 2000; 6:100-2; PMID:10613833; http://dx.doi.org/10.1038/71429
48. Hoda SA, Hoda RS, Merlin S, Shamonki J, Rivera M. Issues relating to lymphovascular invasion in breast carcinoma. Adv Anat Pathol 2006; 13:308-15; PMID:17075296; http://dx.doi.org/10.1097/01.pap.0000213048.69564.26
49. Gajdos C, Tartter PI, Bleiweiss IJ. Lymphatic invasion, tumor size, and age are independent predictors of axillary lymph node metastases in women with T1 breast cancers. Ann Surg 1999; 230:692-6; PMID:10561094; http://dx. doi.org/10.1097/00000658-199911000-00012
50. Weiser MR, Montgomery LL, Tan LK, Susnik B, Leung DY, Borgen PI, et al. Lymphovascular invasion enhances the prediction of non-sentinel node metastases in breast cancer patients with positive sentinel nodes. Ann Surg Oncol 2001; 8:145-9; PMID:11258779; http://dx.doi. org/10.1007/s10434-001-0145-y
51. Schoppmann SF, Bayer G, Aumayr K, Taucher S, Geleff S, Rudas M, et al. Prognostic value of lymphangiogenesis and lymphovascular invasion in invasive breast cancer. Ann Surg 2004; 240:306-12; PMID:15273556; http://dx.doi.org/10. 1097/01.sla.0000133355.48672.22
52. Woo CS, Silberman H, Nakamura SK, Ye W, Sposto R, Colburn W, et al. Lymph node status combined with lymphovascular invasion creates a more powerful tool for predicting outcome in patients with invasive breast cancer. Am J Surg 2002; 184:337-40; PMID:12383896; http://dx.doi.org/10.1016/S0002-9610(02)00950-9
53. Fisher ER, Anderson S, Tan-Chiu E, Fisher B, Eaton L, Wolmark N. Fifteen-year prognostic discriminants for invasive breast carcinoma: National Surgical Adjuvant Breast and Bowel Project Protocol-06. Cancer 2001; 91:1679-87; PMID:11309768; http://dx.doi.org/10.1002/1097-0142(20010415)91:8+,1679::AID- CNCR1183.3.3.CO;2-#
54. El-Gohary YM, Metwally G, Saad RS, Robinson MJ, Mesko T, Poppiti RJ. Prognostic significance of intratumoral and peritumoral lymphatic density and blood vessel density in invasive breast carcinomas. Am J Clin Pathol 2008; 129:578-86; PMID:18343785; http://dx.doi.org/10.1309/2HGNJ1GU57JMBJAQ
55. Ejlertsen B, Jensen MB, Rank F, Rasmussen BB, Christiansen P, Kroman N, et al. Population-based study of peritumoral lymphovascular invasion and outcome among patients with operable breast cancer. J Natl Cancer Inst 2009; 101:729-35; PMID:19436035; http://dx.doi.org/10.1093/jnci/djp090
56. Goetz JG, Minguet S, Navarro-Lérida I, Lazcano JJ, Samaniego R, Calvo E, et al. Biomechanical Remodeling of the Microenvironment by Stromal Caveolin-1Favors Tumor Invasion and metastasis. Cell 2011; 146:148-63; PMID:21729786; http://dx.doi. org/10.1016/j.cell.2011.05.040
57. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the premetastatic niche. Nature 2005; 438:820-7; PMID: 16341007; http://dx.doi.org/10.1038/nature04186
58. Schedin P, Elias A. Multistep tumorigenesis and the microenvironment. Breast Cancer Res 2004; 6:93-101; PMID:14979914; http://dx.doi.org/10.1186/ bcr772
59. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003; 33(Suppl):245-54; PMID:12610534; http://dx.doi.org/10.1038/ng1089
60. Lin HJL, Zuo T, Lin CH, Kuo CT, Liyanarachchi S, Sun S, et al. Breast cancer-associated fibroblasts confer AKT1-mediated epigenetic silencing of Cystatin M in epithelial cells. Cancer Res 2008; 68:10257-66; PMID:19074894; http://dx.doi.org/10.1158/0008-5472.CAN-08-0288
61. Soares J, Pinto AE, Cunha CV, André S, Barão I, Sousa JM, et al. Global DNA hypomethylation in breast carcinoma: correlation with prognostic factors and tumor progression. Cancer 1999; 85:112-8; PMID:9921982; http://dx.doi.org/10.1002/(SICI)1097-0142(19990101)85:1〈112:: AID-CNCR16〉3.3.CO;2-K
62. Giacinti L, Claudio PP, Lopez M, Giordano A. Epigenetic information and estrogen receptor alpha expression in breast cancer. Oncologist 2006; 11: 1-8; PMID:16401708; http://dx.doi.org/10.1634/ theoncologist.11-1-1
63. Baylin SB. DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2005; 2(Suppl 1): S4-11; PMID:16341240; http://dx.doi.org/10.1038/ ncponc0354
64. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3:415-28; PMID:12042769
65. Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 2000; 92:564-9; PMID: 10749912; http://dx.doi.org/10.1093/jnci/92.7.564
66. Plachot C, Lelièvre SA. DNA methylation control of tissue polarity and cellular differentiation in the mammary epithelium. Exp Cell Res 2004; 298: 122-32; PMID:15242767; http://dx.doi.org/10.1016/j.yexcr.2004.04.024
67. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer 2001; 1:46-54; PMID:11900251; http://dx.doi.org/10.1038/35094059
68. Dumont N, Wilson MB, Crawford YG, Reynolds PA, Sigaroudinia M, Tlsty TD. Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc Natl Acad Sci USA 2008; 105:14867-72; PMID: 18806226; http://dx.doi.org/10.1073/pnas. 0807146105
69. Hu M, Yao J, Cai L, Bachman KE, van den Brule F, Velculescu V, Polyak K, et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 2005; 37:899-905; PMID:16007089; http:// dx.doi.org/10.1038/ng1596
70. Fiegl H, Millinger S, Goebel G, Muller-Holzner E, Marth C, Laird PW, et al. Breast Cancer DNA Methylation Profiles in Cancer Cells and Tumor Stroma: Association with HER-2/neu Status in Primary Breast Cancer. Cancer Res 2006; 66:29-33; PMID:16397211; http://dx.doi.org/10.1158/0008-5472.CAN-05-2508
71. Ruan K, Fang X, Ouyang G. MicroRNAs: Novel regulators in the hallmarks of human cancer. Cancer Lett 2009; 285:116-26; PMID:19464788; http://dx.doi.org/ 10.1016/j.canlet.2009.04.031
72. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116:281-97; PMID: 14744438; http://dx.doi.org/10.1016/S0092-8674(04) 00045-5
73. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004; 5: 522-31; PMID:15211354; http://dx.doi.org/10. 1038/nrg1379
74. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004; 101:2999-3004; PMID:14973191; http://dx. doi.org/10.1073/pnas.0307323101
75. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res 2005; 65:7065-70; PMID:16103053; http://dx.doi.org/10.1158/0008-5472.CAN-05-1783
76. Dalmay T, Edwards DR. MicroRNAs and the hallmarks of cancer. Oncogene 2006; 25:6170-5; PMID: 17028596; http://dx.doi.org/10.1038/sj.onc.1209911
77. Lujambio A, Ropero S, Ballestar E, Fraga MF, Cerrato C, Setién F, et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res 2007; 67:1424-9; PMID:17308079; http://dx.doi.org/10.1158/ 0008-5472.CAN-06-4218
78. Lehmann U, Hasemeier B, Christgen M, Müller M, Römermann D, Länger F, et al. Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer. J Pathol 2008; 214:17-24; PMID:17948228; http://dx.doi.org/10.1002/path.2251
79. Corcoran KE, Rameshwar P. Nuclear factor-kappaB accounts for the repressor effects of high stromal cell-derived factor-1alpha levels on Tac1 expression in nontumorigenic breast cells. Mol Cancer Res 2007; 5:373-81; PMID:17409218; http://dx.doi.org/10.1158/1541-7786.MCR-06-0396
80. Patel SA, Heinrich AC, Reddy BY, Srinivas B, Heidaran N, Rameshwar P. Breast cancer biology: the multifaceted roles of mesenchymal stem cells. J Oncol 2008; 425895; PMID:19277104
81. Hitchler MJ, Oberley LW, Domann FE. Epigenetic silencing of SOD2 by histone modifications in human breast cancer cells. Free Radic Biol Med 2008; 45: 1573-80; PMID:18845242; http://dx.doi.org/10.1016/j.freeradbiomed.2008.09. 005
82. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 403:41-5; PMID: 10638745; http://dx.doi.org/10.1038/47412
83. Sandal T, Valyi-Nagy K, Spencer VA, Folberg R, Bissell MJ, Maniotis AJ. Epigenetic reversion of breast carcinoma phenotype is accompanied by changes in DNA sequestration as measured by AluI restriction enzyme. Am J Pathol 2007; 170:1739-49; PMID: 17456778; http://dx.doi.org/10.2353/ajpath.2007.060922
84. Florin L, Maas-Szabowski N, Werner S, Szabowski A, Angel P. Increased keratinocyte proliferation by JUN-dependent expression of PTN and SDF-1 in fibroblasts. J Cell Sci 2005; 118:1981-9; PMID:15840658; http://dx.doi.org/10. 1242/jcs.02303
85. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003; 83:835-70; PMID:12843410
86. Sibilia M, Kroismayr R, Lichtenberger BM, Natarajan A, Hecking M, Holcmann M. The epidermal growth factor receptor: from development to tumorigenesis. Differentiation 2007; 75:770-87; PMID:17999740; http://dx.doi.org/10.1111/j.1432-0436.2007.00238.x
87. Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 2002; 12:22-9; PMID:11790550; http://dx.doi.org/10.1016/S0959-437X(01)00259-3
88. Yu JL, Rak J. Host microenvironment in breast cancer development: Inflammatory and immune cells in tumour angiogenesis and arteriogenesis. Breast Cancer Res 2003; 5:83-8; PMID:12631386; http://dx.doi.org/ 10.1186/bcr573
89. Lin EY, Pollard JW. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res 2007; 67:5064-6; PMID:17545580; http://dx. doi.org/10.1158/0008-5472.CAN-07-0912
90. Lewis CE, Hughes R. Inflammation and breast cancer. Microenvironmental factors regulating macrophage function in breast tumours: hypoxia and angiopoietin-2. Breast Cancer Res 2007; 9:209; PMID:17601353; http://dx.doi.org/10.1186/bcr1679
91. Ben-Baruch A. Inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions. . Breast Cancer Res 2003; 5:31-36; PMID:12559043; http://dx.doi. org/10.1186/bcr554
92. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420:860-7; PMID:12490959; http://dx. doi.org/10.1038/nature01322
93. Klaunig JE, Kamendulis LM. The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 2004; 44:239-67; PMID:14744246; http://dx.doi.org/ 10.1146/annurev.pharmtox.44.101802.121851
94. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006; 160: 1-40; PMID:16430879; http://dx.doi.org/10.1016/j. cbi.2005.12.009
95. Roberts RA, Laskin DL, Smith CV, Robertson FM, Allen EMG, Doorn JA, et al. Nitrative and oxidative stress in toxicology and disease. Toxicol Sci 2009; 112: 4-16; PMID:19656995; http://dx.doi.org/10.1093/ toxsci/kfp179
96. Curtis CD, Thorngren DL, Nardulli AM. Immunohistochemical analysis of oxidative stress and DNA repair proteins in normal mammary and breast cancer tissue. BMC Cancer 2010; 10:9; PMID:20064251; http://dx.doi.org/10.1186/1471- 2407-10-9
97. Schultz-Norton JR, McDonald WH, Yates JR, Nardulli AM. Protein disulfide isomerase serves as a molecular chaperone to maintain estrogen receptor alpha structure and function. Mol Endocrinol 2006; 20:1982-95; PMID:16690750; http://dx.doi.org/10. 1210/me.2006-0006
98. Rao AK, Ziegler YS, McLeod IX, Yates JR, Nardulli AM. Effects of Cu/Zn superoxide dismutase on estrogen responsiveness and oxidative stress in human breast cancer cells. Mol Endocrinol 2008; 22:1113-24; PMID: 18258688; http://dx.doi.org/10.1210/me.2007-0381
99. Rao AK, Ziegler YS, McLeod IX, Yates JR, Nardulli AM. Thioredoxin and thioredoxin reductase influence estrogen receptor alpha-mediated gene expression in human breast cancer cells. J Mol Endocrinol 2009; 43:251-61; PMID:19620238; http://dx.doi.org/10. 1677/JME-09-0053
100. Curtis CD, Thorngren DL, Ziegler YS, Sarkeshik A, Yates JR, Nardulli AM. Apurinic/apyrimidinic endonuclease 1 alters estrogen receptor activity and estrogen-responsive gene expression. Mol Endocrinol 2009; 23:1346-59; PMID:19460860; http://dx.doi. org/10.1210/me.2009-0093
101. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86:353-64; PMID:8756718; http://dx.doi.org/10.1016/S0092-8674(00)80108-7
102. Shibuya M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol 2006; 39:469-78; PMID: 17002866; http://dx.doi.org/10.5483/BMBRep.2006. 39.5.469
103. Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 2009; 10:165-77; PMID:19234476; http:// dx.doi.org/10.1038/nrm2639
104. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 2009; 21:154-65; PMID: 19230644; http://dx.doi.org/10.1016/j.ceb.2008.12.012
105. Saharinen P, Bry M, Alitalo K. How do angiopoietins Tie in with vascular endothelial growth factors? Curr Opin Hematol 2010; 17:198-205; PMID:20375888
106. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3:401-10; PMID:12778130; http://dx.doi.org/10.1038/nrc1093
107. Acevedo VD, Ittmann M, Spencer DM. Paths of FGFR-driven tumorigenesis. Cell Cycle 2009; 8:580-8; PMID: 19182515; http://dx.doi.org/10.4161/cc.8.4.7657
108. Ciruna B, Rossant J. FGF Signaling Regulates Mesoderm Cell Fate Specification and Morphogenetic Movement at the Primitive Streak. Dev Cell 2001; 1:37-49; PMID:11703922; http://dx.doi.org/10.1016/S1534-5807(01)00017-X
109. Mezquita B, Mezquita J, Pau M, Mezquita C. A novel intracellular isoform of VEGFR-1 activates Src and promotes cell invasion in MDA-MB-231 breast cancer cells. J Cell Biochem 2010; 110:732-42; PMID: 20512933; http://dx.doi.org/10. 1002/jcb.22584
110. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008; 454:436-44; PMID: 18650914; http://dx.doi.org/10.1038/nature07205
111. Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 2007; 13:1211-8; PMID:17906636; http://dx.doi.org/10.1038/nm1649
112. Sparmann A, Bar-Sagi D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 2004; 6:447-58; PMID: 15542429; http://dx.doi.org/10.1016/j.ccr.2004.09.028
113. Vakkila J, Lotze MT. Inflammation and necrosis promote tumour growth. Nat Rev Immunol 2004; 4:641-8; PMID:15286730; http://dx.doi.org/10.1038/nri1415
114. Zong WX, Thompson CB. Necrotic death as a cell fate. Genes Dev 2006; 20:1-15; PMID:16391229; http://dx.doi.org/10.1101/gad.1376506
115. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140:883-99; PMID:20303878; http://dx.doi.org/10.1016/j.cell.2010.01. 025
116. Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 2004; 104:2224-34; PMID:15231578; http:// dx.doi.org/10.1182/blood-2004-03-1109
117. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell 2009; 16:183-94; PMID:19732719; http://dx.doi.org/10.1016/j.ccr.2009.06.017
118. Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 2008; 27:6958-69; PMID:19029937; http://dx.doi.org/10.1038/onc.2008.346
119. Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 2007; 8:221-33; PMID: 17318226; http://dx.doi.org/10.1038/nrm2125
120. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006; 69:562-73; PMID:16405877; http://dx.doi.org/10.1016/j.cardiores.2005.12.002
121. Köhrmann A, Kammerer U, Kapp M, Dietl J, Anacker J. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: New findings and review of the literature. BMC Cancer 2009; 9:188; PMID:19531263; http://dx.doi.org/10.1186/1471-2407-9-188
122. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010; 141:52-67; PMID:20371345; http://dx.doi.org/10.1016/j.cell.2010.03.015
123. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000; 14:163-76; PMID:10652271
124. Li JR, Li MQ, Bao JT, Li JZ. Correlation between expression of metastasis-associated gene 1 and matrix metalloproteinase 9 and invasion and metastasis of breast cancer. Zhonghua Yi Xue Za Zhi 2008; 88: 2278-80; PMID:19087679
125. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000; 2:737-44; PMID:11025665; http://dx.doi. org/10.1038/35036374
126. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 2005; 436:123-7; PMID:16001073; http://dx.doi.org/10.1038/ nature03688
127. Jeon HW, Lee YM. Inhibition of histone deacetylase attenuates hypoxia-induced migration and invasion of cancer cells via the restoration of RECK expression. Mol Cancer Ther 2010; 9:1361-70; PMID:20442303; http://dx.doi.org/10.1158/1535-7163.MCT-09-0717
128. Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2004; 2:E7; PMID:14737219; http://dx.doi.org/10.1371/journal.pbio.0020007
129. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315:1650-9; PMID:3537791
130. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999; 59:5002-11; PMID:10519415
131. Bhowmick NA, Moses HL. Tumor-stroma interactions. Curr Opin Genet Dev 2005; 15:97-101; PMID: 15661539; http://dx.doi.org/10.1016/j.gde.2004.12.003
132. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449:557-63; PMID:17914389; http:// dx.doi.org/10.1038/nature06188
133. Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development. Annu Rev Pathol 2006; 1:119-50; PMID:18039110; http://dx.doi.org/10.1146/ annurev.pathol.1.110304.100224
134. Bergamaschi A, Tagliabue E, Sørlie T, Naume B, Triulzi T, Orlandi R, et al. Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. J Pathol 2008; 214:357-67; PMID: 18044827; http://dx.doi.org/10.1002/path.2278
135. Rajski M, Zanetti-Dällenbach R, Vogel B, Herrmann R, Rochlitz C, Buess M. IGF-I induced genes in stromal fibroblasts predict the clinical outcome of breast and lung cancer patients. BMC Med 2010; 8:1; PMID: 20051100; http://dx.doi.org/10.1186/1741-7015-8-1
136. Sharma M, Beck AH, Webster JA, Espinosa I, Montgomery K, Varma S, et al. Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ. Breast Cancer Res Treat 2010; 123:397-404; PMID:19949854; http://dx.doi.org/10. 1007/s10549-009-0654-0