Chemotherapy-induced immunological breast cancer dormancy: a new function for old drugs?

Abstract

Breast cancer remains the main cause of cancer-related mortality for women world-wide. Main cause of death is the development of therapy-resistant metastases. Relapses occur with a bimodal temporal distribution, with a first peak at 1-2 years after initial therapy and a second peak 2-3 years later. This discontinuous growth kinetics is consistent with the notion that disseminated cancer cells can remain dormant over a prolonged period of time before resuming growth. How cancer cells enter, sustain and exit dormancy, are unanswered questions with relevance to cancer biology, monitoring and therapy. Investigating mechanisms of breast cancer dormancy remains challenging, as in patients the condition is elusive and experimentally there are only a few models that recapitulate the clinical condition. Thus, developing new models to identify clinically relevant mechanisms and candidate therapeutic targets may open new avenues for novel therapies to induce and prolong dormancy. We have observed that cells surviving chemotherapy can enter a state of immunological dormancy. Using this model, we identified IRF-7/Interferon type I/IFNRA as signaling axis essential for this effect. Here we will review concepts and recent developments in cancer metastasis and dormancy with emphasis on breast cancer, and elaborate strategies to exploit them therapeutically.

Keywords

Breast cancer / chemotherapy / resistance / dormancy / T lymphocytes / interferon

References

[1] Chaffer CL.A perspective on cancer cell metastasis..Science2011;331:1559-64

[2] Hanahan D.Hallmarks of cancer: the next generation..Cell2011;144:646-74

[3] Chaffer CL.How does multistep tumorigenesis really proceed?.Cancer Discov2015;5:22-4 PMCID:PMC4295623

[4] Massague J.Metastatic colonization by circulating tumour cells..Nature2016;529:298-306 PMCID:PMC5029466

[5] Obenauf AC.Surviving at a distance: organ-specific metastasis..Trends Cancer2015;1:76-91 PMCID:PMC4673677

[6] Lorusso G.New insights into the mechanisms of organ-specific breast cancer metastasis..Seminar Cancer Biol2012;22:226-33

[7] Chiang AC.Molecular basis of metastasis..N Engl J Med2008;359:2814-23 PMCID:PMC4189180

[8] Sleeman JP,Fodde R,Berx G.Concepts of metastasis in flux: the stromal progression model..Semin Cancer Biol2012;22:174-86

[9] Bussard KM,Stumpf K,Marini FC.Tumor-associated stromal cells as key contributors to the tumor microenvironment..Breast Cancer Res2016;18:84 PMCID:PMC4982339

[10] Mao Y,Garfield DH,Wang J.Stromal cells in tumor microenvironment and breast cancer..Cancer Metastasis Rev2013;32:303-15 PMCID:PMC4432936

[11] Lorusso G.The tumor microenvironment and its contribution to tumor evolution toward metastasis..Histochem Cell Biol2008;130:1091-103

[12] Cserni G,Cserni B.The new TNM-based staging of breast cancer..Virchows Arch2018;472:697-703

[13] Herbst RS,Lippman SM.Lung cancer..N Engl J Med2008;359:1367-80

[14] Nicum S,Kerr DJ.Colorectal cancer..Acta Oncol2003;42:263-75

[15] Damber JE.Prostate cancer..Lancet2008;371:1710-21

[16] Demicheli R,Ardoino I,Coradini D.Recurrence and mortality dynamics for breast cancer patients undergoing mastectomy according to estrogen receptor status: different mortality but similar recurrence..Cancer Sci2010;101:826-30

[17] Retsky M.Multimodal hazard rate for relapse in breast cancer: quality of data and calibration of computer simulation..Cancers (Basel)2014;6:2343-55 PMCID:PMC4276970

[18] DeSantis C,Bryan L.Breast cancer statistics, 2013..CA Cancer J Clin2014;64:52-62

[19] Waks AG.Breast cancer treatment: a review..JAMA2019;321:288-300

[20] Yersal O.Biological subtypes of breast cancer: prognostic and therapeutic implications..World J Clin Oncol2014;5:412-24 PMCID:PMC4127612

[21] Prat A,Adamo B,Fernandez A.Clinical implications of the intrinsic molecular subtypes of breast cancer..Breast.2015;24 Suppl 2:S26-35

[22] Foulkes WD,Reis-Filho JS.Triple-negative breast cancer..N Engl J Med2010;363:1938-48

[23] Loibl S.HER2-positive breast cancer..Lancet2017;389:2415-29

[24] Friend S.The changing landscape of breast cancer: how biology drives therapy..Medicines (Basel)2016;3:E2 PMCID:PMC5456232

[25] Guler EN.Gene expression profiling in breast cancer and its effect on therapy selection in early-stage breast cancer..Eur J Breast Health2017;13:168-74 PMCID:PMC5648272

[26] Colozza M,Cardoso F,Piccart MJ.Breast cancer: achievements in adjuvant systemic therapies in the pre-genomic era..Oncologist2006;11:111-25

[27] Brady-West DC.Triple negative breast cancer: therapeutic and prognostic implications..Asian Pac J Cancer Prev2011;12:2139-43

[28] Goldvaser H,Majeed H,Amir E.Absolute benefit from adjuvant chemotherapy in contemporary clinical trials: A systemic review and meta-analysis..Cancer Treat Rev2018;71:68-75

[29] Coates AS,Goldhirsch A,Gnant M.Tailoring therapies-improving the management of early breast cancer: St Gallen international expert consensus on the primary therapy of early breast cancer 2015..Ann Oncol2015;26:1533-46 PMCID:PMC4511219

[30] von Minckwitz G,Maisch A.Lessons from the neoadjuvant setting on how best to choose adjuvant therapies..Breast.2011;20 Suppl 3:S142-5

[31] Zardavas D,Piccart M.Optimal adjuvant treatment for patients with HER2-positive breast cancer in 2015..Breast.2015;24 Suppl 2:S143-8

[32] Wahba HA.Current approaches in treatment of triple-negative breast cancer..Cancer Biol Med2015;12:106-16 PMCID:PMC4493381

[33] Hirshfield KM.Triple-negative breast cancer: molecular subtypes and targeted therapy..Curr Opin Obstet Gynecol2014;26:34-40

[34] Malvezzi M,Levi F,Negri E.European cancer mortality predictions for the year 2012..Ann Oncol2012;23:1044-52

[35] Di Leo A,Dieras V,Sotiriou C.New approaches for improving outcomes in breast cancer in Europe..Breast2015;24:321-30

[36] Pantel K.Dissecting the metastatic cascade..Nat Rev Cancer2004;4:448-56

[37] Gupta GP.Cancer metastasis: building a framework..Cell2006;127:679-95

[38] Kang Y.Tumor cell dissemination: emerging biological insights from animal models and cancer patients..Cancer Cell2013;23:573-81 PMCID:PMC3667710

[39] Ajani JA,Hochster HS.Cancer stem cells: the promise and the potential..Semin Oncol.2015;42 Suppl 1:S3-17

[40] Beck B.Unravelling cancer stem cell potential..Nat Rev Cancer2013;13:727-38

[41] Magee JA,Morrison SJ.Cancer stem cells: impact, heterogeneity, and uncertainty..Cancer Cell2012;21:283-96 PMCID:PMC4504432

[42] Lytle NK,Reya T.Stem cell fate in cancer growth, progression and therapy resistance..Nat Rev Cancer2018;18:669-80

[43] Monteiro J.Cancer stemness and metastasis: therapeutic consequences and perspectives..Eur J Cancer2010;46:1198-203

[44] Allan AL,Tuck AB.Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis..Breast Dis2006;26:87-98

[45] Wilson A.Bone-marrow haematopoietic-stem-cell niches..Nat Rev Immunol2006;6:93-106

[46] Valastyan S.Tumor metastasis: molecular insights and evolving paradigms..Cell2011;147:275-92 PMCID:PMC3261217

[47] Lambert AW,Weinberg RA.Emerging biological principles of metastasis..Cell2017;168:670-91 PMCID:PMC5308465

[48] Badve S.Breast-cancer stem cells-beyond semantics..Lancet Oncol2012;13:e43-8

[49] Antoniou A,Dom G,Maenhaut C.Cancer stem cells, a fuzzy evolving concept: a cell population or a cell property?.Cell Cycle2013;12:3743-8 PMCID:PMC3905066

[50] Huang Z,Liu AY.Differentiation and transdifferentiation potentials of cancer stem cells..Oncotarget2015;6:39550-63 PMCID:PMC4741845

[51] Bai X,Beretov J,Li Y.Cancer stem cell in breast cancer therapeutic resistance..Cancer Treat Rev2018;69:152-63

[52] Smalley M,Clarkson R.Breast cancer stem cells: obstacles to therapy..Cancer Lett2013;338:57-62

[53] Luo M,Wicha MS.Epithelial-mesenchymal plasticity of breast cancer stem cells: implications for metastasis and therapeutic resistance..Curr Pharm Des2015;21:1301-10 PMCID:PMC4498673

[54] Margaryan NV,Seftor REB.Targeting the stem cell properties of adult breast cancer cells: using combinatorial strategies to overcome drug resistance..Curr Mol Biol Rep2017;3:159-64 PMCID:PMC5687579

[55] Pinto CA,Waltham M.Breast cancer stem cells and epithelial mesenchymal plasticity - Implications for chemoresistance..Cancer Lett2013;341:56-62

[56] Hong D,Zaidi SK,Nickerson JA.Epithelial-to-mesenchymal transition and cancer stem cells contribute to breast cancer heterogeneity..J Cell Physiol2018;233:9136-44 PMCID:PMC6185773

[57] Morel AP,Thomas C,Ansieau S.Generation of breast cancer stem cells through epithelial-mesenchymal transition..PLoS One2008;3:e2888 PMCID:PMC2492808

[58] Vanharanta S.Origins of metastatic traits..Cancer Cell2013;24:410-21 PMCID:PMC3998120

[59] Greaves M.Clonal evolution in cancer..Nature2012;481:306-13 PMCID:PMC3367003

[60] Klein CA.Parallel progression of primary tumours and metastases..Nat Rev Cancer2009;9:302-12

[61] Reeves MQ,Harris S,Balmain A.Multicolour lineage tracing reveals clonal dynamics of squamous carcinoma evolution from initiation to metastasis..Nat Cell Biol2018;20:699-709 PMCID:PMC6400587

[62] Reiter JG,Gerold JM,Attiyeh MA.Minimal functional driver gene heterogeneity among untreated metastases..Science2018;361:1033-7 PMCID:PMC6329287

[63] Yachida S,Bozic I,Leary R.Distant metastasis occurs late during the genetic evolution of pancreatic cancer..Nature2010;467:1114-7 PMCID:PMC3148940

[64] Leung ML,Gao R,Wang Y.Single-cell DNA sequencing reveals a late-dissemination model in metastatic colorectal cancer..Genome Res2017;27:1287-99 PMCID:PMC5538546

[65] Desmedt C,Kulka J.Catalog of genetic progression of human cancers: breast cancer..Cancer Metastasis Rev2016;35:49-62

[66] Brown D,Szekely B,Szasz AM.Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations..Nat Commun2017;8:14944 PMCID:PMC5474888

[67] Yates LR,Wedge D,Gonzalez S.Genomic evolution of breast cancer metastasis and relapse..Cancer Cell2017;32:169-84.e7 PMCID:PMC5559645

[68] Kroigard AB,Laenkholm AV,Jensen JD.Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis..Oncotarget2015;6:5634-49 PMCID:PMC4467391

[69] Weckermann D,Ragg T,Schlimok G.Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer..J Clin Oncol2009;27:1549-56

[70] Stoecklein NH,Bezler M,Hartmann CH.Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer..Cancer Cell2008;13:441-53

[71] Schmidt-Kittler O,Daskalakis A,Ahr A.From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression..Proc Natl Acad Sci U S A2003;100:7737-42 PMCID:PMC164657

[72] Schardt JA,Hartmann CH,Schmidt-Kittler O.Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer..Cancer Cell2005;8:227-39

[73] Biondini M,Meyer-Schaller N,Camonis J.RalB regulates contractility-driven cancer dissemination upon TGFbeta stimulation via the RhoGEF GEF-H1..Sci Rep2015;5:11759 PMCID:PMC4495419

[74] Oft M,Balmain A.Metastasis is driven by sequential elevation of H-ras and Smad2 levels..Nat Cell Biol2002;4:487-94

[75] Ansieau S,Doreau A,Bouchet BP.Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence..Cancer Cell2008;14:79-89

[76] Naxerova K.Using tumour phylogenetics to identify the roots of metastasis in humans..Nat Rev Clin Oncol2015;12:258-72

[77] Harper KL,Entenberg D,Cheung JF.Mechanism of early dissemination and metastasis in Her2+ mammary cancer..Nature2016;540:588-92 PMCID:PMC5471138

[78] Marshall E.Cancer research and the $90 billion metaphor..Science2011;331:1540-1

[79] Dagogo-Jack I.Tumour heterogeneity and resistance to cancer therapies..Nat Rev Clin Oncol2018;15:81-94

[80] Meacham CE.Tumour heterogeneity and cancer cell plasticity..Nature2013;501:328-37 PMCID:PMC4521623

[81] Marusyk A,Altrock PM,Michor F.Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity..Nature2014;514:54-8 PMCID:PMC4184961

[82] Aceto N,Miyamoto DT,Wittner BS.Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis..Cell2014;158:1110-22 PMCID:PMC4149753

[83] Gkountela S,Szczerba BM,Landin J.Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding..Cell2019;176:98-112.e14 PMCID:PMC6363966

[84] Kmieciak M,Wang XY.IFN-gamma Ralpha is a key determinant of CD8+ T cell-mediated tumor elimination or tumor escape and relapse in FVB mouse..PLoS One2013;8:e82544 PMCID:PMC3855782

[85] Demicheli R.Tumour dormancy: findings and hypotheses from clinical research on breast cancer..Semin Cancer Biol2001;11:297-306

[86] Demicheli R,Hrushesky WJ.Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures..Nat Clin Pract Oncol2007;4:699-710

[87] Endo H.Dormancy in cancer..Cancer Sci2019;110:474-80 PMCID:PMC6361606

[88] Demicheli R,Boracchi P,Retsky MW.Recurrence dynamics does not depend on the recurrence site..Breast Cancer Res2008;10:R83 PMCID:PMC2614518

[89] Dillekas H,Ardoino I,Biganzoli E.The recurrence pattern following delayed breast reconstruction after mastectomy for breast cancer suggests a systemic effect of surgery on occult dormant micrometastases..Breast Cancer Res Treat2016;158:169-78 PMCID:PMC4937089

[90] Hanin L.Does extirpation of the primary breast tumor give boost to growth of metastases? Evidence revealed by mathematical modeling..Math Biosci2010;223:133-41

[91] Manjili MH.Tumor dormancy and relapse: from a natural byproduct of evolution to a disease state..Cancer Res2017;77:2564-9 PMCID:PMC5459601

[92] Gelao L,Fumagalli L,Manunta S.Tumour dormancy and clinical implications in breast cancer..Ecancermedicalscience2013;7:320 PMCID:PMC3660156

[93] Rancoita PM,Demicheli R,Di Serio C.Tumor dormancy and frailty models: a novel approach..Biometrics2017;73:260-70

[94] Klein CA.Systemic cancer progression and tumor dormancy: mathematical models meet single cell genomics..Cell Cycle2006;5:1788-98

[95] Klauber-DeMore N,Linkov I,Gerald WL.Biological behavior of human breast cancer micrometastases..Clin Cancer Res2001;7:2434-9

[96] Naumov GN,Weinmeister PM,Nadkarni KV.Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy..Cancer Res2002;62:2162-8

[97] Goodison S,Hihara J,Yang M.Prolonged dormancy and site-specific growth potential of cancer cells spontaneously disseminated from nonmetastatic breast tumors as revealed by labeling with green fluorescent protein..Clin Cancer Res2003;9:3808-14

[98] Makita M,Ogiya A,Morizono H.Optimal surveillance for postoperative metastasis in breast cancer patients..Breast Cancer2016;23:286-94

[99] Aguirre-Ghiso JA.Models, mechanisms and clinical evidence for cancer dormancy..Nat Rev Cancer2007;7:834-46 PMCID:PMC2519109

[100] Hensel JA,Theodorescu D.Clinical opportunities and challenges in targeting tumour dormancy..Nat Rev Clin Oncol2013;10:41-51

[101] Dittmer J.Mechanisms governing metastatic dormancy in breast cancer..Semin Cancer Biol2017;44:72-82

[102] Paez D,Bohanes P,Benhanim L.Cancer dormancy: a model of early dissemination and late cancer recurrence..Clin Cancer Res2012;18:645-53

[103] Giancotti FG.Mechanisms governing metastatic dormancy and reactivation..Cell2013;155:750-64 PMCID:PMC4354734

[104] Aguirre-Ghiso JA,Mignatti A,Ossowski L.Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo..Mol Biol Cell2001;12:863-79 PMCID:PMC32272

[105] Osisami M.Mechanisms of Metastatic Tumor Dormancy..J Clin Med2013;2:136-50 PMCID:PMC4470233

[106] Sosa MS,Maia AG,Bosch A.NR2F1 controls tumour cell dormancy via SOX9- and RARbeta-driven quiescence programmes..Nat Commun2015;6:6170 PMCID:PMC4313575

[107] Borgen E,Sosa MS,Schlichting E.NR2F1 stratifies dormant disseminated tumor cells in breast cancer patients..Breast Cancer Res2018;20:120 PMCID:PMC6190561

[108] Aguirre-Ghiso JA,Liu D.ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK)..Cancer Res2003;63:1684-95

[109] Jo H,Subramanian KK,Luo HR.Cancer cell-derived clusterin modulates the phosphatidylinositol 3'-kinase-Akt pathway through attenuation of insulin-like growth factor 1 during serum deprivation..Mol Cell Biol2008;28:4285-99 PMCID:PMC2447147

[110] Vera-Ramirez L,Nini R,Green JE.Autophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence..Nat Commun2018;9:1944 PMCID:PMC5964069

[111] Lu Z,Lu Y,Yu Q.The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells..J Clin Invest2008;118:3917-29 PMCID:PMC2582930

[112] Balz LM,Andreas A,Niggemann B.The interplay of HER2/HER3/PI3K and EGFR/HER2/PLC-gamma1 signalling in breast cancer cell migration and dissemination..J Pathol2012;227:234-44

[113] Amaravadi RK.Autophagy-induced tumor dormancy in ovarian cancer..J Clin Invest2008;118:3837-40 PMCID:PMC2582935

[114] Schewe DM.ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo..Proc Natl Acad Sci U S A2008;105:10519-24 PMCID:PMC2492459

[115] Malladi S,Jin X,Basnet H.Metastatic latency and immune evasion through autocrine inhibition of WNT..Cell2016;165:45-60 PMCID:PMC4808520

[116] Barkan D,Chambers AF.Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth..Eur J Cancer2010;46:1181-8 PMCID:PMC2856784

[117] Walker ND,Munoz JL,Guiro K.The bone marrow niche in support of breast cancer dormancy..Cancer Lett2016;380:263-71

[118] Korah R,Wieder R.Integrin alpha5beta1 promotes survival of growth-arrested breast cancer cells: an in vitro paradigm for breast cancer dormancy in bone marrow..Cancer Res2004;64:4514-22

[119] Wheeler SE,Taylor DP,Pillai VC.Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system..Br J Cancer2014;111:2342-50 PMCID:PMC4264444

[120] Clark AM,Young CL,Shepard Neiman J.A liver microphysiological system of tumor cell dormancy and inflammatory responsiveness is affected by scaffold properties..Lab Chip2016;17:156-68 PMCID:PMC5242229

[121] El Touny LH,Mendoza A,Hoenerhoff MJ.Combined SFK/MEK inhibition prevents metastatic outgrowth of dormant tumor cells..J Clin Invest2014;124:156-68 PMCID:PMC3871237

[122] Ghajar CM,Mori H,Evason KJ.The perivascular niche regulates breast tumour dormancy..Nat Cell Biol2013;15:807-17 PMCID:PMC3826912

[123] Sriram R,Pryce B,Mears AJ.Loss of periostin/OSF-2 in ErbB2/Neu-driven tumors results in androgen receptor-positive molecular apocrine-like tumors with reduced Notch1 activity..Breast Cancer Res2015;17:7 PMCID:PMC4355979

[124] Pontier SM.Integrins in breast cancer dormancy..APMIS2008;116:677-84

[125] Barkan D.beta1-integrin: a potential therapeutic target in the battle against cancer recurrence..Clin Cancer Res2011;17:7219-23

[126] Sosa MS,Debnath J.Regulation of tumor cell dormancy by tissue microenvironments and autophagy..Adv Exp Med Biol2013;734:73-89 PMCID:PMC3651695

[127] Aqbi HF,Keim RC,Thekkudan T.Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy..Oncotarget2018;9:22113-22 PMCID:PMC5955162

[128] Tierney MT.Inducing and evaluating skeletal muscle injury by notexin and barium chloride..Methods Mol Biol2016;1460:53-60

[129] Agudo J,Rose SA,Sweeney R.Quiescent tissue stem cells evade immune surveillance..Immunity2018;48:271-85.e5 PMCID:PMC5824652

[130] Trumpp A,Wilson A.Awakening dormant haematopoietic stem cells..Nat Rev Immunol2010;10:201-9

[131] Aguirre-Ghiso JA.How dormant cancer persists and reawakens..Science2018;361:1314-5 PMCID:PMC6415964

[132] Hayflick L.The biology of human aging..Am J Med Sci1973;265:432-45

[133] Roninson IB.Tumor cell senescence in cancer treatment..Cancer Res2003;63:2705-15

[134] Campisi J.Cellular senescence as a tumor-suppressor mechanism..Trends Cell Biol2001;11:S27-31

[135] Campisi J.Cell biology: the beginning of the end..Nature2014;505:35-6 PMCID:PMC4167797

[136] Campisi J.Aging, cellular senescence, and cancer..Annu Rev Physiol2013;75:685-705 PMCID:PMC4166529

[137] Di Leonardo A,Clarkin K.DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts..Genes Dev1994;8:2540-51

[138] Schmitt CA,Yang M,Baranov E.A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy..Cell2002;109:335-46

[139] Braig M,Loddenkemper C,Peters AH.Oncogene-induced senescence as an initial barrier in lymphoma development..Nature2005;436:660-5

[140] Collado M,Efeyan A,Schuhmacher AJ.Tumour biology: senescence in premalignant tumours..Nature2005;436:642

[141] Land H,Weinberg RA.Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes..Nature1983;304:596-602

[142] Serrano M,McCurrach ME,Lowe SW.Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a..Cell1997;88:593-602

[143] Beausejour CM,Galimi F,Lowe SW.Reversal of human cellular senescence: roles of the p53 and p16 pathways..EMBO J2003;22:4212-22 PMCID:PMC175806

[144] Mu XC,Higgins PJ.Increased transcription and modified growth state-dependent expression of the plasminogen activator inhibitor type-1 gene characterize the senescent phenotype in human diploid fibroblasts..J Cell Physiol1998;174:90-8

[145] McConnell BB,Brookes S.Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts..Curr Biol1998;8:351-4

[146] Zou W.Immunosuppressive networks in the tumour environment and their therapeutic relevance..Nat Rev Cancer2005;5:263-74

[147] Metcalf D.The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors..Blood1986;67:257-67

[148] Braumüller H,Brenner E,Hahn M.T-helper-1-cell cytokines drive cancer into senescence..Nature2013;494:361-5

[149] Bragado P,Keely P,Aguirre-Ghiso JA.Microenvironments dictating tumor cell dormancy..Recent Results Cancer Res2012;195:25-39 PMCID:PMC3516301

[150] Naumov GN,Straume O.Tumor dormancy due to failure of angiogenesis: role of the microenvironment..Clin Exp Metastasis2009;26:51-60

[151] Kienast Y,Fuhrmann M,Goldbrunner R.Real-time imaging reveals the single steps of brain metastasis formation..Nat Med2010;16:116-22

[152] Bergers G.Tumorigenesis and the angiogenic switch..Nat Rev Cancer2003;3:401-10

[153] Carmeliet P.Molecular mechanisms and clinical applications of angiogenesis..Nature2011;473:298-307 PMCID:PMC4049445

[154] Indraccolo S.Insights into the regulation of tumor dormancy by angiogenesis in experimental tumors..Adv Exp Med Biol2013;734:37-52

[155] Indraccolo S,Amadori A.Dormant tumors awaken by a short-term angiogenic burst: the spike hypothesis..Cell Cycle2006;5:1751-5

[156] Gao D,Mellick AS,McDonnell K.Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis..Science2008;319:195-8

[157] Laurent J,Botta F,Ruegg C.Emerging paradigms and questions on pro-angiogenic bone marrow-derived myelomonocytic cells..Int J Dev Biol2011;55:527-34

[158] Qian BZ.Macrophage diversity enhances tumor progression and metastasis..Cell2010;141:39-51 PMCID:PMC4994190

[159] DeNardo DG,Andreu P,Tawfik D.CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages..Cancer Cell2009;16:91-102 PMCID:PMC2778576

[160] Zhang XH,Gerald W,Norton L.Latent bone metastasis in breast cancer tied to Src-dependent survival signals..Cancer Cell2009;16:67-78 PMCID:PMC2749247

[161] Bragado P,Parikh F,Capobianco C.TGF-beta2 dictates disseminated tumour cell fate in target organs through TGF-beta-RIII and p38alpha/beta signalling..Nat Cell Biol2013;15:1351-61 PMCID:PMC4006312

[162] Lu X,Wei Y,Yang Q.VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors..Cancer Cell2011;20:701-14 PMCID:PMC3241854

[163] Sosnoski DM,Grove CD,Mastro AM.Dormancy and growth of metastatic breast cancer cells in a bone-like microenvironment..Clin Exp Metastasis2015;32:335-44

[164] Dunn GP,Ikeda H,Schreiber RD.Cancer immunoediting: from immunosurveillance to tumor escape..Nat Immunol2002;3:991-8

[165] Schreiber RD,Smyth MJ.Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion..Science2011;331:1565-70

[166] Teng MW,Koebel CM,Smyth MJ.Immune-mediated dormancy: an equilibrium with cancer..J Leukoc Biol2008;84:988-93

[167] Tuccitto A,Vergani E,Huber V.Immunosuppressive circuits in tumor microenvironment and their influence on cancer treatment efficacy..Virchows Arch2019;474:407-20

[168] Najafi M,Farhood B,Solhjoo S.Tumor microenvironment: Interactions and therapy..J Cell Physiol2019;234:5700-21

[169] Groth C,Weber R,Altevogt P.Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression..Br J Cancer2019;120:16-25

[170] Bates JP,Jones L.Mechanisms of immune evasion in breast cancer..BMC Cancer2018;18:556 PMCID:PMC5948714

[171] Pommier A,Memos N,Gouronnec A.Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases..Science2018;360:eaao4908

[172] Matser YAH,Nadalin S,de Boer J.Transmission of breast cancer by a single multiorgan donor to 4 transplant recipients..Am J Transplant2018;18:1810-4

[173] Motz GT.The parallel lives of angiogenesis and immunosuppression: cancer and other tales..Nat Rev Immunol2011;11:702-11

[174] Griffioen AW.Angiostasis as a way to improve immunotherapy..Thromb Haemost2009;101:1025-31

[175] De Sanctis F,Facciponte J.The dark side of tumor-associated endothelial cells..Semin Immunol2018;35:35-47

[176] Khan KA.Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa..Nat Rev Clin Oncol2018;15:310-24

[177] Chen DS.Combinations of bevacizumab with cancer immunotherapy..Cancer J2018;24:193-204

[178] Gabrilovich DI,Girgis KR,Meny GM.Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells..Nat Med1996;2:1096-103

[179] Bai WK,Hu B.Vascular endothelial growth factor suppresses dendritic cells function of human prostate cancer..Onco Targets Ther2018;11:1267-74 PMCID:PMC5846303

[180] Shi Y,Zeng D,Lei X.Suppression of vascular endothelial growth factor abrogates the immunosuppressive capability of murine gastric cancer cells and elicits antitumor immunity..FEBS J2014;281:3882-93

[181] Secondini C,Spagnuolo L,Peyvandi S.Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade..Oncoimmunology2017;6:e1316437 PMCID:PMC5486183

[182] Schmittnaegel M,Kadioglu E,Wyser Rmili C.Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade..Sci Transl Med2017;9:eaak9670

[183] Schmittnaegel M.Reprogramming tumor blood vessels for enhancing immunotherapy..Trends Cancer2017;3:809-12

[184] Goddard ET,Riddell SR.Dormant tumour cells, their niches and the influence of immunity..Nat Cell Biol2018;20:1240-9

[185] Ghajar CM.Metastasis prevention by targeting the dormant niche..Nat Rev Cancer2015;15:238-47 PMCID:PMC4842412

[186] Bedard PL,Piccart-Gebhart MJ.Taxanes: optimizing adjuvant chemotherapy for early-stage breast cancer..Nat Rev Clin Oncol2010;7:22-36

[187] Schuetz F.Adjuvant systemic therapy of breast cancer..Breast Care (Basel)2011;6:179-83 PMCID:PMC3132964

[188] Ejlertsen B.Adjuvant chemotherapy in early breast cancer..Dan Med J2016;63:

[189] Hosseini H,Hoffmann M,Sosa MS.Early dissemination seeds metastasis in breast cancer..Nature2016; PMCID:PMC5390864

[190] Touil Y,Corvaisier M,Vandomme J.Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis..Clin Cancer Res2014;20:837-46 PMCID:PMC4387277

[191] Ebinger S,Ziegenhain C,Castro Alves C.Characterization of rare, dormant, and therapy-resistant cells in acute lymphoblastic leukemia..Cancer Cell2016;30:849-62 PMCID:PMC5156313

[192] Pal D,Vormoor J.Dormancy stems the tide of chemotherapy..Cancer Cell2016;30:825-6

[193] Wu FH,Li XL,Liu H.Characterization and functional analysis of a slow-cycling subpopulation in colorectal cancer enriched by cell cycle inducer combined chemotherapy..Oncotarget2017;8:78466-79 PMCID:PMC5667975

[194] Keeratichamroen S,Svasti J.Mechanism of ECM-induced dormancy and chemoresistance in A549 human lung carcinoma cells..Oncol Rep2018;39:1765-74

[195] Nakamura T,Jono H,Ueda M.Intrinsic TGF-beta2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance and a slow-cycling state in bone marrow-disseminated tumor cells..Oncotarget2015;6:1008-19 PMCID:PMC4359213

[196] Quayle LA,Holen I.Chemotherapy resistance and stemness in mitotically quiescent human breast cancer cells identified by fluorescent dye retention..Clin Exp Metastasis2018;35:831-46 PMCID:PMC6267670

[197] Steg AD,Katre AA,Dobbin ZC.Stem cell pathways contribute to clinical chemoresistance in ovarian cancer..Clin Cancer Res2012;18:869-81 PMCID:PMC3271164

[198] McCubrey JA,Fitzgerald TL,Martelli AM.Roles of signaling pathways in drug resistance, cancer initiating cells and cancer progression and metastasis..Adv Biol Regul2015;57:75-101

[199] Takebe N,Harris PJ,Bando H.Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update..Nat Rev Clin Oncol2015;12:445-64 PMCID:PMC4520755

[200] Schoning JP,Gu W.Drug resistance and cancer stem cells: the shared but distinct roles of hypoxia-inducible factors HIF1alpha and HIF2alpha..Clin Exp Pharmacol Physiol2017;44:153-61

[201] Pan ST,He ZX,Zhou SF.Molecular mechanisms for tumour resistance to chemotherapy..Clin Exp Pharmacol Physiol2016;43:723-37

[202] Kolenda J,Aaberg-Jessen C,Andersen C.Effects of hypoxia on expression of a panel of stem cell and chemoresistance markers in glioblastoma-derived spheroids..J Neurooncol2011;103:43-58

[203] He M,Jiang Q,Han L.Hypoxia-inducible factor-2alpha directly promotes BCRP expression and mediates the resistance of ovarian cancer stem cells to adriamycin..Mol Oncol2019;13:403-21 PMCID:PMC6360369

[204] Maugeri-Sacca M,De Maria R.Cancer stem cells and chemosensitivity..Clin Cancer Res2011;17:4942-7

[205] Crowder SW,Hwang YS.Cancer Stem Cells under Hypoxia as a Chemoresistance Factor in Breast and Brain..Curr Pathobiol Rep2014;2:33-40 PMCID:PMC3935368

[206] Yan Y,Han L,Chen J.HIF-2alpha promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways..J Exp Clin Cancer Res2018;37:256 PMCID:PMC6194720

[207] Uribe D,Rocha JD,Oyarzun C.Multidrug resistance in glioblastoma stem-like cells: role of the hypoxic microenvironment and adenosine signaling..Mol Aspects Med2017;55:140-51

[208] Qin J,Lu Y,Li M.Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression..Sci Rep2017;7:10592 PMCID:PMC5587562

[209] Doktorova H,Khalil MA.Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1..Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub2015;159:166-77

[210] Stanton SE.Clinical significance of tumor-infiltrating lymphocytes in breast cancer..J Immunother Cancer2016;4:59 PMCID:PMC5067916

[211] Dushyanthen S,Savas P,Zhou C.Relevance of tumor-infiltrating lymphocytes in breast cancer..BMC Med2015;13:202 PMCID:PMC4547422

[212] de Melo Gagliato D,Curigliano G,Denkert C.Tumor-infiltrating lymphocytes in Breast Cancer and implications for clinical practice..Biochim Biophys Acta Rev Cancer2017;1868:527-37

[213] Kroemer G,Galluzzi L,Zitvogel L.Natural and therapy-induced immunosurveillance in breast cancer..Nat Med2015;21:1128-38

[214] Galluzzi L,Kepp O,Kroemer G.Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents..Cancer Cell2015;28:690-714

[215] Loi S,Salgado R,Jose V.Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial..Ann Oncol2014;25:1544-50

[216] Lee HJ,Song IH,Kim JY.Tertiary lymphoid structures: prognostic significance and relationship with tumour-infiltrating lymphocytes in triple-negative breast cancer..J Clin Pathol2016;69:422-30

[217] Wang K,Zhang T.Tumor-infiltrating lymphocytes in breast cancer predict the response to chemotherapy and survival outcome: a meta-analysis..Oncotarget2016;7:44288-98 PMCID:PMC5190096

[218] Adams S,Demaria S,Perez EA.Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199..J Clin Oncol2014;32:2959-66 PMCID:PMC4162494

[219] Salgado R,Demaria S,Klauschen F.The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014..Ann Oncol2015;26:259-71 PMCID:PMC6267863

[220] Forero A,Chen D,Updike KL.Expression of the MHC class II pathway in triple-negative breast cancer tumor cells is associated with a good prognosis and infiltrating lymphocytes..Cancer Immunol Res2016;4:390-9 PMCID:PMC4878913

[221] Ladoire S,Apetoh L,Martin F.Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells..Clin Cancer Res2008;14:2413-20

[222] Luen SJ,Fox SB,Loi S.Tumour-infiltrating lymphocytes and the emerging role of immunotherapy in breast cancer..Pathology2017;49:141-55

[223] Ma Y,Yang H,Hannani D.ATP-dependent recruitment, survival and differentiation of dendritic cell precursors in the tumor bed after anticancer chemotherapy..Oncoimmunology2013;2:e24568 PMCID:PMC3716753

[224] Ma Y,Mattarollo SR,Aymeric L.Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells..Immunity2013;38:729-41

[225] Acharyya S,Vanharanta S,Kim J.A CXCL1 paracrine network links cancer chemoresistance and metastasis..Cell2012;150:165-78 PMCID:PMC3528019

[226] Lan Q,Duffey N,Barras D.Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer..Oncogene2018;

[227] Sistigu A,Vacchelli E,Enot DP.Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy..Nat Med2014;20:1301-9

[228] Legrier ME,Gaston J,Yvonnet V.Activation of IFN/STAT1 signalling predicts response to chemotherapy in oestrogen receptor-negative breast cancer..Br J Cancer2016;114:177-87 PMCID:PMC4815803

[229] Sisirak V,Gobert M,Vey N.Impaired IFN-alpha production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression..Cancer Res2012;72:5188-97

[230] Ignatiadis M,Desmedt C,Criscitiello C.Gene modules and response to neoadjuvant chemotherapy in breast cancer subtypes: a pooled analysis..J Clin Oncol2012;30:1996-2004

[231] Desmedt C,Wirapati P,Larsimont D.Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes..Clin Cancer Res2008;14:5158-65

[232] Bidwell BN,Withana NP,Cao Y.Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape..Nat Med2012;18:1224-31

[233] Liu Y,Liu J,Jin X.STAT3/p53 pathway activation disrupts IFN-beta-induced dormancy in tumor-repopulating cells..J Clin Invest2018;128:1057-73 PMCID:PMC5824876

[234] Dunn GP,Schreiber RD.Interferons, immunity and cancer immunoediting..Nat Rev Immunol2006;6:836-48

[235] Muller-Hermelink N,Pichler B,Mailhammer R.TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis..Cancer Cell2008;13:507-18

[236] Dormond O,Ruegg C.Modulation of cdk2, cyclin D1, p16INK4a, p21WAF and p27Kip1 expression in endothelial cells by TNF/IFN gamma..Anticancer Res2002;22:3159-63

[237] Retsky MW,Hrushesky WJ,Gukas ID.Dormancy and surgery-driven escape from dormancy help explain some clinical features of breast cancer..APMIS2008;116:730-41

[238] Retsky M,Hrushesky W,Gukas I.Surgery triggers outgrowth of latent distant disease in breast cancer: an inconvenient truth?.Cancers (Basel)2010;2:305-37 PMCID:PMC3835080

[239] Kelsey CR,Ambrogi F,Boyd JA.Metastasis dynamics for non-small-cell lung cancer: effect of patient and tumor-related factors..Clin Lung Cancer2013;14:425-32

[240] Demicheli R,Ambrogi F,Boyd JA.Recurrence dynamics for non-small-cell lung cancer: effect of surgery on the development of metastases..J Thorac Oncol2012;7:723-30

[241] Hanin L.Reconstruction of the natural history of metastatic cancer and assessment of the effects of surgery: Gompertzian growth of the primary tumor..Math Biosci2014;247:47-58

[242] Dillekas H,Ardoino I,Biganzoli E.The recurrence pattern following delayed breast reconstruction after mastectomy for breast cancer suggests a systemic effect of surgery on occult dormant micrometastases..Breast Cancer Res Treat2016;158:169-78 PMCID:PMC4937089

[243] Van Dierendonck JH,Cornelisse CJ.Surgically induced cytokinetic responses in experimental rat mammary tumor models..Cancer1991;68:759-67

[244] Abramovitch R,Meir G.Stimulation of tumour angiogenesis by proximal wounds: spatial and temporal analysis by MRI..Br J Cancer1998;77:440-7 PMCID:PMC2151289

[245] Gunduz N,Saffer EA.Effect of surgical removal on the growth and kinetics of residual tumor..Cancer Res1979;39:3861-5

[246] Krall JA,Mercury OA,Brooks MW.The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy..Sci Transl Med2018;10: PMCID:PMC6364295

[247] Danish HH,Taunk NK,Moran MS.Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) as a prognostic marker for local control in T1-2 N0 breast cancer treated with breast-conserving surgery and radiation therapy (BCS + RT)..Breast J2013;19:231-9 PMCID:PMC5523984

[248] De Cock JM,Dongre A,Reinhardt F.Inflammation triggers Zeb1-dependent escape from tumor latency..Cancer Res2016;76:6778-84 PMCID:PMC5135644

[249] Albrengues J,Ng D,Ambrico A.Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice..Science2018;361:

[250] Okubo M,Nakashima H,Mitsudo K.M2-polarized macrophages contribute to neovasculogenesis, leading to relapse of oral cancer following radiation..Sci Rep2016;6:27548 PMCID:PMC4897643

[251] Machida H,Takiuchi T,Tierney KE.Significance of monocyte counts at recurrence on survival outcome of women with endometrial cancer..Int J Gynecol Cancer2017;27:302-10

[252] Bowers LW,Brenner AJ,Hursting SD.NSAID use reduces breast cancer recurrence in overweight and obese women: role of prostaglandin-aromatase interactions..Cancer Res2014;74:4446-57

[253] Pierce BL,Bernstein L,Neuhouser ML.Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients..J Clin Oncol2009;27:3437-44 PMCID:PMC2717751

[254] Retsky M,Demicheli R,Gukas I.NSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: particular relevance to triple negative subgroup..Breast Cancer Res Treat2012;134:881-8

[255] Desmedt C,Fornili M,Duca M.Potential Benefit of Intra-operative Administration of Ketorolac on Breast Cancer Recurrence According to the Patient's Body Mass Index..J Natl Cancer Inst2018;110:1115-22

[256] Recasens A.Targeting cancer cell dormancy..Trends Pharmacol Sci2019;40:128-41

[257] Li J,Wang X,Zhang L.Dormant cells: the original cause of tumor recurrence and metastasis..Cell Biochem Biophys2015;72:317-20

[258] Cuzick J,Baron JA,Burn J.Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement..Lancet Oncol2009;10:501-7

[259] Stagg J,Loi S.Immunomodulation via chemotherapy and targeted therapy: a new paradigm in breast cancer therapy?.Breast Care (Basel)2012;7:267-72 PMCID:PMC3515790

[260] Miolo G,Martorelli D,Scalone S.Anthracycline-free neoadjuvant therapy induces pathological complete responses by exploiting immune proficiency in HER2+ breast cancer patients..BMC Cancer2014;14:954 PMCID:PMC4302069

[261] Wang BX,Fish EN.Interferon: current status and future prospects in cancer therapy..J Interferon Cytokine Res2011;31:545-52

[262] Brockwell NK.Tumor inherent interferons: impact on immune reactivity and immunotherapy..Cytokine2018;

[263] Ramos MC,Tirone NR,Murta EF.The clinical use of type 1 interferon in gynecology..Eur J Gynaecol Oncol2010;31:145-50

[264] Corrales L.Molecular pathways: targeting the stimulator of interferon genes (STING) in the immunotherapy of cancer..Clin Cancer Res2015;21:4774-9 PMCID:PMC4750108

[265] Alsaab HO,Alzhrani R,Bhise K.PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome..Front Pharmacol2017;8:561 PMCID:PMC5572324

[266] Vikas P,Zhang W.The clinical promise of immunotherapy in triple-negative breast cancer..Cancer Manag Res2018;10:6823-33 PMCID:PMC6292225

[267] Schutz F,Mayer L,Domschke C.PD-1/PD-L1 pathway in breast cancer..Oncol Res Treat2017;40:294-7

[268] Bianchini G,Pienkowski T,Bianchi GV.Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial..Ann Oncol2015;26:2429-36

[269] Sanchez K,McArthur HL.Immunotherapy in breast cancer: an overview of modern checkpoint blockade strategies and vaccines..Curr Probl Cancer2016;40:151-62

[270] Brockwell NK,Zanker D,Rautela J.Neoadjuvant interferons: critical for effective PD-1-based immunotherapy in TNBC..Cancer Immunol Res2017;5:871-84

[271] Alix-Panabieres C.Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy..Cancer Discov2016;6:479-91

[272] Spiliotaki M,Kapranou K,Kallergi G.Evaluation of proliferation and apoptosis markers in circulating tumor cells of women with early breast cancer who are candidates for tumor dormancy..Breast Cancer Res2014;16:485 PMCID:PMC4303210

[273] Vishnoi M,Yin W,George GC.The isolation and characterization of CTC subsets related to breast cancer dormancy..Sci Rep2015;5:17533 PMCID:PMC4668355

[274] Shaw JA,Blighe K,Guttery D.Genomic analysis of circulating cell-free DNA infers breast cancer dormancy..Genome Res2012;22:220-31 PMCID:PMC3266030

[275] Perez-Rivas LG,Fernandez-De Sousa CE,Quero C.Serum protein levels following surgery in breast cancer patients: a protein microarray approach..Int J Oncol2012;41:2200-6