ELF5 modulates the estrogen receptor cistrome in breast cancer

English version

Autoři: Catherine L. Piggin ^aff001; Daniel L. Roden ^aff001; Andrew M. K. Law ^aff001; Mark P. Molloy ^aff003; Christoph Krisp ^aff003; Alexander Swarbrick ^aff001; Matthew J. Naylor ^aff001; Maria Kalyuga ^aff001; Warren Kaplan ^aff001; Samantha R. Oakes ^aff001; David Gallego-Ortega ^aff001; Susan J. Clark ^aff001; Jason S. Carroll ^aff005; Nenad Bartonicek ^aff001; Christopher J. Ormandy ^aff001
Působiště autorů: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Victoria Street Darlinghurst Sydney, NSW, Australia ^aff001; St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Australia ^aff002; Australian Proteome Analysis Facility, Macquarie University, Sydney, Australia ^aff003; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Australia ^aff004; Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre Robinson Way, Cambridge, United Kingdom ^aff005
Vyšlo v časopise: ELF5 modulates the estrogen receptor cistrome in breast cancer. PLoS Genet 16(1): e32767. doi:10.1371/journal.pgen.1008531
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008531

Souhrn

Acquired resistance to endocrine therapy is responsible for half of the therapeutic failures in the treatment of breast cancer. Recent findings have implicated increased expression of the ETS transcription factor ELF5 as a potential modulator of estrogen action and driver of endocrine resistance, and here we provide the first insight into the mechanisms by which ELF5 modulates estrogen sensitivity. Using chromatin immunoprecipitation sequencing we found that ELF5 binding overlapped with FOXA1 and ER at super enhancers, enhancers and promoters, and when elevated, caused FOXA1 and ER to bind to new regions of the genome, in a pattern that replicated the alterations to the ER/FOXA1 cistrome caused by the acquisition of resistance to endocrine therapy. RNA sequencing demonstrated that these changes altered estrogen-driven patterns of gene expression, the expression of ER transcription-complex members, and 12 genes known to be involved in driving the acquisition of endocrine resistance. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, and proximity ligation assays, we found that ELF5 interacted physically with members of the ER transcription complex, such as DNA-PKcs. We found 2 cases of endocrine-resistant brain metastases where ELF5 levels were greatly increased and ELF5 patterns of gene expression were enriched, compared to the matched primary tumour. Thus ELF5 alters ER-driven gene expression by modulating the ER/FOXA1 cistrome, by interacting with it, and by modulating the expression of members of the ER transcriptional complex, providing multiple mechanisms by which ELF5 can drive endocrine resistance.

Klíčová slova:

Binding analysis – Breast cancer – DNA transcription – Endocrine therapy – Estrogens – Gene expression – Sequence motif analysis – Transcription factors

Zdroje

1. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annual Review of Medicine. 2011;62:233–47. doi: 10.1146/annurev-med-070909-182917 20887199.

2. Colleoni M, Sun Z, Price KN, Karlsson P, Forbes JF, Thurlimann B, et al. Annual Hazard Rates of Recurrence for Breast Cancer During 24 Years of Follow-Up: Results From the International Breast Cancer Study Group Trials I to V. J Clin Oncol. 2016;34(9):927–35. doi: 10.1200/JCO.2015.62.3504 26786933; PubMed Central PMCID: PMC4933127.

3. Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15(5):261–75. doi: 10.1038/nrc3920 25907219.

4. Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009;9(9):631–43. Epub 2009/08/25. doi: 10.1038/nrc2713 19701242.

5. Fuqua SA, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, et al. Variant human breast tumor estrogen receptor with constitutive transcriptional activity. Cancer Res. 1991;51(1):105–9. Epub 1991/01/01. 1988075.

6. Stone A, Zotenko E, Locke WJ, Korbie D, Millar EK, Pidsley R, et al. DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer. Nat Commun. 2015;6:7758. Epub 2015/07/15. doi: 10.1038/ncomms8758 26169690; PubMed Central PMCID: PMC4510968.

7. Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008;29(2):217–33. Epub 2008/01/25. doi: 10.1210/er.2006-0045 18216219; PubMed Central PMCID: PMC2528847.

8. Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nature genetics. 2011;43(1):27–33. doi: 10.1038/ng.730 21151129; PubMed Central PMCID: PMC3024537.

9. Jeselsohn R, Cornwell M, Pun M, Buchwalter G, Nguyen M, Bango C, et al. Embryonic transcription factor SOX9 drives breast cancer endocrine resistance. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(22):E4482–E91. doi: 10.1073/pnas.1620993114 28507152; PubMed Central PMCID: PMC5465894.

10. Lupien M, Meyer CA, Bailey ST, Eeckhoute J, Cook J, Westerling T, et al. Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance. Genes Dev. 2010;24(19):2219–27. doi: 10.1101/gad.1944810 20889718; PubMed Central PMCID: PMC2947773.

11. Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, et al. Progesterone receptor modulates ERalpha action in breast cancer. Nature. 2015;523(7560):313–7. doi: 10.1038/nature14583 26153859; PubMed Central PMCID: PMC4650274.

12. Ross-Innes CS, Stark R, Teschendorff AE, Holmes KA, Ali HR, Dunning MJ, et al. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature. 2012;481(7381):389–93. doi: 10.1038/nature10730 22217937; PubMed Central PMCID: PMC3272464.

13. Sanders DA, Ross-Innes CS, Beraldi D, Carroll JS, Balasubramanian S. Genome-wide mapping of FOXM1 binding reveals co-binding with estrogen receptor alpha in breast cancer cells. Genome Biol. 2013;14(1):R6. doi: 10.1186/gb-2013-14-1-r6 23347430; PubMed Central PMCID: PMC3663086.

14. Oakes SR, Naylor MJ, Asselin-Labat ML, Blazek KD, Gardiner-Garden M, Hilton HN, et al. The Ets transcription factor Elf5 specifies mammary alveolar cell fate. Genes Dev. 2008;22(5):581–6. doi: 10.1101/gad.1614608 18316476; PubMed Central PMCID: PMC2259028.

15. Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. 2010;468(7320):98–102. Epub 2010/10/01. doi: 10.1038/nature09387 20881962; PubMed Central PMCID: PMC3084017.

16. Lee HJ, Hinshelwood RA, Bouras T, Gallego-Ortega D, Valdes-Mora F, Blazek K, et al. Lineage specific methylation of the Elf5 promoter in mammary epithelial cells. Stem Cells. 2011;29(10):1611–9. doi: 10.1002/stem.706 21823211.

17. Lee HJ, Gallego-Ortega D, Ledger A, Schramek D, Joshi P, Szwarc MM, et al. Progesterone drives mammary secretory differentiation via RankL-mediated induction of Elf5 in luminal progenitor cells. Development (Cambridge, England). 2013;140(7):1397–401. Epub 2013/03/07. doi: 10.1242/dev.088948 23462470.

18. Lee HJ, Ormandy CJ. Elf5, hormones and cell fate. Trends Endocrinol Metab. 2012;23(6):292–8. doi: 10.1016/j.tem.2012.02.006 22464677.

19. Kalyuga M, Gallego-Ortega D, Lee HJ, Roden DL, Cowley MJ, Caldon CE, et al. ELF5 Suppresses Estrogen Sensitivity and Underpins the Acquisition of Antiestrogen Resistance in Luminal Breast Cancer. PLoS Biol. 2012;10(12):e1001461. Epub 2013/01/10. doi: 10.1371/journal.pbio.1001461 23300383; PubMed Central PMCID: PMC3531499.

20. Gallego-Ortega D, Ledger A, Roden DL, Law AM, Magenau A, Kikhtyak Z, et al. ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells. PLoS Biol. 2015;13(12):e1002330. doi: 10.1371/journal.pbio.1002330 26717410; PubMed Central PMCID: PMC4696735.

21. Lee AV, Oesterreich S, Davidson NE. MCF-7 cells—changing the course of breast cancer research and care for 45 years. J Natl Cancer Inst. 2015;107(7). Epub 2015/04/02. doi: 10.1093/jnci/djv073 25828948.

22. Piggin CL, Roden DL, Gallego-Ortega D, Lee HJ, Oakes SR, Ormandy CJ. ELF5 isoform expression is tissue-specific and significantly altered in cancer. Breast Cancer Res. 2016;18(1):4. Epub 2016/01/08. doi: 10.1186/s13058-015-0666-0 26738740; PubMed Central PMCID: PMC4704400.

23. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9(9):R137. doi: 10.1186/gb-2008-9-9-r137 18798982; PubMed Central PMCID: PMC2592715.

24. Bailey TL, Boden M, Buske FA, Frith M, Grant CE, Clementi L, et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 2009;37(Web Server issue):W202–8. Epub 2009/05/22. doi: 10.1093/nar/gkp335 19458158; PubMed Central PMCID: PMC2703892.

25. McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, et al. GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010;28(5):495–501. doi: 10.1038/nbt.1630 20436461; PubMed Central PMCID: PMC4840234.

26. Bao W, Kojima KK, Kohany O. Repbase Update, a database of repetitive elements in eukaryotic genomes. Mob DNA. 2015;6:11. Epub 2015/06/06. doi: 10.1186/s13100-015-0041-9 26045719; PubMed Central PMCID: PMC4455052.

27. Yip KY, Cheng C, Bhardwaj N, Brown JB, Leng J, Kundaje A, et al. Classification of human genomic regions based on experimentally determined binding sites of more than 100 transcription-related factors. Genome Biol. 2012;13(9):R48. Epub 2012/09/07. doi: 10.1186/gb-2012-13-9-r48 22950945; PubMed Central PMCID: PMC3491392.

28. Bouttier M, Laperriere D, Memari B, Mangiapane J, Fiore A, Mitchell E, et al. Alu repeats as transcriptional regulatory platforms in macrophage responses to M. tuberculosis infection. Nucleic Acids Res. 2016;44(22):10571–87. Epub 2016/09/09. doi: 10.1093/nar/gkw782 27604870; PubMed Central PMCID: PMC5159539.

29. de Souza FS, Franchini LF, Rubinstein M. Exaptation of transposable elements into novel cis-regulatory elements: is the evidence always strong? Mol Biol Evol. 2013;30(6):1239–51. Epub 2013/03/15. doi: 10.1093/molbev/mst045 23486611; PubMed Central PMCID: PMC3649676.

30. Testori A, Caizzi L, Cutrupi S, Friard O, De Bortoli M, Cora D, et al. The role of Transposable Elements in shaping the combinatorial interaction of Transcription Factors. BMC Genomics. 2012;13:400. Epub 2012/08/18. doi: 10.1186/1471-2164-13-400 22897927; PubMed Central PMCID: PMC3478180.

31. Cao F, Fang Y, Tan HK, Goh Y, Choy JYH, Koh BTH, et al. Super-Enhancers and Broad H3K4me3 Domains Form Complex Gene Regulatory Circuits Involving Chromatin Interactions. Sci Rep. 2017;7(1):2186. Epub 2017/05/21. doi: 10.1038/s41598-017-02257-3 28526829; PubMed Central PMCID: PMC5438348.

32. Lex A, Gehlenborg N, Strobelt H, Vuillemot R, Pfister H. UpSet: Visualization of Intersecting Sets. IEEE Trans Vis Comput Graph. 2014;20(12):1983–92. Epub 2015/09/12. doi: 10.1109/TVCG.2014.2346248 26356912; PubMed Central PMCID: PMC4720993.

33. Ramirez-Valle F, Braunstein S, Zavadil J, Formenti SC, Schneider RJ. eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy. J Cell Biol. 2008;181(2):293–307. Epub 2008/04/23. doi: 10.1083/jcb.200710215 18426977; PubMed Central PMCID: PMC2315676.

34. Mohammed H, Taylor C, Brown GD, Papachristou EK, Carroll JS, D'Santos CS. Rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) for analysis of chromatin complexes. Nature protocols. 2016;11(2):316–26. doi: 10.1038/nprot.2016.020 26797456.

35. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44(W1):W90–7. doi: 10.1093/nar/gkw377 27141961; PubMed Central PMCID: PMC4987924.

36. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome research. 2003;13(11):2498–504. Epub 2003/11/05. doi: 10.1101/gr.1239303 14597658; PubMed Central PMCID: PMC403769.

37. Merico D, Isserlin R, Stueker O, Emili A, Bader GD. Enrichment Map: A Network-Based Method for Gene-Set Enrichment Visualization and Interpretation. PLOS ONE. 2010;5(11):e13984. doi: 10.1371/journal.pone.0013984 21085593

38. Swinstead EE, Miranda TB, Paakinaho V, Baek S, Goldstein I, Hawkins M, et al. Steroid Receptors Reprogram FoxA1 Occupancy through Dynamic Chromatin Transitions. Cell. 2016;165(3):593–605. Epub 2016/04/12. doi: 10.1016/j.cell.2016.02.067 27062924; PubMed Central PMCID: PMC4842147.

39. Fu X, Jeselsohn R, Pereira R, Hollingsworth EF, Creighton CJ, Li F, et al. FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(43):E6600–E9. Epub 2016/10/30. doi: 10.1073/pnas.1612835113 27791031; PubMed Central PMCID: PMC5087040.

40. Liang Y, Han H, Liu L, Duan Y, Yang X, Ma C, et al. CD36 plays a critical role in proliferation, migration and tamoxifen-inhibited growth of ER-positive breast cancer cells. Oncogenesis. 2018;7(12):98. Epub 2018/12/24. doi: 10.1038/s41389-018-0107-x 30573731; PubMed Central PMCID: PMC6302092.

41. Lopes R, Korkmaz G, Revilla SA, van Vliet R, Nagel R, Custers L, et al. CUEDC1 is a primary target of ERalpha essential for the growth of breast cancer cells. Cancer Lett. 2018;436:87–95. Epub 2018/08/27. doi: 10.1016/j.canlet.2018.08.018 30145202.

42. Nagelkerke A, Sieuwerts AM, Bussink J, Sweep FC, Look MP, Foekens JA, et al. LAMP3 is involved in tamoxifen resistance in breast cancer cells through the modulation of autophagy. Endocr Relat Cancer. 2014;21(1):101–12. Epub 2014/01/18. doi: 10.1530/ERC-13-0183 24434718.

43. Qian XL, Li YQ, Yu B, Gu F, Liu FF, Li WD, et al. Syndecan binding protein (SDCBP) is overexpressed in estrogen receptor negative breast cancers, and is a potential promoter for tumor proliferation. PLoS One. 2013;8(3):e60046. Epub 2013/03/28. doi: 10.1371/journal.pone.0060046 23533663; PubMed Central PMCID: PMC3606191.

44. Goto N, Hiyoshi H, Ito I, Tsuchiya M, Nakajima Y, Yanagisawa J. Estrogen and antiestrogens alter breast cancer invasiveness by modulating the transforming growth factor-beta signaling pathway. Cancer Sci. 2011;102(8):1501–8. doi: 10.1111/j.1349-7006.2011.01977.x 21564419.

45. Baniwal SK, Chimge NO, Jordan VC, Tripathy D, Frenkel B. Prolactin-induced protein (PIP) regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner. PLoS One. 2014;8(6):e62361. doi: 10.1371/journal.pone.0062361 23755096; PubMed Central PMCID: PMC3670933.

46. Mohammed H, D'Santos C, Serandour AA, Ali HR, Brown GD, Atkins A, et al. Endogenous purification reveals GREB1 as a key estrogen receptor regulatory factor. Cell reports. 2013;3(2):342–9. doi: 10.1016/j.celrep.2013.01.010 23403292.

47. Medunjanin S, Weinert S, Schmeisser A, Mayer D, Braun-Dullaeus RC. Interaction of the double-strand break repair kinase DNA-PK and estrogen receptor-alpha. Mol Biol Cell. 2010;21(9):1620–8. Epub 2010/03/12. doi: 10.1091/mbc.E09-08-0724 20219974; PubMed Central PMCID: PMC2861619.

48. Goodwin JF, Knudsen KE. Beyond DNA repair: DNA-PK function in cancer. Cancer Discov. 2014;4(10):1126–39. Epub 2014/08/30. doi: 10.1158/2159-8290.CD-14-0358 25168287; PubMed Central PMCID: PMC4184981.

49. Latos PA, Sienerth AR, Murray A, Senner CE, Muto M, Ikawa M, et al. Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks. Genes Dev. 2015;29(23):2435–48. doi: 10.1101/gad.268821.115 26584622; PubMed Central PMCID: PMC4691948.

50. Vareslija D, Priedigkeit N, Fagan A, Purcell S, Cosgrove N, O'Halloran PJ, et al. Transcriptome Characterization of Matched Primary Breast and Brain Metastatic Tumors to Detect Novel Actionable Targets. J Natl Cancer Inst. 2019;111(4):388–98. Epub 2018/07/03. doi: 10.1093/jnci/djy110 29961873; PubMed Central PMCID: PMC6449168.

51. Korkmaz G, Lopes R, Ugalde AP, Nevedomskaya E, Han R, Myacheva K, et al. Functional genetic screens for enhancer elements in the human genome using CRISPR-Cas9. Nat Biotechnol. 2016;34(2):192–8. Epub 2016/01/12. doi: 10.1038/nbt.3450 26751173.

52. Naderi A. Prolactin-induced protein in breast cancer. Adv Exp Med Biol. 2015;846:189–200. doi: 10.1007/978-3-319-12114-7_8 25472539.

53. Perillo B, Ombra MN, Bertoni A, Cuozzo C, Sacchetti S, Sasso A, et al. DNA oxidation as triggered by H3K9me2 demethylation drives estrogen-induced gene expression. Science. 2008;319(5860):202–6. Epub 2008/01/12. doi: 10.1126/science.1147674 18187655.

54. Holmes KA, Brown GD, Carroll JS. Chromatin Immunoprecipitation-Sequencing (ChIP-seq) for Mapping of Estrogen Receptor-Chromatin Interactions in Breast Cancer. Methods Mol Biol. 2016;1366:79–98. Epub 2015/11/21. doi: 10.1007/978-1-4939-3127-9_8 26585129.

55. Machanick P, Bailey TL. MEME-ChIP: motif analysis of large DNA datasets. Bioinformatics. 2011;27(12):1696–7. doi: 10.1093/bioinformatics/btr189 21486936; PubMed Central PMCID: PMC3106185.

56. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. doi: 10.1093/bioinformatics/bts635 23104886; PubMed Central PMCID: PMC3530905.

57. Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011;12:323. doi: 10.1186/1471-2105-12-323 21816040; PubMed Central PMCID: PMC3163565.

58. Robinson MD, Oshlack A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 2010;11(3):R25. doi: 10.1186/gb-2010-11-3-r25 20196867; PubMed Central PMCID: PMC2864565.

59. Law CW, Chen Y, Shi W, Smyth GK. voom: Precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 2014;15(2):R29. doi: 10.1186/gb-2014-15-2-r29 24485249; PubMed Central PMCID: PMC4053721.

60. Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3. doi: 10.2202/1544-6115.1027 16646809.

61. Taberlay PC, Statham AL, Kelly TK, Clark SJ, Jones PA. Reconfiguration of nucleosome-depleted regions at distal regulatory elements accompanies DNA methylation of enhancers and insulators in cancer. Genome research. 2014;24(9):1421–32. doi: 10.1101/gr.163485.113 24916973; PubMed Central PMCID: PMC4158760.