Why the stroma matters in breast cancer: Insights into breast cancer patient outcomes through the examination of stromal biomarkers

Cell Adhesion and Migration

Volumn 6, Issue 3, 2012, Pages 249-260

  Conklin, Matthew W ^a   Keely, Patricia J ^a  

^a UNIVERSITY OF WISCONSIN   (United States)

Author keywords

Biomarker; Breast cancer; Caveolin 1; Collagen; Extracellular matrix; Fibroblast; Gene expression signature; Invasion; Lymphocyte; Macrophage; Metastasis; Multiphoton microscopy; Prognosis; Second harmonic generation; Stroma; Survival; Syndecan

Indexed keywords

BIOLOGICAL MARKER; CAVEOLIN 1; TUMOR MARKER;

BASEMENT MEMBRANE; BREAST CANCER; BREAST CARCINOMA; CANCER CELL; CANCER INVASION; CANCER PATIENT; CANCER RECURRENCE; CANCER STAGING; CANCER SURVIVAL; CARCINOGENESIS; CELL ADHESION; CELL MIGRATION; CYTOLOGY; DISEASE FREE INTERVAL; EXTRACELLULAR MATRIX; FIBROBLAST; FOCAL ADHESION; GENE EXPRESSION; GENE EXPRESSION PROFILING; HISTOPATHOLOGY; HUMAN; IMMUNOHISTOCHEMISTRY; LYMPHOCYTE; MACROPHAGE; MAMMOGRAPHY; MOLECULAR IMAGING; MULTIPHOTON MICROSCOPY; NONHUMAN; OUTCOME ASSESSMENT; PROPORTIONAL HAZARDS MODEL; PROTEIN BINDING; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; STROMA; TUMOR GROWTH; TUMOR VOLUME;

EID: 84864943044     PISSN: 19336918     EISSN: 19336926     Source Type: Journal    
DOI: 10.4161/cam.20567     Document Type: Review

References (121)

1. Polyak K, Kalluri R. The role of the microenvironment in mammary gland development and cancer. Cold Spring Harb Perspect Biol 2010; 2:a003244; PMID:20591988; http://dx.doi.org/10.1101/cshperspect.a003244
2. Ingber DE. Cellular tensegrity: defining new rules of biological design that govern the cytoskeleton. J Cell Sci 1993; 104:613-27; PMID:8314865
3. Butcher DT, Alliston T, Weaver VM. A tense situation: forcing tumour progression. Nat Rev Cancer 2009; 9:108-22; PMID:19165226; http://dx.doi.org/10. 1038/nrc2544
4. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 2005; 8:241-54; PMID:16169468; http://dx.doi.org/10.1016/j.ccr.2005.08.010
5. Provenzano PP, Keely PJ. Mechanical signaling through the cytoskeleton regulates cell proliferation by coordinated focal adhesion and Rho GTPase signaling. J Cell Sci 2011; 124:1195-205; PMID:21444750; http://dx.doi.org/10. 1242/jcs.067009
6. Ingber DE. Can cancer be reversed by engineering the tumor microenvironment? Semin Cancer Biol 2008; 18:356-64; PMID:18472275; http://dx.doi.org/10.1016/j.semcancer.2008.03.016
7. Boyd NF, Dite GS, Stone J, Gunasekara A, English DR, McCredie MR, et al. Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med 2002; 347:886-94; PMID:12239257; http://dx.doi.org/10.1056/NEJMoa013390
8. Ursin G, Hovanessian-Larsen L, Parisky YR, Pike MC, Wu AH. Greatly increased occurrence of breast cancers in areas of mammographically dense tissue. Breast Cancer Res 2005; 7:R605-8; PMID:16168104; http://dx.doi.org/10. 1186/bcr1260
9. Li T, Sun L, Miller N, Nicklee T, Woo J, Hulse-Smith L, et al. The association of measured breast tissue characteristics with mammographic density and other risk factors for breast cancer. Cancer Epidemiol Biomarkers Prev 2005; 14:343-9; PMID:15734956; http://dx.doi.org/10.1158/1055-9965.EPI-04-0490
10. Martin LJ, Boyd NF. Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence. Breast Cancer Res 2008; 10:201; PMID:18226174; http://dx.doi.org/10.1186/bcr1831
11. Park CC, Rembert J, Chew K, Moore D, Kerlikowske K. High mammographic breast density is independent predictor of local but not distant recurrence after lumpectomy and radiotherapy for invasive breast cancer. Int J Radiat Oncol Biol Phys 2009; 73:75-9; PMID:18692323; http://dx.doi.org/10.1016/j.ijrobp. 2008.04.007
12. Cil T, Fishell E, Hanna W, Sun P, Rawlinson E, Narod SA, et al. Mammographic density and the risk of breast cancer recurrence after breast-conserving surgery. Cancer 2009; 115:5780-7; PMID:19902459; http://dx.doi.org/10.1002/cncr.24638
13. Kelemen LE, Sellers TA, Vachon CM. Can genes for mammographic density inform cancer aetiology? Nat Rev Cancer 2008; 8:812-23; PMID:18772892; http://dx.doi.org/10.1038/nrc2466
14. Sprague BL, Trentham-Dietz A, Gangnon RE, Buist DS, Burnside ES, Aiello Bowles EJ, et al. The vitamin D pathway and mammographic breast density among postmenopausal women. Breast Cancer Res Treat 2012; 131:255-65; PMID:21847642; http://dx.doi.org/10.1007/s10549-011-1726-5
15. Sprague BL, Trentham-Dietz A, Gangnon RE, Buist DS, Burnside ES, Bowles EJ, et al. Circulating sex hormones and mammographic breast density among postmenopausal women. Horm Cancer 2011; 2:62-72; PMID:21318123; http://dx.doi.org/10.1007/s12672-010-0056-0
16. Liu X, Wu H, Byrne M, Jeffrey J, Krane S, Jaenisch R. A targeted mutation at the known collagenase cleavage site in mouse type I collagen impairs tissue remodeling. J Cell Biol 1995; 130:227-37; PMID:7790374; http://dx.doi.org/10. 1083/jcb.130.1.227
17. Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, et al. Collagen density promotes mammary tumor initiation and progression. BMC Med 2008; 6:11; PMID:18442412; http://dx.doi.org/10.1186/1741-7015-6-11
18. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009; 139:891-906; PMID:19931152; http://dx.doi.org/10.1016/j.cell.2009.10.027
19. Campagnola PJ, Clark HA, Mohler WA, Lewis A, Loew LM. Second-harmonic imaging microscopy of living cells. J Biomed Opt 2001; 6:277-86; PMID:11516317; http://dx.doi.org/10.1117/1.1383294
20. Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med 2006; 4:38; PMID:17190588; http://dx.doi.org/10.1186/1741- 7015-4-38
21. Campagnola PJ, Wei MD, Lewis A, Loew LM. High-resolution nonlinear optical imaging of live cells by second harmonic generation. Biophys J 1999; 77:3341-9; PMID:10585956; http://dx.doi.org/10.1016/S0006-3495(99)77165-1
22. Maglione JE, Moghanaki D, Young LJ, Manner CK, Ellies LG, Joseph SO, et al. Transgenic Polyoma middle-T mice model premalignant mammary disease. Cancer Res 2001; 61:8298-305; PMID:11719463
23. Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 2003; 163:2113-26; PMID:14578209; http://dx.doi.org/10.1016/S0002-9440(10)63568-7
24. Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, et al. Collagen density promotes mammary tumor initiation and progression. BMC Med 2008; 6:11; PMID:18442412; http://dx.doi.org/10.1186/1741-7015-6-11
25. Wyckoff JB, Wang Y, Lin EY, Li JF, Goswami S, Stanley ER, et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 2007; 67:2649-56; PMID:17363585; http://dx.doi.org/10.1158/0008- 5472.CAN-06-1823
26. Wang W, Wyckoff JB, Frohlich VC, Oleynikov Y, Hüttelmaier S, Zavadil J, et al. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res 2002; 62:6278-88; PMID:12414658
27. Provenzano PP, Inman DR, Eliceiri KW, Trier SM, Keely PJ. Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCKdependent matrix reorganization. Biophys J 2008; 95:5374-84; PMID:18775961; http://dx.doi.org/10.1529/biophysj.108.133116
28. Walker RA. The complexities of breast cancer desmoplasia. Breast Cancer Res 2001; 3:143-5; PMID:11305947; http://dx.doi.org/10.1186/bcr287
29. Lagacé R, Grimaud JA, Schürch W, Seemayer TA. Myofibroblastic stromal reaction in carcinoma of the breast: variations of collagenous matrix and structural glycoproteins. Virchows Arch A Pathol Anat Histopathol 1985; 408:49-59; PMID:3933171; http://dx.doi.org/10.1007/BF00739962
30. Tamimi SO, Ahmed A. Stromal changes in invasive breast carcinoma: an ultrastructural study. J Pathol 1987; 153:163-70; PMID:3694320; http://dx.doi.org/10.1002/path.1711530209
31. Conklin MW, Eickhoff JC, Riching KM, Pehlke CA, Eliceiri KW, Provenzano PP, et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am J Pathol 2011; 178:1221-32; PMID: 21356373; http://dx.doi.org/10.1016/j.ajpath.2010.11.076
32. Leivonen M, Lundin J, Nordling S, von Boguslawski K, Haglund C. Prognostic value of syndecan-1 expression in breast cancer. Oncology 2004; 67:11-8; PMID:15459490; http://dx.doi.org/10.1159/000080280
33. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121:335-48; PMID:15882617; http://dx.doi.org/10.1016/j.cell.2005.02.034
34. Wiseman BS, Werb Z. Stromal effects on mammary gland development and breast cancer. Science 2002; 296:1046-9; PMID:12004111; http://dx.doi.org/10. 1126/science.1067431
35. Beauvais DM, Burbach BJ, Rapraeger AC. The syndecan-1 ectodomain regulates alphavbeta3 integrin activity in human mammary carcinoma cells. J Cell Biol 2004; 167:171-81; PMID:15479743; http://dx.doi.org/10.1083/jcb.200404171
36. Beauvais DM, Rapraeger AC. Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation. J Cell Sci 2010; 123:3796-807; PMID:20971705; http://dx.doi.org/10.1242/jcs.067645
37. Bernfield M, Götte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, et al. Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 1999; 68:729-77; PMID:10872465; http://dx.doi.org/10.1146/annurev.biochem.68.1. 729
38. Maeda T, Desouky J, Friedl A. Syndecan-1 expression by stromal fibroblasts promotes breast carcinoma growth in vivo and stimulates tumor angiogenesis. Oncogene 2006; 25:1408-12; PMID:16247452; http://dx.doi.org/10. 1038/sj.onc.1209168
39. Baba F, Swartz K, van Buren R, Eickhoff J, Zhang Y, Wolberg W, et al. Syndecan-1 and syndecan-4 are overexpressed in an estrogen receptor-negative, highly proliferative breast carcinoma subtype. Breast Cancer Res Treat 2006; 98:91-8; PMID:16636895; http://dx.doi.org/10.1007/s10549-005-9135-2
40. Yang N, Mosher R, Seo S, Beebe D, Friedl A. Syndecan-1 in breast cancer stroma fibroblasts regulates extracellular matrix fiber organization and carcinoma cell motility. Am J Pathol 2011; 178:325-35; PMID:21224069; http://dx.doi.org/10.1016/j.ajpath.2010.11.039
41. Svensson KJ, Christianson HC, Kucharzewska P, Fagerström V, Lundstedt L, Borgquist S, et al. Chondroitin sulfate expression predicts poor outcome in breast cancer. Int J Oncol 2011; 39:1421-8; PMID:21850370
42. Bauer M, Eickhoff JC, Gould MN, Mundhenke C, Maass N, Friedl A. Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of poor prognosis in human primary breast cancer. Breast Cancer Res Treat 2008; 108:389-97; PMID:17554627; http://dx.doi.org/10.1007/s10549-007-9619-3
43. Watson CJ. Involution: apoptosis and tissue remodelling that convert the mammary gland from milk factory to a quiescent organ. Breast Cancer Res 2006; 8:203; PMID:16677411; http://dx.doi.org/10.1186/bcr1401
44. Daling JR, Malone KE, Doody DR, Anderson BO, Porter PL. The relation of reproductive factors to mortality from breast cancer. Cancer Epidemiol Biomarkers Prev 2002; 11:235-41; PMID:11895871
45. Whiteman MK, Hillis SD, Curtis KM, McDonald JA, Wingo PA, Marchbanks PA. Reproductive history and mortality after breast cancer diagnosis. Obstet Gynecol 2004; 104:146-54; PMID:15229014; http://dx.doi.org/10.1097/01.AOG.0000128173. 01611.ff
46. Dodds L, Fell DB, Joseph KS, Dewar R, Scott H, Platt R, et al. Relationship of time since childbirth and other pregnancy factors to premenopausal breast cancer prognosis. Obstet Gynecol 2008; 111:1167-73; PMID:18448751; http://dx.doi.org/10.1097/AOG.0b013e31816fd778
47. Stensheim H, Møller B, van Dijk T, Fosså SD. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol 2009; 27:45-51; PMID:19029418; http://dx.doi.org/10.1200/JCO.2008.17.4110
48. Keleher AJ, Theriault RL, Gwyn KM, Hunt KK, Stelling CB, Singletary SE, et al. Multidisciplinary management of breast cancer concurrent with pregnancy. J Am Coll Surg 2002; 194:54-64; PMID: 11800340; http://dx.doi.org/10.1016/S1072- 7515(01)01105-X
49. O'Brien J, Lyons T, Monks J, Lucia MS, Wilson RS, Hines L, et al. Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species. Am J Pathol 2010; 176:1241-55; PMID:20110414; http://dx.doi.org/10.2353/ajpath.2010.090735
50. O'Brien J, Hansen K, Barkan D, Green J, Schedin P, O'Brien J, et al. Non-steroidal anti-inflammatory drugs target the pro-tumorigenic extracellular matrix of the postpartum mammary gland. Int J Dev Biol 2011; 55:745-55; PMID:22161831; http://dx.doi.org/10.1387/ijdb.113379jo
51. Provenzano PP, Inman DR, Eliceiri KW, Keely PJ. Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene 2009; 28:4326-43; PMID:19826415; http://dx.doi.org/10.1038/onc.2009.299
52. Lyons TR, O'Brien J, Borges VF, Conklin MW, Keely PJ, Eliceiri KW, et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 2011; 17:1109-15; PMID:21822285; http://dx.doi.org/10.1038/nm.2416
53. Markosyan N, Chen EP, Ndong VN, Yao Y, Sterner CJ, Chodosh LA, et al. Deletion of cyclooxygenase 2 in mouse mammary epithelial cells delays breast cancer onset through augmentation of type 1 immune responses in tumors. Carcinogenesis 2011; 32:1441-9; PMID: 21771729; http://dx.doi.org/10.1093/ carcin/bgr134
54. Howe LR, Subbaramaiah K, Patel J, Masferrer JL, Deora A, Hudis C, et al. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res 2002; 62:5405-7; PMID:12359744
55. Howe LR, Chang SH, Tolle KC, Dillon R, Young LJ, Cardiff RD, et al. HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. Cancer Res 2005; 65:10113-9; PMID:16267038; http://dx.doi.org/10.1158/0008-5472.CAN-05-1524
56. Lanza-Jacoby S, Miller S, Flynn J, Gallatig K, Daskalakis C, Masferrer JL, et al. The cyclooxygenase-2 inhibitor, celecoxib, prevents the development of mammary tumors in Her-2/neu mice. Cancer Epidemiol Biomarkers Prev 2003; 12:1486-91; PMID:14693742
57. Ristimäki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, et al. Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 2002; 62:632-5; PMID:11830510
58. Grisendi G, Bussolari R, Veronesi E, Piccinno S, Burns JS, De Santis G, et al. Understanding tumor-stroma interplays for targeted therapies by armed mesenchymal stromal progenitors: the Mesenkillers. Am J Cancer Res 2011; 1:787-805; PMID:22016827
59. Meng L, Zhou J, Sasano H, Suzuki T, Zeitoun KM, Bulun SE. Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma: mechanism of desmoplastic reaction. Cancer Res 2001; 61:2250-5; PMID:11280794
60. Dave H, Trivedi S, Shah M, Shukla S. Transforming growth factor beta 2: a predictive marker for breast cancer. Indian J Exp Biol 2011; 49:879-87; PMID:22126020
61. Massagué J. TGFbeta in Cancer. Cell 2008; 134:215-30; PMID:18662538; http://dx.doi.org/10.1016/j.cell.2008.07.001
62. Guerrero J, Tobar N, Cáceres M, Espinoza L, Escobar P, Dotor J, et al. Soluble factors derived from tumor mammary cell lines induce a stromal mammary adipose reversion in human and mice adipose cells. Possible role of TGF-beta1 and TNF-alpha. Breast Cancer Res Treat 2010; 119:497-508; PMID:19649705; http://dx.doi.org/10.1007/s10549-009-0491-1
63. Dave H, Shah M, Trivedi S, Shukla S. Prognostic utility of circulating transforming growth factor beta 1 in breast cancer patients. Int J Biol Markers 2012; 27:53-9; PMID:22020368; http://dx.doi.org/10.5301/JBM.2011.8736
64. Cirri P, Chiarugi P. Cancer associated fibroblasts: the dark side of the coin. Am J Cancer Res 2011; 1:482-97; PMID:21984967
65. Helleman J, Jansen MP, Ruigrok-Ritstier K, van Staveren IL, Look MP, Meijer-van Gelder ME, et al. Association of an extracellular matrix gene cluster with breast cancer prognosis and endocrine therapy response. Clin Cancer Res 2008; 14:5555-64; PMID:18765548; http://dx.doi.org/10.1158/1078-0432.CCR-08-0555
66. Jahkola T, Toivonen T, Virtanen I, von Smitten K, Nordling S, von Boguslawski K, et al. Tenascin-C expression in invasion border of early breast cancer: a predictor of local and distant recurrence. Br J Cancer 1998; 78:1507-13; PMID:9836485; http://dx.doi.org/10.1038/bjc.1998.714
67. Suwiwat S, Ricciardelli C, Tammi R, Tammi M, Auvinen P, Kosma VM, et al. Expression of extracellular matrix components versican, chondroitin sulfate, tenascin, and hyaluronan, and their association with disease outcome in node-negative breast cancer. Clin Cancer Res 2004; 10:2491-8; PMID:15073129; http://dx.doi.org/10.1158/1078-0432.CCR-03-0146
68. Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 2011; 17:867-74; PMID:21706029; http://dx.doi.org/10.1038/nm.2379
69. Guttery DS, Shaw JA, Lloyd K, Pringle JH, Walker RA. Expression of tenascin-C and its isoforms in the breast. Cancer Metastasis Rev 2010; 29:595-606; PMID:20814719; http://dx.doi.org/10.1007/s10555-010-9249-9
70. Pollard JW. Macrophages define the invasive micro-environment in breast cancer. J Leukoc Biol 2008; 84:623-30; PMID:18467655; http://dx.doi.org/10.1189/ jlb.1107762
71. Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol 2012; 65:159-63; PMID:22049225; http://dx.doi.org/10.1136/jclinpath-2011- 200355
72. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 1996; 56:4625-9; PMID:8840975
73. Tsutsui S, Yasuda K, Suzuki K, Tahara K, Higashi H, Era S. Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. Oncol Rep 2005; 14:425-31; PMID:16012726
74. Verjans E, Noetzel E, Bektas N, Schütz AK, Lue H, Lennartz B, et al. Dual role of macrophage migration inhibitory factor (MIF) in human breast cancer. BMC Cancer 2009; 9:230; PMID:19602265; http://dx.doi.org/10.1186/1471- 2407-9-230
75. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011; 475:222-5; PMID:21654748; http://dx.doi.org/10.1038/nature10138
76. Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 2004; 64:7022-9; PMID:15466195; http://dx.doi.org/10.1158/0008-5472.CAN-04-1449
77. Ingman WV,Wyckoff J, Gouon-Evans V, Condeelis J, Pollard JW. Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev Dyn 2006; 235:3222-9; PMID: 17029292; http://dx.doi.org/10. 1002/dvdy.20972
78. Rody A, Karn T, Liedtke C, Pusztai L, Ruckhaeberle E, Hanker L, et al. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res 2011; 13:R97; PMID:21978456; http://dx.doi.org/10. 1186/bcr3035
79. Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat 2012; 132:545-53; PMID:21671016; http://dx.doi.org/10. 1007/s10549-011-1620-1
80. de Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 2005; 7:411-23; PMID:15894262; http://dx.doi.org/10.1016/j.ccr.2005.04.014
81. Houghton AN, Uchi H, Wolchok JD. The role of the immune system in early epithelial carcinogenesis: B-ware the double-edged sword. Cancer Cell 2005; 7:403-5; PMID:15894259; http://dx.doi.org/10.1016/j.ccr.2005.04.026
82. Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res 2010; 70:7465-75; PMID:20841473; http://dx.doi.org/10.1158/0008-5472.CAN-10-1439
83. Levy SM, Herberman RB, Lippman M, D'Angelo T, Lee J. Immunological and psychosocial predictors of disease recurrence in patients with early-stage breast cancer. Behav Med 1991; 17:67-75; PMID:1878611; http://dx.doi.org/10. 1080/08964289.1991.9935161
84. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98:10869-74; PMID:11553815; http://dx.doi.org/10.1073/pnas.191367098
85. 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
86. van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002; 415:530-6; PMID:11823860; http://dx.doi.org/10.1038/415530a
87. van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002; 347:1999-2009; PMID:12490681; http://dx.doi.org/10.1056/ NEJMoa021967
88. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res 2006; 66:605-12; PMID:16423985; http://dx.doi.org/10.1158/0008-5472.CAN-05-4005
89. Kao KJ, Chang KM, Hsu HC, Huang AT. Correlation of microarray-based breast cancer molecular subtypes and clinical outcomes: implications for treatment optimization. BMC Cancer 2011; 11:143; PMID:21501481; http://dx.doi.org/10.1186/1471-2407-11-143
90. 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
91. Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci U S A 2011; 108:2909-14; PMID:21282607; http://dx.doi.org/10.1073/pnas.1018892108
92. Planche A, Bacac M, Provero P, Fusco C, Delorenzi M, Stehle JC, et al. Identification of prognostic molecular features in the reactive stroma of human breast and prostate cancer. PLoS One 2011; 6:e18640; PMID:21611158; http://dx.doi.org/10.1371/journal.pone.0018640
93. 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
94. Chang HY, Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sørlie T, et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci U S A 2005; 102:3738-43; PMID:15701700; http://dx.doi.org/10.1073/pnas.0409462102
95. Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, Ibrahim NK, et al. Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J Clin Oncol 2010; 28:4316-23; PMID:20805453; http://dx.doi.org/10.1200/JCO.2009.27.2419
96. Ma XJ, Dahiya S, Richardson E, Erlander M, Sgroi DC. Gene expression profiling of the tumor micro-environment during breast cancer progression. Breast Cancer Res 2009; 11:R7; PMID:19187537; http://dx.doi.org/10.1186/bcr2222
97. Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 2004; 117:1495-502; PMID:14996910; http://dx.doi.org/10.1242/jcs.01000
98. Wozniak MA, Desai R, Solski PA, Der CJ, Keely PJ. ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. J Cell Biol 2003; 163:583-95; PMID:14610060; http://dx.doi.org/10.1083/jcb.200305010
99. Sahai E, Marshall CJ. Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol 2003; 5:711-9; PMID:12844144; http://dx.doi.org/10.1038/ncb1019
100. Dai J, Sheetz MP. Axon membrane flows from the growth cone to the cell body. Cell 1995; 83:693-701; PMID:8521486; http://dx.doi.org/10.1016/0092- 8674(95)90182-5
101. Conklin MW, Ada-Nguema A, Parsons M, Riching KM, Keely PJ. R-Ras regulates beta1-integrin trafficking via effects on membrane ruffling and endocytosis. BMC Cell Biol 2010; 11:14; PMID:20167113; http://dx.doi.org/10. 1186/1471-2121-11-14
102. Provenzano PP, Inman DR, Eliceiri KW, Beggs HE, Keely PJ. Mammary epithelial-specific disruption of focal adhesion kinase retards tumor formation and metastasis in a transgenic mouse model of human breast cancer. Am J Pathol 2008; 173:1551-65; PMID:18845837; http://dx.doi.org/10.2353/ajpath.2008.080308
103. Lahlou H, Sanguin-Gendreau V, Zuo D, Cardiff RD, McLean GW, Frame MC, et al. Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression. Proc Natl Acad Sci U S A 2007; 104:20302-7; PMID:18056629; http://dx.doi.org/10.1073/pnas.0710091104
104. Giancotti FG, Ruoslahti E. Integrin signaling. Science 1999; 285:1028-32; PMID:10446041; http://dx.doi.org/10.1126/science.285.5430.1028
105. Goetz JG, Minguet S, Navarro-Lérida I, Lazcano JJ, Samaniego R, Calvo E, et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 2011; 146:148-63; PMID:21729786; http://dx.doi.org/10.1016/j.cell.2011.05.040
106. Sloan EK, Ciocca DR, Pouliot N, Natoli A, Restall C, Henderson MA, et al. Stromal cell expression of caveolin-1 predicts outcome in breast cancer. Am J Pathol 2009; 174:2035-43; PMID:19411449; http://dx.doi.org/10.2353/ajpath.2009. 080924
107. Witkiewicz AK, Dasgupta A, Sotgia F, Mercier I, Pestell RG, Sabel M, et al. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol 2009; 174:2023-34; PMID:19411448; http://dx.doi.org/10.2353/ajpath.2009.080873
108. Provenzano PP, Inman DR, Eliceiri KW, Trier SM, Keely PJ. Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization. Biophys J 2008; 95:5374-84; PMID:18775961; http://dx.doi.org/10.1529/biophysj.108.133116
109. Grande-García A, Echarri A, de Rooij J, Alderson NB, Waterman-Storer CM, Valdivielso JM, et al. Caveolin-1 regulates cell polarization and directional migration through Src kinase and Rho GTPases. J Cell Biol 2007; 177:683-94; PMID:17517963; http://dx.doi.org/10.1083/jcb. 200701006
110. Joshi B, Strugnell SS, Goetz JG, Kojic LD, Cox ME, Griffith OL, et al. Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion. Cancer Res 2008; 68:8210-20; PMID:18922892; http://dx.doi.org/10.1158/0008-5472.CAN-08-0343
111. Bachmeier BE, Iancu CM, Jochum M, Nerlich AG. Matrix metalloproteinases in cancer: comparison of known and novel aspects of their inhibition as a therapeutic approach. Expert Rev Anticancer Ther 2005; 5:149-63; PMID:15757447; http://dx.doi.org/10.1586/14737140.5.1.149
112. Boström P, Söderström M, Vahlberg T, Söderström KO, Roberts PJ, Carpén O, et al. MMP-1 expression has an independent prognostic value in breast cancer. BMC Cancer 2011; 11:348; PMID:21835023; http://dx.doi.org/10.1186/1471-2407-11-348
113. Têtu B, Brisson J, Wang CS, Lapointe H, Beaudry G, Blanchette C, et al. The influence of MMP-14, TIMP-2 and MMP-2 expression on breast cancer prognosis. Breast Cancer Res 2006; 8:R28; PMID:16776850; http://dx.doi.org/10. 1186/bcr1503
114. Zhang B, Cao X, Liu Y, Cao W, Zhang F, Zhang S, et al. Tumor-derived matrix metalloproteinase-13 (MMP-13) correlates with poor prognoses of invasive breast cancer. BMC Cancer 2008; 8:83; PMID: 18373849; http://dx.doi.org/10.1186/ 1471-2407-8-83
115. Ranogajec I, Jakić-Razumović J, Puzović V, Gabrilovac J. Prognostic value of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and aminopeptidase N/CD13 in breast cancer patients. Med Oncol 2012; 29:561-9; PMID:21611838; http://dx.doi.org/10.1007/s12032-011- 9984-y
116. Nakopoulou L, Panayotopoulou EG, Giannopoulou I, Alexandrou P, Katsarou S, Athanassiadou P, et al. Stromelysin-3 protein expression in invasive breast cancer: relation to proliferation, cell survival and patients' outcome. Mod Pathol 2002; 15:1154-61; PMID:12429794; http://dx.doi.org/10.1097/01.MP. 0000037317.84782.CD
117. 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
118. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410:50-6; PMID:11242036; http://dx.doi.org/10.1038/35065016
119. Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A, et al. CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival. Eur J Cancer 2009; 45:2579-87; PMID:19646861; http://dx.doi.org/10.1016/j.ejca.2009.06.026
120. Ramos EA, Grochoski M, Braun-Prado K, Seniski GG, Cavalli IJ, Ribeiro EM, et al. Epigenetic changes of CXCR4 and its ligand CXCL12 as prognostic factors for sporadic breast cancer. PLoS One 2011; 6: e29461; PMID:22220212; http://dx.doi.org/10.1371/journal.pone.0029461
121. Palmieri D, Astigiano S, Barbieri O, Ferrari N, Marchisio S, Ulivi V, et al. Procollagen I COOH-terminal fragment induces VEGF-A and CXCR4 expression in breast carcinoma cells. Exp Cell Res 2008; 314:2289-98; PMID:18570923; http://dx.doi.org/10.1016/j.yexcr.2008.04.016