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  • Review Article
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The ETS family of oncogenic transcription factors in solid tumours

Nature Reviews Cancer volume 17, pages 337–351 (2017)Cite this article

Subjects

Key Points

  • ETS factor expression is aberrantly upregulated in solid tumours through chromosomal translocation and amplification.

  • Activating mutations in KIT stabilize the ETV1 protein through the MEK–ERK pathway, thus driving an oncogenic transcriptional programme in gastrointestinal stromal tumours.

  • Disruption of constitutive photomorphogenesis protein 1 (COP1)-mediated proteasomal degradation of ETS factors increases their protein stability and subsequent transcriptional activity in prostate and breast cancers.

  • Mutations in the telomerase reverse transcriptase (TERT) promoter that generate an ETS-binding site are emerging as among the most frequent mutations in solid tumours.

  • Gain of function cis-acting mutations in p53 (p53-GOF mutants) result in ETS2 protein–protein interactions and altered target gene expression affecting tumour growth, metastasis and chemotherapeutic resistance.

  • ETS factors mediate lineage specification altering stem and progenitor populations in multiple cancer types.

  • ETS fusion proteins interact with poly(ADP-ribose) polymerase 1 (PARP1) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), both of which are mediators of DNA repair and genomic stability.

  • ETS2 functions with p53-GOF mutants to epigenetically regulate super-enhancers.

  • ETS factors function in both cell-autonomous and non-cell-autonomous manners in the tumour microenvironment to enhance cancer progression.

  • Therapeutic strategies targeting ETS factor biology are emerging and should translate clinically in the next decade.

Abstract

Findings over the past decade have identified aberrant activation of the ETS transcription factor family throughout all stages of tumorigenesis. Specifically in solid tumours, gene rearrangement and amplification, feed-forward growth factor signalling loops, formation of gain-of-function co-regulatory complexes and novel cis-acting mutations in ETS target gene promoters can result in increased ETS activity. In turn, pro-oncogenic ETS signalling enhances tumorigenesis through a broad mechanistic toolbox that includes lineage specification and self-renewal, DNA damage and genome instability, epigenetics and metabolism. This Review discusses these different mechanisms of ETS activation and subsequent oncogenic implications, as well as the clinical utility of ETS factors.

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Figure 1: Discoveries of ETS factors in cancer.
Figure 2: Mechanisms of ETS factor activation and inactivation in solid tumours.
Figure 3: Molecular and cellular mechanisms of ETS factors in solid tumours.
Figure 4: ETS factors as therapeutic targets.

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References

  1. Leprince, D. et al. A putative second cell-derived oncogene of the avian leukaemia retrovirus E26. Nature 306, 395–397 (1983).

    Article  CAS  PubMed  Google Scholar 

  2. Nunn, M. F., Seeburg, P. H., Moscovici, C. & Duesberg, P. H. Tripartite structure of the avian erythroblastosis virus E26 transforming gene. Nature 306, 391–395 (1983).

    Article  CAS  PubMed  Google Scholar 

  3. Nunn, M. F. & Hunter, T. The ets sequence is required for induction of erythroblastosis in chickens by avian retrovirus E26. J. Virol. 63, 398–402 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Golay, J., Introna, M. & Graf, T. A single point mutation in the v-ets oncogene affects both erythroid and myelomonocytic cell differentiation. Cell 55, 1147–1158 (1988).

    Article  CAS  PubMed  Google Scholar 

  5. Findlay, V. J., LaRue, A. C., Turner, D. P., Watson, P. M. & Watson, D. K. Understanding the role of ETS-mediated gene regulation in complex biological processes. Adv. Cancer Res. 119, 1–61 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Charlot, C., Dubois-Pot, H., Serchov, T., Tourrette, Y. & Wasylyk, B. A review of post-translational modifications and subcellular localization of Ets transcription factors: possible connection with cancer and involvement in the hypoxic response. Methods Mol. Biol. 647, 3–30 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Hollenhorst, P. C., McIntosh, L. P. & Graves, B. J. Genomic and biochemical insights into the specificity of ETS transcription factors. Annu. Rev. Biochem. 80, 437–471 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. De Braekeleer, E. et al. ETV6 fusion genes in hematological malignancies: a review. Leuk. Res. 36, 945–961 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Kar, A. & Gutierrez-Hartmann, A. Molecular mechanisms of ETS transcription factor-mediated tumorigenesis. Crit. Rev. Biochem. Mol. Biol. 48, 522–543 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Seth, A. & Watson, D. K. ETS transcription factors and their emerging roles in human cancer. Eur. J. Cancer 41, 2462–2478 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Turc-Carel, C., Philip, I., Berger, M. P., Philip, T. & Lenoir, G. Chromosomal translocation (11; 22) in cell lines of Ewing's sarcoma. C. R. Seances Acad. Sci. III 296, 1101–1103 (in French) (1983).

    CAS  PubMed  Google Scholar 

  12. Whang-Peng, J. et al. Chromosome translocation in peripheral neuroepithelioma. N. Engl. J. Med. 311, 584–585 (1984).

    Article  CAS  PubMed  Google Scholar 

  13. Delattre, O. et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 359, 162–165 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Zucman, J. et al. Combinatorial generation of variable fusion proteins in the Ewing family of tumours. EMBO J. 12, 4481–4487 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sorensen, P. H. et al. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat. Genet. 6, 146–151 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Tognon, C. et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2, 367–376 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005). This is the first study to report ETS gene fusions ( TMPRSS2–ERG and TMPRSS2 – ETV1 ) in an epithelium-derived cancer.

    Article  CAS  PubMed  Google Scholar 

  18. Lin, B. et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res. 59, 4180–4184 (1999).

    CAS  PubMed  Google Scholar 

  19. Afar, D. E. et al. Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia. Cancer Res. 61, 1686–1692 (2001).

    CAS  PubMed  Google Scholar 

  20. Tomlins, S. A. et al. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res. 66, 3396–3400 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Helgeson, B. E. et al. Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer Res. 68, 73–80 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Mehra, R. et al. Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod. Pathol. 20, 538–544 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Mehra, R. et al. Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Res. 68, 3584–3590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tomlins, S. A. et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448, 595–599 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Klezovitch, O. et al. A causal role for ERG in neoplastic transformation of prostate epithelium. Proc. Natl Acad. Sci. USA 105, 2105–2110 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Carver, B. S. et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat. Genet. 41, 619–624 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. King, J. C. et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat. Genet. 41, 524–526 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shin, S. et al. Induction of prostatic intraepithelial neoplasia and modulation of androgen receptor by ETS variant 1/ETS-related protein 81. Cancer Res. 69, 8102–8110 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen, Y. et al. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat. Med. 19, 1023–1029 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bastian, B. C., LeBoit, P. E., Hamm, H., Brocker, E. B. & Pinkel, D. Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. Cancer Res. 58, 2170–2175 (1998).

    CAS  PubMed  Google Scholar 

  31. Jane-Valbuena, J. et al. An oncogenic role for ETV1 in melanoma. Cancer Res. 70, 2075–2084 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mesquita, B. et al. Frequent copy number gains at 1q21 and 1q32 are associated with overexpression of the ETS transcription factors ETV3 and ELF3 in breast cancer irrespective of molecular subtypes. Breast Cancer Res. Treat. 138, 37–45 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Huang, F. W. et al. Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957–959 (2013). References 33 and 34 report the ground-breaking discoveries showing that mutations within the TERT promoter generate 'GGAA' de novo ETS-binding motifs in human tumours, leading to anomalous TERT expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vinagre, J. et al. Frequency of TERT promoter mutations in human cancers. Nat. Commun. 4, 2185 (2013).

    Article  PubMed  CAS  Google Scholar 

  36. Labussiere, M. et al. TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations. Br. J. Cancer 111, 2024–2032 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li, Y. et al. Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation. Nat. Cell Biol. 17, 1327–1338 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bell, R. J. et al. Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science 348, 1036–1039 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Muller, P. A. & Vousden, K. H. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25, 304–317 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Do, P. M. et al. Mutant p53 cooperates with ETS2 to promote etoposide resistance. Genes Dev. 26, 830–845 (2012). This is the first study to show that ETS consensus motifs colocalize with p53-GOF-binding sites on target genes in cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xiong, S. et al. Pla2g16 phospholipase mediates gain-of-function activities of mutant p53. Proc. Natl Acad. Sci. USA 111, 11145–11150 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhu, J. et al. Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature 525, 206–211 (2015). This is the first study to report that p53-GOF and ETS2 cooperate in genome-wide epigenetic regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Carrero, Z. I., Kollareddy, M., Chauhan, K. M., Ramakrishnan, G. & Martinez, L. A. Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation. Oncotarget 7, 12554–12567 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Chi, P. et al. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature 467, 849–853 (2010). This study provides evidence for a KIT–ETV1 feed-forward loop in GIST that enhances survival of the ICCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ran, L. et al. Combined inhibition of MAP kinase and KIT signaling synergistically destabilizes ETV1 and suppresses GIST tumor growth. Cancer Discov. 5, 304–315 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hayashi, Y. et al. Platelet-derived growth factor receptor-alpha regulates proliferation of gastrointestinal stromal tumor cells with mutations in KIT by stabilizing ETV1. Gastroenterology 149, 420–432.e16 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Baert, J. L. et al. The E3 ubiquitin ligase complex component COP1 regulates PEA3 group member stability and transcriptional activity. Oncogene 29, 1810–1820 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Vitari, A. C. et al. COP1 is a tumour suppressor that causes degradation of ETS transcription factors. Nature 474, 403–406 (2011). This was the initial study to identify gross overexpression of ETS fusion proteins due to loss of a COP1-binding site.

    Article  CAS  PubMed  Google Scholar 

  49. Lu, G. et al. Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor. Cancer Cell 26, 222–234 (2014). This paper established that SRC-mediated phosphorylation of ETS1 inhibits COP1-mediated proteasomal degradation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Span, P. N. et al. Expression of the transcription factor Ets-1 is an independent prognostic marker for relapse-free survival in breast cancer. Oncogene 21, 8506–8509 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Myers, E. et al. Associations and interactions between Ets-1 and Ets-2 and coregulatory proteins, SRC-1, AIB1, and NCoR in breast cancer. Clin. Cancer Res. 11, 2111–2122 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Oakes, S. R. et al. The Ets transcription factor Elf5 specifies mammary alveolar cell fate. Genes Dev. 22, 581–586 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chakrabarti, R. et al. Elf5 regulates mammary gland stem/progenitor cell fate by influencing notch signaling. Stem Cells 30, 1496–1508 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chakrabarti, R. et al. Elf5 inhibits the epithelial–mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. Nat. Cell Biol. 14, 1212–1222 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Phillips, S. & Kuperwasser, C. SLUG: critical regulator of epithelial cell identity in breast development and cancer. Cell Adh. Migr. 8, 578–587 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Kalyuga, M. et al. ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer. PLoS Biol. 10, e1001461 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Buchwalter, G. et al. PDEF promotes luminal differentiation and acts as a survival factor for ER-positive breast cancer cells. Cancer Cell 23, 753–767 (2013). This work confirmed that PDEF functions as an oncoprotein in luminal breast cancer and described its role in endocrine resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Levy, C., Khaled, M. & Fisher, D. E. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol. Med. 12, 406–414 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Polson, E. S. et al. Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells. Nat. Commun. 4, 1623 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Casey, O. M. et al. TMPRSS2- driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation. PLoS ONE 7, e41668 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mounir, Z. et al. TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation. Oncogene 34, 3815–3825 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Cai, C. et al. ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer. J. Clin. Invest. 123, 1109–1122 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Brenner, J. C. et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19, 664–678 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Han, S. et al. Targeted radiosensitization of ETS fusion-positive prostate cancer through PARP1 inhibition. Neoplasia 15, 1207–1217 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Chatterjee, P. et al. The TMPRSS2–ERG gene fusion blocks XRCC4-mediated nonhomologous end-joining repair and radiosensitizes prostate cancer cells to PARP inhibition. Mol. Cancer Ther. 14, 1896–1906 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Brenner, J. C. et al. PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma. Cancer Res. 72, 1608–1613 (2012). This study defined a cooperative interaction of an ETS fusion protein with PARP1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Soldatenkov, V. A. et al. Regulation of the human poly(ADP-ribose) polymerase promoter by the ETS transcription factor. Oncogene 18, 3954–3962 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Li, D. et al. Poly (ADP-ribose) polymerase 1 transcriptional regulation: a novel crosstalk between histone modification H3K9ac and ETS1 motif hypomethylation in BRCA1-mutated ovarian cancer. Oncotarget 5, 291–297 (2014).

    PubMed  Google Scholar 

  69. Legrand, A. J. et al. The level of Ets-1 protein is regulated by poly(ADP-ribose) polymerase-1 (PARP-1) in cancer cells to prevent DNA damage. PLoS ONE 8, e55883 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ibrahim, Y. H. et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2, 1036–1047 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Baker, K. M., Wei, G., Schaffner, A. E. & Ostrowski, M. C. Ets-2 and components of mammalian SWI/SNF form a repressor complex that negatively regulates the BRCA1 promoter. J. Biol. Chem. 278, 17876–17884 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Atlas, E., Stramwasser, M., Whiskin, K. & Mueller, C. R. GA-binding protein α/β is a critical regulator of the BRCA1 promoter. Oncogene 19, 1933–1940 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Thompson, C., MacDonald, G. & Mueller, C. R. Decreased expression of BRCA1 in SK-BR-3 cells is the result of aberrant activation of the GABP beta promoter by an NRF-1-containing complex. Mol. Cancer 10, 62 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ritter, H. D., Antonova, L. & Mueller, C. R. The unliganded glucocorticoid receptor positively regulates the tumor suppressor gene BRCA1 through GABP beta. Mol. Cancer Res. 10, 558–569 (2012).

    Article  CAS  PubMed  Google Scholar 

  75. Yu, J. et al. An integrated network of androgen receptor, polycomb, and TMPRSS2–ERG gene fusions in prostate cancer progression. Cancer Cell 17, 443–454 (2010). This study revealed that TMPRSS2–ERG enforces epigenetic reprograming that blocks prostatic lineage differentiation, which leads to cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zong, Y. et al. ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells. Proc. Natl Acad. Sci. USA 106, 12465–12470 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hnisz, D. et al. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol. Cell 58, 362–370 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yang, H. et al. ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas. eLife 4, e10870 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Takeda, S. et al. HGF–MET signals via the MLL–ETS2 complex in hepatocellular carcinoma. J. Clin. Invest. 123, 3154–3165 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kollareddy, M. et al. Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities. Nat. Commun. 6, 7389 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Verschoor, M. L., Verschoor, C. P. & Singh, G. Ets-1 global gene expression profile reveals associations with metabolism and oxidative stress in ovarian and breast cancers. Cancer Metab. 1, 17 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Verschoor, M. L. & Singh, G. Ets-1 regulates intracellular glutathione levels: key target for resistant ovarian cancer. Mol. Cancer 12, 138 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Meller, S. et al. Integration of tissue metabolomics, transcriptomics and immunohistochemistry reveals ERG- and gleason score- specific metabolomic alterations in prostate cancer. Oncotarget 7, 1421–1438 (2015).

    PubMed Central  Google Scholar 

  84. Powell, K. et al. ERG/AKR1C3/AR constitutes a feed-forward loop for AR signaling in prostate cancer cells. Clin. Cancer Res. 21, 2569–2579 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Baena, E. et al. ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients. Genes Dev. 27, 683–698 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Randi, A. M., Sperone, A., Dryden, N. H. & Birdsey, G. M. Regulation of angiogenesis by ETS transcription factors. Biochem. Soc. Trans. 37, 1248–1253 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Oettgen, P. The role of Ets factors in tumor angiogenesis. J. Oncol. 2010, 767384 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Heo, S. H., Lee, J. Y., Yang, K. M. & Park, K. S. ELK3 expression correlates with cell migration, invasion, and membrane type 1-matrix metalloproteinase expression in MDA-MB-231 breast cancer cells. Gene Expr. 16, 197–203 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tian, T. V. et al. Identification of novel TMPRSS2:ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2. Oncogene 33, 2204–2214 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Gallego-Ortega, D. et al. ELF5 drives lung metastasis in luminal breast cancer through recruitment of Gr1+ CD11b+ myeloid-derived suppressor cells. PLoS Biol. 13, e1002330 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Wei, G. et al. Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis. Blood 114, 1123–1130 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yuan, L. et al. ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene. J. Biol. Chem. 287, 6582–6591 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Birdsey, G. M. et al. The transcription factor Erg regulates expression of histone deacetylase 6 and multiple pathways involved in endothelial cell migration and angiogenesis. Blood 119, 894–903 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Birdsey, G. M. et al. The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/beta-catenin signaling. Dev. Cell 32, 82–96 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Trimboli, A. J. et al. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461, 1084–1091 (2009). This study provided genetic evidence that stromal fibroblasts can exert tumour-suppressive effects within the TME.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Man, A. K. et al. Ets2-dependent stromal regulation of mouse mammary tumors. Mol. Cell. Biol. 23, 8614–8625 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wallace, J. A. et al. Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer. PLoS ONE 8, e71533 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bronisz, A. et al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat. Cell Biol. 14, 159–167 (2012).

    Article  CAS  Google Scholar 

  99. Zabuawala, T. et al. An Ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res. 70, 1323–1333 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mathsyaraja, H. et al. CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth. Oncogene 34, 3651–3661 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. Pitarresi, J. R. et al. Stromal ETS2 regulates chemokine production and immune cell recruitment during acinar-to-ductal metaplasia. Neoplasia 18, 541–552 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yoshimoto, M. et al. Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Mod. Pathol. 21, 1451–1460 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Reid, A. H. et al. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br. J. Cancer 102, 678–684 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Leinonen, K. A. et al. Association of SPINK1 expression and TMPRSS2:ERG fusion with prognosis in endocrine-treated prostate cancer. Clin. Cancer Res. 16, 2845–2851 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Boormans, J. L. et al. Expression of the androgen-regulated fusion gene TMPRSS2–ERG does not predict response to endocrine treatment in hormone-naive, node-positive prostate cancer. Eur. Urol. 57, 830–835 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Minner, S. et al. ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy. Clin. Cancer Res. 17, 5878–5888 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Berg, K. D. et al. The predictive value of ERG protein expression for development of castration-resistant prostate cancer in hormone-naive advanced prostate cancer treated with primary androgen deprivation therapy. Prostate 75, 1499–1509 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Karnes, R. J. et al. The ability of biomarkers to predict systemic progression in men with high-risk prostate cancer treated surgically is dependent on ERG status. Cancer Res. 70, 8994–9002 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Attard, G. et al. Improvements in radiographic progression-free survival stratified by ERG gene status in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate. Clin. Cancer Res. 21, 1621–1627 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Rosen, P. et al. Clinical potential of the ERG oncoprotein in prostate cancer. Nat. Rev. Urol. 9, 131–137 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Feng, F. Y., Brenner, J. C., Hussain, M. & Chinnaiyan, A. M. Molecular pathways: targeting ETS gene fusions in cancer. Clin. Cancer Res. 20, 4442–4448 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Attard, G. et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 69, 2912–2918 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Danila, D. C. et al. TMPRSS2–ERG status in circulating tumor cells as a predictive biomarker of sensitivity in castration-resistant prostate cancer patients treated with abiraterone acetate. Eur. Urol. 60, 897–904 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tomlins, S. A. et al. Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Sci. Transl Med. 3, 94ra72 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02588404 (2016).

  116. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02573636 (2017).

  117. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02303327 (2017).

  118. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02288936 (2016).

  119. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01942837 (2016).

  120. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01350180 (2017).

  121. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00910884 (2015).

  122. Garnett, M. J. et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483, 570–575 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00048984 (2013).

  124. Chatterjee, P. et al. PARP inhibition sensitizes to low dose-rate radiation TMPRSS2–ERG fusion gene-expressing and PTEN-deficient prostate cancer cells. PLoS ONE 8, e60408 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Mateo, J. et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373, 1697–1708 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lee, H. J. et al. Combining PARP-1 inhibition and radiation in Ewing sarcoma results in lethal DNA damage. Mol. Cancer Ther. 12, 2591–2600 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Choy, E. et al. Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer 14, 813 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Asangani, I. A. et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510, 278–282 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Asangani, I. A. et al. BET bromodomain inhibitors enhance efficacy and disrupt resistance to AR antagonists in the treatment of prostate cancer. Mol. Cancer Res. 14, 324–331 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hensel, T. et al. Targeting the EWS–ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma. Oncotarget 7, 1451–1463 (2016).

    Article  PubMed  Google Scholar 

  131. Shao, L. et al. Highly specific targeting of the TMPRSS2/ERG fusion gene using liposomal nanovectors. Clin. Cancer Res. 18, 6648–6657 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang, S. et al. Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Proc. Natl Acad. Sci. USA 111, 4251–4256 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Erkizan, H. V. et al. A small molecule blocking oncogenic protein EWS–FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat. Med. 15, 750–756 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rahim, S. et al. YK-4-279 inhibits ERG and ETV1 mediated prostate cancer cell invasion. PLoS ONE 6, e19343 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Rahim, S. et al. A small molecule inhibitor of ETV1, YK-4-279, prevents prostate cancer growth and metastasis in a mouse xenograft model. PLoS ONE 9, e114260 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Lamhamedi-Cherradi, S. E. et al. An oral formulation of YK-4-279: preclinical efficacy and acquired resistance patterns in Ewing sarcoma. Mol. Cancer Ther. 14, 1591–1604 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Grohar, P. J. et al. Identification of an inhibitor of the EWS–FLI1 oncogenic transcription factor by high-throughput screening. J. Natl Cancer Inst. 103, 962–978 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Grohar, P. J. et al. Ecteinascidin 743 interferes with the activity of EWS–FLI1 in Ewing sarcoma cells. Neoplasia 13, 145–153 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Grohar, P. J. et al. Dual targeting of EWS–FLI1 activity and the associated DNA damage response with trabectedin and SN38 synergistically inhibits Ewing sarcoma cell growth. Clin. Cancer Res. 20, 1190–1203 (2014).

    Article  CAS  PubMed  Google Scholar 

  140. Ordonez, J. L. et al. The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin. Oncotarget 6, 18875–18890 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Baruchel, S. et al. A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: a report from the Children's Oncology Group. Eur. J. Cancer 48, 579–585 (2012).

    Article  CAS  PubMed  Google Scholar 

  142. Heinrich, M. C. et al. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin. Cancer Res. 18, 4375–4384 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01243346 (2014).

  144. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02847429 (2017).

  145. Montero, J. C., Seoane, S., Ocana, A. & Pandiella, A. Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin. Cancer Res. 17, 5546–5552 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Araujo, J. & Logothetis, C. Dasatinib: a potent SRC inhibitor in clinical development for the treatment of solid tumors. Cancer Treat. Rev. 36, 492–500 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Pop, M. S. et al. A small molecule that binds and inhibits the ETV1 transcription factor oncoprotein. Mol. Cancer Ther. 13, 1492–1502 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Mantovani, F., Walerych, D. & Sal, G. D. Targeting mutant p53 in cancer: a long road to precision therapy. FEBS J. http://dx.doi.org/10.1111/febs.13948 (2016).

  149. Skaar, J. R., Pagan, J. K. & Pagano, M. SCF ubiquitin ligase-targeted therapies. Nat. Rev. Drug Discov. 13, 889–903 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Karim, F. D. et al. The ETS-domain: a new DNA-binding motif that recognizes a purine-rich core DNA sequence. Genes Dev. 4, 1451–1453 (1990).

    Article  CAS  PubMed  Google Scholar 

  151. Wei, G. H. et al. Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo. EMBO J. 29, 2147–2160 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Liang, H. et al. The secondary structure of the ets domain of human Fli-1 resembles that of the helix–turn–helix DNA-binding motif of the Escherichia coli catabolite gene activator protein. Proc. Natl Acad. Sci. USA 91, 11655–11659 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Donaldson, L. W., Petersen, J. M., Graves, B. J. & McIntosh, L. P. Solution structure of the ETS domain from murine Ets-1: a winged helix-turn-helix DNA binding motif. EMBO J. 15, 125–134 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Sharrocks, A. D. The ETS-domain transcription factor family. Nat. Rev. Mol. Cell Biol. 2, 827–837 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Klambt, C. The Drosophila gene pointed encodes two ETS-like proteins which are involved in the development of the midline glial cells. Development 117, 163–176 (1993).

    CAS  PubMed  Google Scholar 

  156. Lacronique, V. et al. A TEL–JAK2 fusion protein with constitutive kinase activity in human leukemia. Science 278, 1309–1312 (1997).

    Article  CAS  PubMed  Google Scholar 

  157. Kim, C. A. et al. Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression. EMBO J. 20, 4173–4182 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Baker, D. A., Mille-Baker, B., Wainwright, S. M., Ish-Horowicz, D. & Dibb, N. J. Mae mediates MAP kinase phosphorylation of Ets transcription factors in Drosophila. Nature 411, 330–334 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Bell, R. J. et al. Understanding TERT promoter mutations: a common path to immortality. Mol. Cancer Res. 14, 315–323 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02324998 (2017).

  161. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01576172 (2016).

  162. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01353625 (2016).

  163. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02657005 (2016).

  164. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02509234 (2015).

  165. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02398058 (2016).

  166. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01991379 (2016).

  167. Alipov, G. et al. Overexpression of Ets-1 proto-oncogene in latent and clinical prostatic carcinomas. Histopathology 46, 202–208 (2005).

    Article  CAS  PubMed  Google Scholar 

  168. Behrens, P., Rothe, M., Wellmann, A., Krischler, J. & Wernert, N. The Ets-1 transcription factor is up-regulated together with MMP 1 and MMP 9 in the stroma of pre-invasive breast cancer. J. Pathol. 194, 43–50 (2001).

    Article  CAS  PubMed  Google Scholar 

  169. Dittmer, J. The role of the transcription factor Ets1 in carcinoma. Semin. Cancer Biol. 35, 20–38 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Shaikhibrahim, Z. & Wernert, N. ETS transcription factors and prostate cancer: the role of the family prototype ETS-1 (review). Int. J. Oncol. 40, 1748–1754 (2012).

    CAS  Google Scholar 

  171. Buggy, Y. et al. Ets2 transcription factor in normal and neoplastic human breast tissue. Eur. J. Cancer 42, 485–491 (2006).

    Article  CAS  PubMed  Google Scholar 

  172. Shimizu, K. et al. An ets-related gene, ERG, is rearranged in human myeloid leukemia with t(16;21) chromosomal translocation. Proc. Natl Acad. Sci. USA 90, 10280–10284 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Shing, D. C. et al. FUS/ERG gene fusions in Ewing's tumors. Cancer Res. 63, 4568–4576 (2003).

    CAS  PubMed  Google Scholar 

  174. Gavrilov, D., Kenzior, O., Evans, M., Calaluce, R. & Folk, W. R. Expression of urokinase plasminogen activator and receptor in conjunction with the ets family and AP-1 complex transcription factors in high grade prostate cancers. Eur. J. Cancer 37, 1033–1040 (2001).

    Article  CAS  PubMed  Google Scholar 

  175. Scheiber, M. N. et al. FLI1 expression is correlated with breast cancer cellular growth, migration, and invasion and altered gene expression. Neoplasia 16, 801–813 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Peter, M. et al. A new member of the ETS family fused to EWS in Ewing tumors. Oncogene 14, 1159–1164 (1997).

    Article  CAS  PubMed  Google Scholar 

  177. Ando, M. et al. Mutational landscape and antiproliferative functions of ELF transcription factors in human cancer. Cancer Res. 76, 1814–1824 (2016).

    Article  CAS  PubMed  Google Scholar 

  178. Yao, J. J. et al. Tumor promoting properties of the ETS protein MEF in ovarian cancer. Oncogene 26, 4032–4037 (2007).

    Article  CAS  PubMed  Google Scholar 

  179. Seki, Y. et al. The ETS transcription factor MEF is a candidate tumor suppressor gene on the X chromosome. Cancer Res. 62, 6579–6586 (2002).

    CAS  PubMed  Google Scholar 

  180. Wu, B. et al. Epigenetic regulation of Elf5 is associated with epithelial–mesenchymal transition in urothelial cancer. PLoS ONE 10, e0117510 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Yao, B. et al. Elf5 inhibits TGF-β-driven epithelial-mesenchymal transition in prostate cancer by repressing SMAD3 activation. Prostate 75, 872–882 (2015).

    Article  CAS  PubMed  Google Scholar 

  182. Brenne, K., Nymoen, D. A., Hetland, T. E., Trope, C. G. & Davidson, B. Expression of the Ets transcription factor EHF in serous ovarian carcinoma effusions is a marker of poor survival. Hum. Pathol. 43, 496–505 (2012).

    Article  CAS  PubMed  Google Scholar 

  183. Cangemi, R. et al. Reduced expression and tumor suppressor function of the ETS transcription factor ESE-3 in prostate cancer. Oncogene 27, 2877–2885 (2008).

    Article  CAS  PubMed  Google Scholar 

  184. Longoni, N. et al. ETS transcription factor ESE1/ELF3 orchestrates a positive feedback loop that constitutively activates NF-κB and drives prostate cancer progression. Cancer Res. 73, 4533–4547 (2013).

    Article  CAS  PubMed  Google Scholar 

  185. Wang, J. L. et al. Elf3 drives β-catenin transactivation and associates with poor prognosis in colorectal cancer. Cell Death Dis. 5, e1263 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Sharma, N. L. et al. The ETS family member GABPα modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer. Nucleic Acids Res. 42, 6256–6269 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Gunawardane, R. N. et al. Novel role for PDEF in epithelial cell migration and invasion. Cancer Res. 65, 11572–11580 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Feldman, R. J., Sementchenko, V. I., Gayed, M., Fraig, M. M. & Watson, D. K. Pdef expression in human breast cancer is correlated with invasive potential and altered gene expression. Cancer Res. 63, 4626–4631 (2003).

    CAS  PubMed  Google Scholar 

  189. Noah, T. K., Kazanjian, A., Whitsett, J. & Shroyer, N. F. SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells. Exp. Cell Res. 316, 452–465 (2010).

    Article  CAS  PubMed  Google Scholar 

  190. Turner, D. P., Moussa, O., Sauane, M., Fisher, P. B. & Watson, D. K. Prostate-derived ETS factor is a mediator of metastatic potential through the inhibition of migration and invasion in breast cancer. Cancer Res. 67, 1618–1625 (2007).

    Article  CAS  PubMed  Google Scholar 

  191. Martin, M. E., Piette, J., Yaniv, M., Tang, W. J. & Folk, W. R. Activation of the polyomavirus enhancer by a murine activator protein 1 (AP1) homolog and two contiguous proteins. Proc. Natl Acad. Sci. USA 85, 5839–5843 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Wasylyk, B. et al. The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation. Nature 346, 191–193 (1990).

    Article  CAS  PubMed  Google Scholar 

  193. Xin, J. H., Cowie, A., Lachance, P. & Hassell, J. A. Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is differentially expressed in mouse embryonic cells. Genes Dev. 6, 481–496 (1992).

    Article  CAS  PubMed  Google Scholar 

  194. Han, B. et al. A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5–ETV4 fusion protein in prostate cancer. Cancer Res. 68, 7629–7637 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Kaneko, Y. et al. Fusion of an ETS-family gene, EIAF, to EWS by t(17;22)(q12;q12) chromosome translocation in an undifferentiated sarcoma of infancy. Genes Chromosomes Cancer 15, 115–121 (1996).

    Article  CAS  PubMed  Google Scholar 

  196. Urano, F., Umezawa, A., Hong, W., Kikuchi, H. & Hata, J. A novel chimera gene between EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein, in extraosseous Ewing's sarcoma. Biochem. Biophys. Res. Commun. 219, 608–612 (1996).

    Article  CAS  PubMed  Google Scholar 

  197. Chotteau-Lelievre, A. et al. Prognostic value of ERM gene expression in human primary breast cancers. Clin. Cancer Res. 10, 7297–7303 (2004).

    Article  CAS  PubMed  Google Scholar 

  198. Attard, G. et al. Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer. Br. J. Cancer 99, 314–320 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Jeon, I. S. et al. A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene 10, 1229–1234 (1995).

    CAS  PubMed  Google Scholar 

  200. Klemsz, M. J., McKercher, S. R., Celada, A., Van Beveren, C. & Maki, R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell 61, 113–124 (1990).

    Article  CAS  PubMed  Google Scholar 

  201. Moreau-Gachelin, F., Tavitian, A. & Tambourin, P. Spi-1 is a putative oncogene in virally induced murine erythroleukaemias. Nature 331, 277–280 (1988).

    Article  CAS  PubMed  Google Scholar 

  202. Mueller, B. U. et al. Heterozygous PU.1 mutations are associated with acute myeloid leukemia. Blood 100, 998–1007 (2002).

    Article  CAS  PubMed  Google Scholar 

  203. Care, M. A. et al. SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity. Nucleic Acids Res. 42, 7591–7610 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Montes-Moreno, S. et al. SPIB, a novel immunohistochemical marker for human blastic plasmacytoid dendritic cell neoplasms: characterization of its expression in major hematolymphoid neoplasms. Blood 121, 643–647 (2013).

    Article  CAS  PubMed  Google Scholar 

  205. Patki, M. et al. The ETS domain transcription factor ELK1 directs a critical component of growth signaling by the androgen receptor in prostate cancer cells. J. Biol. Chem. 288, 11047–11065 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Zhang, Y. et al. Chimeric transcript generated by cis-splicing of adjacent genes regulates prostate cancer cell proliferation. Cancer Discov. 2, 598–607 (2012).

    Article  CAS  PubMed  Google Scholar 

  207. Brenca, M. et al. Transcriptome sequencing identifies ETV6–NTRK3 as a gene fusion involved in GIST. J. Pathol. 238, 543–549 (2016).

    Article  CAS  PubMed  Google Scholar 

  208. Kumar-Sinha, C., Kalyana-Sundaram, S. & Chinnaiyan, A. M. Landscape of gene fusions in epithelial cancers: seq and ye shall find. Genome Med. 7, 129 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Golub, T. R., Barker, G. F., Lovett, M. & Gilliland, D. G. Fusion of PDGF receptor β to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 77, 307–316 (1994).

    Article  CAS  PubMed  Google Scholar 

  210. Van Vlierberghe, P. et al. ETV6 mutations in early immature human T cell leukemias. J. Exp. Med. 208, 2571–2579 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Cardone, M. et al. The novel ETS factor TEL2 cooperates with Myc in B lymphomagenesis. Mol. Cell. Biol. 25, 2395–2405 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Carella, C. et al. The ETS factor TEL2 is a hematopoietic oncoprotein. Blood 107, 1124–1132 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Sang, Y. et al. TEL2 suppresses metastasis by down-regulating SERPINE1 in nasopharyngeal carcinoma. Oncotarget 6, 29240–29253 (2015).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

M.C.O. acknowledges the US National Institutes of Health (P01-CA097189). G.M.S. was supported by a Congressionally Directed Medical Research Program Postdoctoral Fellowship (W81XWH-14-1-0040). J.R.P. was supported by a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship (F31CA189757). G.M.S., J.R.P, and S.B. were all supported by The Ohio State University Comprehensive Cancer Center Pelotonia Fellowship Program.

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  1. The Comprehensive Cancer Center, The Ohio State University,

    Gina M. Sizemore, Jason R. Pitarresi, Subhasree Balakrishnan & Michael C. Ostrowski

  2. Department of Cancer Biology and Genetics, The Ohio State University, 598 Biomedical Research Tower, 460 W. 12th Avenue, Columbus, 43210, Ohio, USA

    Gina M. Sizemore, Jason R. Pitarresi, Subhasree Balakrishnan & Michael C. Ostrowski

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Cis-acting mutation

A mutation within the regulatory DNA sequence of a gene that alters transcription.

Trans-acting mechanism

Protein–protein interaction that alters the activity of one of the constituents.

Li–Fraumeni syndrome

Hereditary predisposition to cancer due to germline mutations in TP53.

Basal-like breast cancer

(BLBC). Molecular subtype of breast cancer exhibiting basal-like epithelial gene expression and less favourable patient outcome.

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Molecular subtype of breast cancer exhibiting mesenchymal gene expression.

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Molecular subtype of breast cancer exhibiting luminal epithelial gene expression and more favourable patient outcome.

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Referring to the intestinal muscle coat.

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Chemotherapeutic agent that induces DNA breaks.

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Effects observed within the tumour imposed by cells of the microenvironment.

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Sizemore, G., Pitarresi, J., Balakrishnan, S. et al. The ETS family of oncogenic transcription factors in solid tumours. Nat Rev Cancer 17, 337–351 (2017). https://doi.org/10.1038/nrc.2017.20

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