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01-12-2021 | Doxycycline | Research article

Cellular dormancy in minimal residual disease following targeted therapy

Authors: Jason R. Ruth, Dhruv K. Pant, Tien-chi Pan, Hans E. Seidel, Sanjeethan C. Baksh, Blaine A. Keister, Rita Singh, Christopher J. Sterner, Suzanne J. Bakewell, Susan E. Moody, George K. Belka, Lewis A. Chodosh

Published in: Breast Cancer Research | Issue 1/2021

Abstract

Background

Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes.

Methods

To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties.

Results

We demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy.

Conclusions

Residual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence.

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Braun S, Naume B. Circulating and disseminated tumor cells. J Clin Oncol. 2005;23(8):1623–6. https://doi.org/10.1200/JCO.2005.10.073.CrossRefPubMed

Giuliano AE, Hawes D, Ballman KV, Whitworth PW, Blumencranz PW, Reintgen DS, Morrow M, Leitch AM, Hunt KK, McCall LM, et al. Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA. 2011;306(4):385–93. https://doi.org/10.1001/jama.2011.1034.CrossRefPubMedPubMedCentral

Fehm T, Banys M, Rack B, Janni W, Marth C, Blassl C, Hartkopf A, Trope C, Kimmig R, Krawczyk N, Wallwiener D, Wimberger P, Kasimir-Bauer S. Pooled analysis of the prognostic relevance of disseminated tumor cells in the bone marrow of patients with ovarian cancer. Int J Gynecol Cancer. 2013;23(5):839–45. https://doi.org/10.1097/IGC.0b013e3182907109.CrossRefPubMed

Hartkopf AD, Wallwiener M, Fehm TN, Hahn M, Walter CB, Gruber I, Brucker SY, Taran FA. Disseminated tumor cells from the bone marrow of patients with nonmetastatic primary breast cancer are predictive of locoregional relapse. Ann Oncol. 2015;26(6):1155–60. https://doi.org/10.1093/annonc/mdv148.CrossRefPubMed

Demicheli R, Retsky MW, Hrushesky WJ, Baum M. Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures. Nat Clin Pract Oncol. 2007;4(12):699–710. https://doi.org/10.1038/ncponc0999.CrossRefPubMed

Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007;7(11):834–46. https://doi.org/10.1038/nrc2256.CrossRefPubMedPubMedCentral

Vessella RL, Pantel K, Mohla S. Tumor cell dormancy: an NCI workshop report. Cancer Biol Ther. 2007;6(9):1496–504. https://doi.org/10.4161/cbt.6.9.4828.CrossRefPubMed

Pantel K, Alix-Panabieres C, Riethdorf S. Cancer micrometastases. Nat Rev Clin Oncol. 2009;6(6):339–51. https://doi.org/10.1038/nrclinonc.2009.44.CrossRefPubMed

Klein CA. Framework models of tumor dormancy from patient-derived observations. Curr Opin Genet Dev. 2011;21(1):42–9. https://doi.org/10.1016/j.gde.2010.10.011.CrossRefPubMed

10.

Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G, Funke I, Izbicki JR, Riethmuller G. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst. 1993;85(17):1419–24. https://doi.org/10.1093/jnci/85.17.1419.CrossRefPubMed

11.

Karrison TG, Ferguson DJ, Meier P. Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst. 1999;91(1):80–5. https://doi.org/10.1093/jnci/91.1.80.CrossRefPubMed

12.

Braun S, Kentenich C, Janni W, Hepp F, de Waal J, Willgeroth F, Sommer H, Pantel K. Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. J Clin Oncol. 2000;18(1):80–6. https://doi.org/10.1200/JCO.2000.18.1.80.CrossRefPubMed

13.

Muller V, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, Janicke F, Pantel K. Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res. 2005;11(10):3678–85. https://doi.org/10.1158/1078-0432.CCR-04-2469.CrossRefPubMed

14.

Wikman H, Vessella R, Pantel K. Cancer micrometastasis and tumour dormancy. Apmis. 2008;116(7–8):754–70. https://doi.org/10.1111/j.1600-0463.2008.01033.x.CrossRefPubMed

15.

D'Cruz CM, Gunther EJ, Boxer RB, Hartman JL, Sintasath L, Moody SE, Cox JD, Ha SI, Belka GK, Golant A, Cardiff RD, Chodosh LA. c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nat Med. 2001;7(2):235–9. https://doi.org/10.1038/84691.CrossRefPubMed

16.

Moody SE, Sarkisian CJ, Hahn KT, Gunther EJ, Pickup S, Dugan KD, Innocent N, Cardiff RD, Schnall MD, Chodosh LA. Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell. 2002;2(6):451–61. https://doi.org/10.1016/S1535-6108(02)00212-X.CrossRefPubMed

17.

Gunther EJ, Moody SE, Belka GK, Hahn KT, Innocent N, Dugan KD, Cardiff RD, Chodosh LA. Impact of p53 loss on reversal and recurrence of conditional Wnt- induced tumorigenesis. Genes Dev. 2003;17(4):488–501. https://doi.org/10.1101/gad.1051603.CrossRefPubMedPubMedCentral

18.

Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL, Cardiff RD, Chodosh LA. The transcriptional repressor snail promotes mammary tumor recurrence. Cancer Cell. 2005;8(3):197–209. https://doi.org/10.1016/j.ccr.2005.07.009.CrossRefPubMed

19.

D'Cruz CM, Moody SE, Master SR, Hartman JL, Keiper EA, Imielinski MB, Cox JD, Wang JY, Ha SI, Keister BA, et al. Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol Endocrinol. 2002;16(9):2034–51. https://doi.org/10.1210/me.2002-0073.CrossRefPubMed

20.

Sharma SV, Settleman J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 2007;21(24):3214–31. https://doi.org/10.1101/gad.1609907.CrossRefPubMed

21.

Zureikat AH, McKee MD. Targeted therapy for solid tumors: current status. Surg Oncol Clin N Am. 2008;17(2):279–301, vii-viii. https://doi.org/10.1016/j.soc.2008.01.004.CrossRefPubMed

22.

Boxer RB, Jang JW, Sintasath L, Chodosh LA. Lack of sustained regression of c-MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation. Cancer Cell. 2004;6(6):577–86. https://doi.org/10.1016/j.ccr.2004.10.013.CrossRefPubMed

23.

Abravanel DL, Belka GK, Pan TC, Pant DK, Collins MA, Sterner CJ, Chodosh LA. Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy. J Clin Invest. 2015;125(6):2484–96. https://doi.org/10.1172/JCI74883.CrossRefPubMedPubMedCentral

24.

Feng Y, Pan TC, Pant DK, Chakrabarti KR, Alvarez JV, Ruth JR, Chodosh LA. SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. Cancer Discov. 2014;4(7):790–803. https://doi.org/10.1158/2159-8290.CD-13-0548.CrossRefPubMedPubMedCentral

25.

Alvarez JV, Pan TC, Ruth J, Feng Y, Zhou A, Pant D, Grimley JS, Wandless TJ, Demichele A, Chodosh LA. Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Cancer Cell. 2013;24(1):30–44. https://doi.org/10.1016/j.ccr.2013.05.007.CrossRefPubMed

26.

Ecker BL, Lee JY, Sterner CJ, Solomon AC, Pant DK, Shen F, Peraza J, Vaught L, Mahendra S, Belka GK, Pan TC, Schmitz KH, Chodosh LA. Impact of obesity on breast cancer recurrence and minimal residual disease. Breast Cancer Res. 2019;21(1):41. https://doi.org/10.1186/s13058-018-1087-7.CrossRefPubMedPubMedCentral

27.

Fisher B, Anderson S, Fisher ER, Redmond C, Wickerham DL, Wolmark N, Mamounas EP, Deutsch M, Margolese R. Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet. 1991;338(8763):327–31. https://doi.org/10.1016/0140-6736(91)90475-5.CrossRefPubMed

28.

Fortin A, Larochelle M, Laverdiere J, Lavertu S, Tremblay D. Local failure is responsible for the decrease in survival for patients with breast cancer treated with conservative surgery and postoperative radiotherapy. J Clin Oncol. 1999;17(1):101–9. https://doi.org/10.1200/JCO.1999.17.1.101.CrossRefPubMed

29.

Schmoor C, Sauerbrei W, Bastert G, Schumacher M. Role of isolated locoregional recurrence of breast cancer: results of four prospective studies. J Clin Oncol. 2000;18(8):1696–708. https://doi.org/10.1200/JCO.2000.18.8.1696.CrossRefPubMed

30.

Doyle T, Schultz DJ, Peters C, Harris E, Solin LJ. Long-term results of local recurrence after breast conservation treatment for invasive breast cancer. Int J Radiat Oncol Biol Phys. 2001;51(1):74–80. https://doi.org/10.1016/S0360-3016(01)01625-X.CrossRefPubMed

31.

Demicheli R, Bonadonna G, Hrushesky WJ, Retsky MW, Valagussa P. Menopausal status dependence of the timing of breast cancer recurrence after surgical removal of the primary tumour. Breast Cancer Res. 2004;6(6):R689–96. https://doi.org/10.1186/bcr937.CrossRefPubMedPubMedCentral

32.

Demicheli R, Miceli R, Brambilla C, Ferrari L, Moliterni A, Zambetti M, Valagussa P, Bonadonna G. Comparative analysis of breast cancer recurrence risk for patients receiving or not receiving adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF). Data supporting the occurrence of ‘cures’. Breast Cancer Res Treat. 1999;53(3):209–15. https://doi.org/10.1023/A:1006134702484.CrossRefPubMed

33.

Chang HY, Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sorlie T, Dai H, He YD, van't Veer LJ, Bartelink H, 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(10):3738–43. https://doi.org/10.1073/pnas.0409462102.CrossRefPubMedPubMedCentral

34.

Chanrion M, Negre V, Fontaine H, Salvetat N, Bibeau F, Mac Grogan G, Mauriac L, Katsaros D, Molina F, Theillet C, et al. A gene expression signature that can predict the recurrence of tamoxifen-treated primary breast cancer. Clin Cancer Res. 2008;14(6):1744–52. https://doi.org/10.1158/1078-0432.CCR-07-1833.CrossRefPubMedPubMedCentral

35.

Chin K, Devries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo W-L, Lapuk A, Neve RM, Qian Z, Ryder T, et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell. 2006;10(6):529–41. https://doi.org/10.1016/j.ccr.2006.10.009.CrossRefPubMed

36.

Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52. https://doi.org/10.1038/nature10983.CrossRefPubMedPubMedCentral

37.

Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, Viale G, Delorenzi M, Zhang Y, d'Assignies MS, Bergh J, Lidereau R, Ellis P, Harris AL, Klijn JG, Foekens JA, Cardoso F, Piccart MJ, Buyse M, Sotiriou C, TRANSBIG Consortium. Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res. 2007;13(11):3207–14. https://doi.org/10.1158/1078-0432.CCR-06-2765.CrossRefPubMed

38.

Esserman LJ, Berry DA, Cheang MC, Yau C, Perou CM, Carey L, DeMichele A, Gray JW, Conway-Dorsey K, Lenburg ME, et al. Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat. 2012;132(3):1049–62. https://doi.org/10.1007/s10549-011-1895-2.CrossRefPubMed

39.

Hess KR, Anderson K, Symmans WF, Valero V, Ibrahim N, Mejia JA, Booser D, Theriault RL, Buzdar AU, Dempsey PJ, Rouzier R, Sneige N, Ross JS, Vidaurre T, Gómez HL, Hortobagyi GN, Pusztai L. Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol. 2006;24(26):4236–44. https://doi.org/10.1200/JCO.2006.05.6861.CrossRefPubMed

40.

Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J, Lindahl T, Pawitan Y, Hall P, Nordgren H, Wong JEL, Liu ET, Bergh J, Kuznetsov VA, Miller LD. Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res. 2006;66(21):10292–301. https://doi.org/10.1158/0008-5472.CAN-05-4414.CrossRefPubMed

41.

Ma XJ, Wang Z, Ryan PD, Isakoff SJ, Barmettler A, Fuller A, Muir B, Mohapatra G, Salunga R, Tuggle JT, Tran Y, Tran D, Tassin A, Amon P, Wang W, Wang W, Enright E, Stecker K, Estepa-Sabal E, Smith B, Younger J, Balis U, Michaelson J, Bhan A, Habin K, Baer TM, Brugge J, Haber DA, Erlander MG, Sgroi DC. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell. 2004;5(6):607–16. https://doi.org/10.1016/j.ccr.2004.05.015.CrossRefPubMed

42.

Minn AJ, Gupta GP, Padua D, Bos P, Nguyen DX, Nuyten D, Kreike B, Zhang Y, Wang Y, Ishwaran H, Foekens JA, van de Vijver M, Massague J. Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci U S A. 2007;104(16):6740–5. https://doi.org/10.1073/pnas.0701138104.CrossRefPubMedPubMedCentral

43.

Oh DS, Troester MA, Usary J, Hu Z, He X, Fan C, Wu J, Carey LA, Perou CM. Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers. J Clin Oncol. 2006;24(11):1656–64. https://doi.org/10.1200/JCO.2005.03.2755.CrossRefPubMed

44.

Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P, Han X, Holmberg L, Huang F, Klaar S, et al. Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res. 2005;7(6):R953–64. https://doi.org/10.1186/bcr1325.CrossRefPubMedPubMedCentral

45.

Sabatier R, Finetti P, Cervera N, Lambaudie E, Esterni B, Mamessier E, Tallet A, Chabannon C, Extra JM, Jacquemier J, Viens P, Birnbaum D, Bertucci F. A gene expression signature identifies two prognostic subgroups of basal breast cancer. Breast Cancer Res Treat. 2011;126(2):407–20. https://doi.org/10.1007/s10549-010-0897-9.CrossRefPubMed

46.

Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, Lehr HA, Hengstler JG, Kolbl H, Gehrmann M. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 2008;68(13):5405–13. https://doi.org/10.1158/0008-5472.CAN-07-5206.CrossRefPubMed

47.

Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, Nordgren H, Farmer P, Praz V, Haibe-Kains B, Desmedt C, Larsimont D, Cardoso F, Peterse H, Nuyten D, Buyse M, van de Vijver MJ, Bergh J, Piccart M, Delorenzi M. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst. 2006;98(4):262–72. https://doi.org/10.1093/jnci/djj052.CrossRefPubMed

48.

Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, Talantov D, Timmermans M, Meijer-van Gelder ME, Yu J, et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet. 2005;365(9460):671–9. https://doi.org/10.1016/S0140-6736(05)17947-1.CrossRefPubMed

49.

Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4(2):249–64. https://doi.org/10.1093/biostatistics/4.2.249.CrossRefPubMed

50.

Baldi P, Long AD. A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes. Bioinformatics. 2001;17(6):509–19. https://doi.org/10.1093/bioinformatics/17.6.509.CrossRefPubMed

51.

Wertheim GB, Yang TW, Pan TC, Ramne A, Liu Z, Gardner HP, Dugan KD, Kristel P, Kreike B, van de Vijver MJ, et al. The Snf1-related kinase, hunk, is essential for mammary tumor metastasis. Proc Natl Acad Sci U S A. 2009;106(37):15855–60. https://doi.org/10.1073/pnas.0906993106.CrossRefPubMedPubMedCentral

52.

Whitfield ML, Sherlock G, Saldanha AJ, Murray JI, Ball CA, Alexander KE, Matese JC, Perou CM, Hurt MM, Brown PO, Botstein D. Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol Biol Cell. 2002;13(6):1977–2000. https://doi.org/10.1091/mbc.02-02-0030.CrossRefPubMedPubMedCentral

53.

Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, Chi JT, van de Rijn M, Botstein D, Brown PO. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2004;2(2):E7. https://doi.org/10.1371/journal.pbio.0020007.CrossRefPubMedPubMedCentral

54.

Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817–26. https://doi.org/10.1056/NEJMoa041588.CrossRefPubMed

55.

Jerevall PL, Ma XJ, Li H, Salunga R, Kesty NC, Erlander MG, Sgroi DC, Holmlund B, Skoog L, Fornander T, Nordenskjöld B, Stål O. Prognostic utility of HOXB13:IL17BR and molecular grade index in early-stage breast cancer patients from the Stockholm trial. Br J Cancer. 2011;104(11):1762–9. https://doi.org/10.1038/bjc.2011.145.CrossRefPubMedPubMedCentral

56.

van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Bernards R, Friend SH. Expression profiling predicts outcome in breast cancer. Breast Cancer Res. 2002;5(1):57–8.CrossRef

57.

Kim RS, Avivar-Valderas A, Estrada Y, Bragado P, Sosa MS, Aguirre-Ghiso JA, Segall JE. Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. Plos One. 2012;7(4):e35569. https://doi.org/10.1371/journal.pone.0035569.CrossRefPubMedPubMedCentral

58.

Sgroi DC, Carney E, Zarrella E, Steffel L, Binns SN, Finkelstein DM, Szymonifka J, Bhan AK, Shepherd LE, Zhang Y, Schnabel CA, Erlander MG, Ingle JN, Porter P, Muss HB, Pritchard KI, Tu D, Rimm DL, Goss PE. Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker. J Natl Cancer Inst. 2013;105(14):1036–42. https://doi.org/10.1093/jnci/djt146.CrossRefPubMedPubMedCentral

59.

Yau C, Esserman L, Moore DH, Waldman F, Sninsky J, Benz CC. A multigene predictor of metastatic outcome in early stage hormone receptor-negative and triple-negative breast cancer. Breast Cancer Res. 2010;12(5):R85. https://doi.org/10.1186/bcr2753.CrossRefPubMedPubMedCentral

60.

Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol. 2007;8(8):R157. https://doi.org/10.1186/gb-2007-8-8-r157.CrossRefPubMedPubMedCentral

61.

Cheng Q, Chang JT, Gwin WR, Zhu J, Ambs S, Geradts J, Lyerly HK. A signature of epithelial-mesenchymal plasticity and stromal activation in primary tumor modulates late recurrence in breast cancer independent of disease subtype. Breast Cancer Res. 2014;16(4):407. https://doi.org/10.1186/s13058-014-0407-9.CrossRefPubMedPubMedCentral

62.

Ramasamy A, Mondry A, Holmes CC, Altman DG. Key issues in conducting a meta-analysis of gene expression microarray datasets. PLoS Med. 2008;5(9):e184. https://doi.org/10.1371/journal.pmed.0050184.CrossRefPubMedPubMedCentral

63.

Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10(1):101–29. https://doi.org/10.2307/3001666.CrossRef

64.

DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88. https://doi.org/10.1016/0197-2456(86)90046-2.CrossRefPubMed

65.

Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of randomized clinical trials. Stat Med. 1991;10(11):1665–77. https://doi.org/10.1002/sim.4780101105.CrossRefPubMed

66.

Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645–8. https://doi.org/10.1038/367645a0.CrossRefPubMed

67.

Folkman J, Ryeom S. Is oncogene addiction angiogenesis-dependent? Cold Spring Harb Symp Quant Biol. 2005;70(0):389–97. https://doi.org/10.1101/sqb.2005.70.042.CrossRefPubMed

68.

Mayer C, Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene. 2006;25(48):6384–91. https://doi.org/10.1038/sj.onc.1209883.CrossRefPubMed

69.

Aguirre Ghiso JA, Kovalski K, Ossowski L. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol. 1999;147(1):89–104. https://doi.org/10.1083/jcb.147.1.89.CrossRefPubMed

70.

Bragado P, Estrada Y, Parikh F, Krause S, Capobianco C, Farina HG, Schewe DM, Aguirre-Ghiso JA. TGF-beta2 dictates disseminated tumour cell fate in target organs through TGF-beta-RIII and p38alpha/beta signalling. Nat Cell Biol. 2013;15(11):1351–61. https://doi.org/10.1038/ncb2861.CrossRefPubMedPubMedCentral

71.

Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, Almeida D, Koller A, Hajjar KA, Stainier DY, et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013;15(7):807–17. https://doi.org/10.1038/ncb2767.CrossRefPubMedPubMedCentral

72.

Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, Rimm DL, Wong H, Rodriguez A, Herschkowitz JI, Fan C, Zhang X, He X, Pavlick A, Gutierrez MC, Renshaw L, Larionov AA, Faratian D, Hilsenbeck SG, Perou CM, Lewis MT, Rosen JM, Chang JC. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106(33):13820–5. https://doi.org/10.1073/pnas.0905718106.CrossRefPubMedPubMedCentral

73.

Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15. https://doi.org/10.1016/j.cell.2008.03.027.CrossRefPubMedPubMedCentral

74.

Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. Stem cells in normal breast development and breast cancer. Cell Prolif. 2003;36(Suppl 1):59–72. https://doi.org/10.1046/j.1365-2184.36.s.1.6.x.CrossRefPubMedPubMedCentral

75.

Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, Diehn M, Liu H, Panula SP, Chiao E, Dirbas FM, Somlo G, Pera RAR, Lao K, Clarke MF. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell. 2009;138(3):592–603. https://doi.org/10.1016/j.cell.2009.07.011.CrossRefPubMedPubMedCentral

76.

Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645–59. https://doi.org/10.1016/j.cell.2009.06.034.CrossRefPubMedPubMedCentral

77.

Cho RW, Wang X, Diehn M, Shedden K, Chen GY, Sherlock G, Gurney A, Lewicki J, Clarke MF. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors. Stem Cells. 2008;26(2):364–71. https://doi.org/10.1634/stemcells.2007-0440.CrossRefPubMed

78.

Chery L, Lam HM, Coleman I, Lakely B, Coleman R, Larson S, Aguirre-Ghiso JA, Xia J, Gulati R, Nelson PS, et al. Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. Oncotarget. 2014;5(20):9939–51. https://doi.org/10.18632/oncotarget.2480.CrossRefPubMedPubMedCentral

79.

Marshall JC, Collins JW, Nakayama J, Horak CE, Liewehr DJ, Steinberg SM, Albaugh M, Vidal-Vanaclocha F, Palmieri D, Barbier M, et al. Effect of inhibition of the lysophosphatidic acid receptor 1 on metastasis and metastatic dormancy in breast cancer. J Natl Cancer Inst. 2012;104(17):1306–19. https://doi.org/10.1093/jnci/djs319.CrossRefPubMedPubMedCentral

80.

Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C, Wilber A, Watabe K. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med. 2011;208(13):2641–55. https://doi.org/10.1084/jem.20110840.CrossRefPubMedPubMedCentral

81.

Payne AW, Pant DK, Pan TC, Chodosh LA. Ceramide kinase promotes tumor cell survival and mammary tumor recurrence. Cancer Res. 2014;74(21):6352–63. https://doi.org/10.1158/0008-5472.CAN-14-1292.CrossRefPubMedPubMedCentral

82.

Hurley J, Doliny P, Reis I, Silva O, Gomez-Fernandez C, Velez P, Pauletti G, Powell JE, Pegram MD, Slamon DJ. Docetaxel, cisplatin, and trastuzumab as primary systemic therapy for human epidermal growth factor receptor 2-positive locally advanced breast cancer. J Clin Oncol. 2006;24(12):1831–8. https://doi.org/10.1200/JCO.2005.02.8886.CrossRefPubMed

83.

Mittendorf EA, Wu Y, Scaltriti M, Meric-Bernstam F, Hunt KK, Dawood S, Esteva FJ, Buzdar AU, Chen H, Eksambi S, Hortobagyi GN, Baselga J, Gonzalez-Angulo AM. Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes. Clin Can Res. 2009;15(23):7381–8. https://doi.org/10.1158/1078-0432.CCR-09-1735.CrossRef

84.

Nakamura R, Yamamoto N, Onai Y, Watanabe Y, Kawana H, Miyazaki M. Importance of confirming HER2 overexpression of recurrence lesion in breast cancer patients. Breast Cancer. 2013;20(4):336–41. https://doi.org/10.1007/s12282-012-0341-6.CrossRefPubMed

85.

Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.CrossRefPubMedPubMedCentral

86.

Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Donaldson MC, Sequist LV, Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339(6119):580–4. https://doi.org/10.1126/science.1228522.CrossRefPubMedPubMedCentral

Title: Cellular dormancy in minimal residual disease following targeted therapy
Authors: Jason R. Ruth
Dhruv K. Pant
Tien-chi Pan
Hans E. Seidel
Sanjeethan C. Baksh
Blaine A. Keister
Rita Singh
Christopher J. Sterner
Suzanne J. Bakewell
Susan E. Moody
George K. Belka
Lewis A. Chodosh
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Doxycycline
Breast Cancer
Breast Cancer
Targeted Therapy
Published in: Breast Cancer Research / Issue 1/2021
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/s13058-021-01416-9

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