JNK1 stress signaling is hyper-activated in high breast density and the tumor stroma: Connecting fibrosis, inflammation, and stemness for cancer prevention

Cell Cycle

Volumn 13, Issue 4, 2014, Pages 580-599

  Lisanti, Michael P ^a,b   Tsirigos, Aristotelis ^c   Pavlides, Stephanos ^d   Reeves, Kimberley Jayne ^a,b   Peiris Pagès, Maria ^a,b   Chadwick, Amy L ^a,b   Sanchez Alvarez, Rosa ^a,b   Lamb, Rebecca ^a,b   Howell, Anthony ^a   Martinez Outschoorn, Ubaldo E ^e   Sotgia, Federica ^a,b  

^a UNIVERSITY OF MANCHESTER   (United Kingdom)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

^c IBM T J WATSON RESEARCH CENTER   (United States)

^d Postgraduate Research Institute of Science Technology Environment and Medicine Limassol   (Cyprus)

^e THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Breast cancer; Cancer associated fibroblasts; EGF; FGF; Fibrosis; Gene signature; Inflammation; JNK; Mammographic density; Mammography; Microenvironment; PDGF; SAPK; Stress signaling; TGF beta; Tumor stroma; Wound healing

Indexed keywords

ANIMAL TISSUE; ARTICLE; BREAST CANCER; BREAST FIBROSIS; BREAST TUMOR; CANCER PREVENTION; FIBROBLAST; GENETIC ASSOCIATION; GENOME ANALYSIS; HUMAN; HUMAN TISSUE; MAMMOGRAPHY; MASTITIS; NONHUMAN; PHENOTYPE; SIGNAL TRANSDUCTION; SMOOTH MUSCLE FIBER; STRESS; STROMA; UPREGULATION; CANCER STEM CELL; CONGENITAL MALFORMATION; FEMALE; FIBROSIS; GENETICS; INFLAMMATION; MAMMARY GLAND; METABOLISM; PATHOLOGY; TUMOR MICROENVIRONMENT;

STRESS ACTIVATED PROTEIN KINASE 1; TRANSCRIPTOME;

BREAST NEOPLASMS; FEMALE; FIBROBLASTS; FIBROSIS; HUMANS; INFLAMMATION; MAMMARY GLANDS, HUMAN; MITOGEN-ACTIVATED PROTEIN KINASE 8; NEOPLASTIC STEM CELLS; SIGNAL TRANSDUCTION; TRANSCRIPTOME; TUMOR MICROENVIRONMENT;

EID: 84896835463     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.27379     Document Type: Article

References (66)

1. McCormack VA, dos Santos Silva I. Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2006; 15:1159-69; PMID:16775176; http://dx.doi.org/10.1158/1055-9965.EPI- 06-0034
2. Stone J, Dite GS, Gunasekara A, English DR, McCredie MR, Giles GG, Cawson JN, Hegele RA, Chiarelli AM, Yaffe MJ, et al. The heritability of mammographically dense and nondense breast tissue. Cancer Epidemiol Biomarkers Prev 2006; 15:612-7; PMID:16614099; http://dx.doi.org/10.1158/1055-9965.EPI-05- 0127
3. Cuzick J, Warwick J, Pinney E, Duffy SW, Cawthorn S, Howell A, Forbes JF, Warren RM. Tamoxifen-induced reduction in mammographic density and breast cancer risk reduction: a nested case-control study. J Natl Cancer Inst 2011; 103:744-52; PMID:21483019; http://dx.doi.org/10.1093/jnci/djr079
4. Hattar R, Maller O, McDaniel S, Hansen KC, Hedman KJ, Lyons TR, Lucia S, Wilson RS Jr., Schedin P. Tamoxifen induces pleiotrophic changes in mammary stroma resulting in extracellular matrix that suppresses transformed phenotypes. Breast Cancer Res 2009; 11:R5; PMID:19173736; http://dx.doi.org/10.1186/bcr2220
5. Guo YP, Martin LJ, Hanna W, Banerjee D, Miller N, Fishell E, Khokha R, Boyd NF. Growth factors and stromal matrix proteins associated with mammographic densities. Cancer Epidemiol Biomarkers Prev 2001; 10:243-8; PMID:11303594
6. Hawes D, Downey S, Pearce CL, Bartow S, Wan P, Pike MC, Wu AH. Dense breast stromal tissue shows greatly increased concentration of breast epithelium but no increase in its proliferative activity. Breast Cancer Res 2006; 8:R24; PMID:16646977; http://dx.doi.org/10.1186/bcr1408
7. 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
8. DeFilippis RA, Chang H, Dumont N, Rabban JT, Chen YY, Fontenay GV, Berman HK, Gauthier ML, Zhao J, Hu D, et al. CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues. Cancer Discov 2012; 2:826-39; PMID:22777768; http://dx.doi.org/10.1158/2159-8290.CD-12- 0107
9. Yang WT, Lewis MT, Hess K, Wong H, Tsimelzon A, Karadag N, Cairo M, Wei C, Meric-Bernstam F, Brown P, et al. Decreased TGFbeta signaling and increased COX2 expression in high risk women with increased mammographic breast density. Breast Cancer Res Treat 2010; 119:305-14; PMID:19241157; http://dx.doi.org/10. 1007/s10549-009-0350-0
10. Hardwick JC, van den Brink GR, Offerhaus GJ, van Deventer SJ, Peppelenbosch MP. NF-kappaB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps. Oncogene 2001; 20:819-27; PMID:11314016; http://dx.doi.org/10.1038/sj.onc.1204162
11. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, 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
12. Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, et al. Transcriptional evidence for the "Reverse Warburg Effect" in human breast cancer tumor stroma and metastasis: similarities with oxidative stress, inflammation, Alzheimer's disease, and "Neuron-Glia Metabolic Coupling". Aging (Albany NY) 2010; 2:185-99; PMID:20442453
13. Kanazawa S, Fujiwara T, Matsuzaki S, Shingaki K, Taniguchi M, Miyata S, Tohyama M, Sakai Y, Yano K, Hosokawa K, et al. bFGF regulates PI3-kinase-Rac1-JNK pathway and promotes fibroblast migration in wound healing. PLoS One 2010; 5:e12228; PMID:20808927; http://dx.doi.org/10.1371/journal.pone. 0012228
14. Javelaud D, Laboureau J, Gabison E, Verrecchia F, Mauviel A. Disruption of basal JNK activity differentially affects key fibroblast functions important for wound healing. J Biol Chem 2003; 278:24624-8; PMID:12730213; http://dx.doi.org/10.1074/jbc.M301942200
15. Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S, Lisanti MP. Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol 2012; 7:423-67; PMID:22077552; http://dx.doi.org/10.1146/annurev-pathol-011811-120856
16. Sotgia F, Martinez-Outschoorn UE, Lisanti MP. Mitochondrial oxidative stress drives tumor progression and metastasis: should we use antioxidants as a key component of cancer treatment and prevention? BMC Med 2011; 9:62; PMID:21605374; http://dx.doi.org/10.1186/1741-7015-9-62
17. Sotgia F, Martinez-Outschoorn UE, Lisanti MP. Genetic induction of the Warburg effect inhibits tumor growth. Oncotarget 2012; 3:1266-7; PMID:23175502
18. Sotgia F, Martinez-Outschoorn UE, Lisanti MP. Cancer metabolism: new validated targets for drug discovery. Oncotarget 2013; 4:1309-16; PMID:23896568
19. Sotgia F, Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Lisanti MP. Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res 2011; 13:213; PMID:21867571; http://dx.doi.org/10.1186/bcr2892
20. Sotgia F, Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, Howell A, Philp NJ, Pestell RG, Lisanti MP. Mitochondrial metabolism in cancer metastasis: visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue. Cell Cycle 2012; 11:1445-54; PMID:22395432; http://dx.doi.org/10.4161/cc.19841
21. Sotgia F, Whitaker-Menezes D, Martinez-Outschoorn UE, Salem AF, Tsirigos A, Lamb R, Sneddon S, Hulit J, Howell A, Lisanti MP. Mitochondria "fuel" breast cancer metabolism: fifteen markers of mitochondrial biogenesis label epithelial cancer cells, but are excluded from adjacent stromal cells. Cell Cycle 2012; 11:4390-401; PMID:23172368; http://dx.doi.org/10.4161/ cc.22777
22. Martinez-Outschoorn UE, Pestell RG, Howell A, Tykocinski ML, Nagajyothi F, Machado FS, Tanowitz HB, Sotgia F, Lisanti MP. Energy transfer in "parasitic" cancer metabolism: mitochondria are the powerhouse and Achilles' heel of tumor cells. Cell Cycle 2011; 10:4208-16; PMID:22033146; http://dx.doi.org/10.4161/cc.10.24.18487
23. Paulsson J, Sjoblom T, Micke P, Ponten F, Landberg G, Heldin CH, Bergh J, Brennan DJ, Jirstrom K, Ostman A. Prognostic significance of stromal platelet-derived growth factor beta-receptor expression in human breast cancer. Am J Pathol 2009; 175:334-41; PMID:19498003; http://dx.doi.org/10.2353/ajpath. 2009.081030
24. Saito RA, Micke P, Paulsson J, Augsten M, Peña C, Jonsson P, Botling J, Edlund K, Johansson L, Carlsson P, et al. Forkhead box F1 regulates tumor-promoting properties of cancer-associated fibroblasts in lung cancer. Cancer Res 2010; 70:2644-54; PMID:20233876; http://dx.doi.org/10.1158/0008-5472. CAN-09-3644
25. Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, Birbe RC, Howell A, Pavlides S, Gandara R, et al. Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle 2011; 10:1772-83; PMID:21558814; http://dx.doi.org/10.4161/cc.10.11.15659
26. Sabapathy K. Role of the JNK pathway in human diseases. Prog Mol Biol Transl Sci 2012; 106:145-69; PMID:22340717; http://dx.doi.org/10.1016/B978-0-12- 396456-4.00013-4
27. Toone WM, Jones N. Stress-activated signalling pathways in yeast. Genes Cells 1998; 3:485-98; PMID:9797451; http://dx.doi.org/10.1046/j.1365-2443.1998. 00211.x
28. Toone WM, Jones N. AP-1 transcription factors in yeast. Curr Opin Genet Dev 1999; 9:55-61; PMID:10072349; http://dx.doi.org/10.1016/S0959-437X(99)80008- 2
29. Toone WM, Morgan BA, Jones N. Redox control of AP-1-like factors in yeast and beyond. Oncogene 2001; 20:2336-46; PMID:11402331; http://dx.doi.org/10. 1038/sj.onc.1204384
30. Karin M, Gallagher E. From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance. IUBMB Life 2005; 57:283-95; PMID:16036612; http://dx.doi.org/10.1080/15216540500097111
31. Wang X, Destrument A, Tournier C. Physiological roles of MKK4 and MKK7: insights from animal models. Biochim Biophys Acta 2007; 1773:1349-57; PMID:17157936; http://dx.doi.org/10.1016/j.bbamcr.2006.10.016
32. Davies C, Tournier C. Exploring the function of the JNK (c-Jun N-terminal kinase) signalling pathway in physiological and pathological processes to design novel therapeutic strategies. Biochem Soc Trans 2012; 40:85-9; PMID:22260670; http://dx.doi.org/10.1042/BST20110641
33. Chambers JW, Pachori A, Howard S, Iqbal S, LoGrasso PV. Inhibition of JNK mitochondrial localization and signaling is protective against ischemia/reperfusion injury in rats. J Biol Chem 2013; 288:4000-11; PMID:23258542; http://dx.doi.org/10.1074/jbc.M112.406777
34. Haeusgen W, Herdegen T, Waetzig V. The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7. Eur J Cell Biol 2011; 90:536-44; PMID:21333379; http://dx.doi.org/10.1016/j.ejcb.2010.11.008
35. Guma M, Firestein GS. c-Jun N-Terminal Kinase in Inflammation and Rheumatic Diseases. Open Rheumatol J 2012; 6:220-31; PMID:23028407; http://dx.doi.org/10.2174/1874312901206010220
36. Chaanine AH, Jeong D, Liang L, Chemaly ER, Fish K, Gordon RE, Hajjar RJ. JNK modulates FOXO3a for the expression of the mitochondrial death and mitophagy marker BNIP3 in pathological hypertrophy and in heart failure. Cell Death Dis 2012; 3:265; PMID:22297293; http://dx.doi.org/10.1038/cddis.2012.5
37. Masamune A, Kikuta K, Suzuki N, Satoh M, Satoh K, Shimosegawa T. A c-Jun NH2-terminal kinase inhibitor SP600125 (anthra[1,9-cd]pyrazole-6 (2H)-one) blocks activation of pancreatic stellate cells. J Pharmacol Exp Ther 2004; 310:520-7; PMID:15056726; http://dx.doi.org/10.1124/jpet.104.067280
38. Hashimoto S, Gon Y, Takeshita I, Matsumoto K, Maruoka S, Horie T. Transforming growth Factor-beta1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway. Am J Respir Crit Care Med 2001; 163:152-7; PMID:11208641; http://dx.doi.org/10.1164/ajrccm.163.1.2005069
39. Greten FR. TAK1: Another mesh in the NF-κB - JNK controlled network causing hepatocellular carcinoma. J Hepatol 2011; 55:721-3; PMID:21601601; http://dx.doi.org/10.1016/j.jhep.2011.02.037
40. Liu S, Xu SW, Kennedy L, Pala D, Chen Y, Eastwood M, Carter DE, Black CM, Abraham DJ, Leask A. FAK is required for TGFbeta-induced JNK phosphorylation in fibroblasts: implications for acquisition of a matrix-remodeling phenotype. Mol Biol Cell 2007; 18:2169-78; PMID:17409352; http://dx.doi.org/10.1091/mbc.E06- 12-1121
41. Plantevin Krenitsky V, Nadolny L, Delgado M, Ayala L, Clareen SS, Hilgraf R, Albers R, Hegde S, D'Sidocky N, Sapienza J, et al. Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor. Bioorg Med Chem Lett 2012; 22:1433-8; PMID:22244937; http://dx.doi.org/10.1016/j.bmcl.2011.12.027
42. Reinecke K, Eminel S, Dierck F, Roessner W, Kersting S, Chromik AM, Gavrilova O, Laukevicience A, Leuschner I, Waetzig V, et al. The JNK inhibitor XG-102 protects against TNBS-induced colitis. PLoS One 2012; 7:e30985; PMID:22427801; http://dx.doi.org/10.1371/journal.pone.0030985
43. Zhang T, Inesta-Vaquera F, Niepel M, Zhang J, Ficarro SB, Machleidt T, Xie T, Marto JA, Kim N, Sim T, et al. Discovery of potent and selective covalent inhibitors of JNK. Chem Biol 2012; 19:140-54; PMID:22284361; http://dx.doi.org/10.1016/j.chembiol.2011.11.010
44. Bogoyevitch MA, Kobe B. Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases. Microbiol Mol Biol Rev 2006; 70:1061-95; PMID:17158707; http://dx.doi.org/10.1128/MMBR.00025-06
45. Barcus CE, Keely PJ, Eliceiri KW, Schuler LA. Stiff collagen matrices increase tumorigenic prolactin signaling in breast cancer cells. J Biol Chem 2013; 288:12722-32; PMID:23530035; http://dx.doi.org/10.1074/jbc.M112.447631
46. Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ. 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
47. Conklin MW, Eickhoff JC, Riching KM, Pehlke CA, Eliceiri KW, Provenzano PP, Friedl A, Keely PJ. 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
48. You H, Padmashali RM, Ranganathan A, Lei P, Girnius N, Davis RJ, Andreadis ST. JNK regulates compliance-induced adherens junctions formation in epithelial cells and tissues. J Cell Sci 2013; 126:2718-29; PMID:23591817; http://dx.doi.org/10.1242/jcs.122903
49. Mengistu M, Brotzman H, Ghadiali S, Lowe-Krentz L. Fluid shear stress-induced JNK activity leads to actin remodeling for cell alignment. J Cell Physiol 2011; 226:110-21; PMID:20626006; http://dx.doi.org/10.1002/jcp.22311
50. Daoud S, Schinzel R, Neumann A, Loske C, Fraccarollo D, Diez C, Simm A. Advanced glycation endproducts: activators of cardiac remodeling in primary fibroblasts from adult rat hearts. Mol Med 2001; 7:543-51; PMID:11591890
51. Martinez-Outschoorn UE, Curry JM, Ko YH, Lin Z, Tuluc M, Cognetti D, Birbe RC, Pribitkin E, Bombonati A, Pestell RG, et al. Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4. Cell Cycle 2013; 12:2580-97; PMID:23860378; http://dx.doi.org/10.4161/cc.25510
52. Lisanti MP, Martinez-Outschoorn UE, Lin Z, Pavlides S, Whitaker-Menezes D, Pestell RG, Howell A, Sotgia F. Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs "fertilizer". Cell Cycle 2011; 10:2440-9; PMID:21734470; http://dx.doi.org/10.4161/cc.10.15.16870
53. Lisanti MP, Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Pestell RG, Howell A, Sotgia F. Accelerated aging in the tumor microenvironment: connecting aging, inflammation and cancer metabolism with personalized medicine. Cell Cycle 2011; 10:2059-63; PMID:21654190; http://dx.doi.org/10.4161/ cc.10.13.16233
54. Lisanti MP, Martinez-Outschoorn UE, Sotgia F. Oncogenes induce the cancer-associated fibroblast phenotype: metabolic symbiosis and "fibroblast addiction" are new therapeutic targets for drug discovery. Cell Cycle 2013; 12:2723-32; PMID:23860382; http://dx.doi.org/10.4161/cc.25695
55. Gross ND, Boyle JO, Du B, Kekatpure VD, Lantowski A, Thaler HT, Weksler BB, Subbaramaiah K, Dannenberg AJ. Inhibition of Jun NH2-terminal kinases suppresses the growth of experimental head and neck squamous cell carcinoma. Clin Cancer Res 2007; 13:5910-7; PMID:17908987; http://dx.doi.org/10.1158/1078- 0432.CCR-07-0352
56. Ennis BW, Fultz KE, Smith KA, Westwick JK, Zhu D, Boluro-Ajayi M, Bilter GK, Stein B. Inhibition of tumor growth, angiogenesis, and tumor cell proliferation by a small molecule inhibitor of c-Jun N-terminal kinase. J Pharmacol Exp Ther 2005; 313:325-32; PMID:15626722; http://dx.doi.org/10.1124/ jpet.104.078873
57. Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, Whitaker-Menezes D, Daumer KM, Lin Z, Witkiewicz AK, et al. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle 2010; 9:3256-76; PMID:20814239; http://dx.doi.org/10.4161/cc.9.16.12553
58. Martinez-Outschoorn UE, Lin Z, Trimmer C, Flomenberg N, Wang C, Pavlides S, Pestell RG, Howell A, Sotgia F, Lisanti MP. Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors. Cell Cycle 2011; 10:2504-20; PMID:21778829; http://dx.doi.org/10.4161/cc.10.15.16585
59. Chaudhri VK, Salzler GG, Dick SA, Buckman MS, Sordella R, Karoly ED, Mohney R, Stiles BM, Elemento O, Altorki NK, et al. Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Mol Cancer Res 2013; 11:579-92; PMID:23475953; http://dx.doi.org/10.1158/1541-7786.MCR-12-0437-T
60. Lakhani P, Maidment AD, Weinstein SP, Kung JW, Alavi A. Correlation between quantified breast densities from digital mammography and 18F-FDG PET uptake. Breast J 2009; 15:339-47; PMID:19601942; http://dx.doi.org/10.1111/j. 1524-4741.2009.00737.x
61. Mavi A, Cermik TF, Urhan M, Puskulcu H, Basu S, Cucchiara AJ, Yu JQ, Alavi A. The effect of age, menopausal state, and breast density on (18)F-FDG uptake in normal glandular breast tissue. J Nucl Med 2010; 51:347-52; PMID:20150253; http://dx.doi.org/10.2967/jnumed.109.068718
62. Vranjesevic D, Schiepers C, Silverman DH, Quon A, Villalpando J, Dahlbom M, Phelps ME, Czernin J. Relationship between 18F-FDG uptake and breast density in women with normal breast tissue. J Nucl Med 2003; 44:1238-42; PMID:12902413
63. Das M, Garlick DS, Greiner DL, Davis RJ. The role of JNK in the development of hepatocellular carcinoma. Genes Dev 2011; 25:634-45; PMID:21406557; http://dx.doi.org/10.1101/gad.1989311
64. Wu M, Pastor-Pareja JC, Xu T. Interaction between Ras(V12) and scribbled clones induces tumour growth and invasion. Nature 2010; 463:545-8; PMID:20072127; http://dx.doi.org/10.1038/nature08702
65. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005; 102:15545-50; PMID:16199517; http://dx.doi.org/10.1073/pnas.0506580102
66. Tsirigos A, Haiminen N, Bilal E, Utro F. GenomicTools: a computational platform for developing high-throughput analytics in genomics. Bioinformatics 2012; 28:282-3; PMID:22113082; http://dx.doi.org/10.1093/bioinformatics/btr646