Cellular and Molecular Life Sciences

, Volume 73, Issue 6, pp 1159–1172 | Cite as

FOXO transcription factors in cancer development and therapy

  • Alexandra Coomans de Brachène
  • Jean-Baptiste DemoulinEmail author


The forkhead box O (FOXO) transcription factors are considered as tumor suppressors that limit cell proliferation and induce apoptosis. FOXO gene alterations have been described in a limited number of human cancers, such as rhabdomyosarcoma, leukemia and lymphoma. In addition, FOXO proteins are inactivated by major oncogenic signals such as the phosphatidylinositol-3 kinase pathway and MAP kinases. Their expression is also repressed by micro-RNAs in multiple cancer types. FOXOs are mediators of the tumor response to various therapies. However, paradoxical roles of FOXOs in cancer progression were recently described. FOXOs contribute to the maintenance of leukemia-initiating cells in acute and chronic myeloid leukemia. These factors may also promote invasion and metastasis of subsets of colon and breast cancers. Resistance to treatment was also ascribed to FOXO activation in multiple cases, including targeted therapies. In this review, we discuss the complex role of FOXOs in cancer development and response to therapy.


FOXO1 FOXO3 FOXO4 Cancer stem cells Tumor-initiating cells Cell cycle Cell invasion Metastasis 



This project was supported by grants from Salus Sanguinis foundation and from “Actions de Recherche Concertées” (Communauté Française de Belgique, Belgium). We apologize to authors whose excellent work could not be cited due to space limitation.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Fu Z, Tindall DJ (2008) FOXOs, cancer and regulation of apoptosis. Oncogene 27(16):2312–2319. doi: 10.1038/onc.2008.24 PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC (1998) Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Genomics 47(2):187–199. doi: 10.1006/geno.1997.5122 PubMedCrossRefGoogle Scholar
  3. 3.
    Furuyama T, Nakazawa T, Nakano I, Mori N (2000) Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem J 349(Pt 2):629–634PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP (2003) FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 278(38):35959–35967. doi: 10.1074/jbc.M302804200 PubMedCrossRefGoogle Scholar
  5. 5.
    Hosaka T, Biggs WH 3rd, Tieu D, Boyer AD, Varki NM, Cavenee WK, Arden KC (2004) Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci USA 101(9):2975–2980. doi: 10.1073/pnas.0400093101 PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27(16):2276–2288. doi: 10.1038/onc.2008.21 PubMedCrossRefGoogle Scholar
  7. 7.
    Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6):857–868PubMedCrossRefGoogle Scholar
  8. 8.
    Van Der Heide LP, Hoekman MF, Smidt MP (2004) The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochem J 380(Pt 2):297–309. doi: 10.1042/BJ20040167 CrossRefGoogle Scholar
  9. 9.
    Wang Y, Zhou Y, Graves DT (2014) FOXO transcription factors: their clinical significance and regulation. BioMed Res Int 2014:925350. doi: 10.1155/2014/925350 PubMedCentralPubMedGoogle Scholar
  10. 10.
    Essaghir A, Dif N, Marbehant CY, Coffer PJ, Demoulin JB (2009) The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors. J Biol Chem 284(16):10334–10342. doi: 10.1074/jbc.M808848200 PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    van der Vos KE, Coffer PJ (2011) The extending network of FOXO transcriptional target genes. Antioxid Redox Signal 14(4):579–592. doi: 10.1089/ars.2010.3419 PubMedCrossRefGoogle Scholar
  12. 12.
    Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA (2007) FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128(2):309–323. doi: 10.1016/j.cell.2006.12.029 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Shaw RJ, Cantley LC (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441(7092):424–430. doi: 10.1038/nature04869 PubMedCrossRefGoogle Scholar
  14. 14.
    Kharas MG, Deane JA, Wong S, O’Bosky KR, Rosenberg N, Witte ON, Fruman DA (2004) Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells. Blood 103(11):4268–4275. doi: 10.1182/blood-2003-07-2193 PubMedCrossRefGoogle Scholar
  15. 15.
    Scheijen B, Ngo HT, Kang H, Griffin JD (2004) FLT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins. Oncogene 23(19):3338–3349. doi: 10.1038/sj.onc.1207456 PubMedCrossRefGoogle Scholar
  16. 16.
    Reagan-Shaw S, Ahmad N (2006) RNA interference-mediated depletion of phosphoinositide 3-kinase activates forkhead box class O transcription factors and induces cell cycle arrest and apoptosis in breast carcinoma cells. Cancer Res 66(2):1062–1069. doi: 10.1158/0008-5472.CAN-05-1018 PubMedCrossRefGoogle Scholar
  17. 17.
    Prasad SB, Yadav SS, Das M, Govardhan HB, Pandey LK, Singh S, Pradhan S, Narayan G (2014) Down regulation of FOXO1 promotes cell proliferation in cervical cancer. J Cancer 5(8):655–662. doi: 10.7150/jca.6554 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Kelly-Spratt KS, Philipp-Staheli J, Gurley KE, Hoon-Kim K, Knoblaugh S, Kemp CJ (2009) Inhibition of PI-3K restores nuclear p27Kip1 expression in a mouse model of Kras-driven lung cancer. Oncogene 28(41):3652–3662. doi: 10.1038/onc.2009.226 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Weidinger C, Krause K, Mueller K, Klagge A, Fuhrer D (2011) FOXO3 is inhibited by oncogenic PI3K/Akt signaling but can be reactivated by the NSAID sulindac sulfide. J Clin Endocrinol Metab 96(9):E1361–E1371. doi: 10.1210/jc.2010-2453 PubMedCrossRefGoogle Scholar
  20. 20.
    Xie L, Ushmorov A, Leithauser F, Guan H, Steidl C, Farbinger J, Pelzer C, Vogel MJ, Maier HJ, Gascoyne RD, Moller P, Wirth T (2012) FOXO1 is a tumor suppressor in classical Hodgkin lymphoma. Blood 119(15):3503–3511. doi: 10.1182/blood-2011-09-381905 PubMedCrossRefGoogle Scholar
  21. 21.
    Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, Lang JY, Lai CC, Chang CJ, Huang WC, Huang H, Kuo HP, Lee DF, Li LY, Lien HC, Cheng X, Chang KJ, Hsiao CD, Tsai FJ, Tsai CH, Sahin AA, Muller WJ, Mills GB, Yu D, Hortobagyi GN, Hung MC (2008) ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10(2):138–148. doi: 10.1038/ncb1676 PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Sunayama J, Sato A, Matsuda K, Tachibana K, Watanabe E, Seino S, Suzuki K, Narita Y, Shibui S, Sakurada K, Kayama T, Tomiyama A, Kitanaka C (2011) FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity. Stem Cells 29(9):1327–1337. doi: 10.1002/stem.696 PubMedGoogle Scholar
  23. 23.
    Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y, Bao S, Hanada N, Saso H, Kobayashi R, Hung MC (2004) IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117(2):225–237PubMedCrossRefGoogle Scholar
  24. 24.
    Chapuis N, Park S, Leotoing L, Tamburini J, Verdier F, Bardet V, Green AS, Willems L, Agou F, Ifrah N, Dreyfus F, Bismuth G, Baud V, Lacombe C, Mayeux P, Bouscary D (2010) IkappaB kinase overcomes PI3K/Akt and ERK/MAPK to control FOXO3a activity in acute myeloid leukemia. Blood 116(20):4240–4250. doi: 10.1182/blood-2009-12-260711 PubMedCrossRefGoogle Scholar
  25. 25.
    Guo JP, Tian W, Shu S, Xin Y, Shou C, Cheng JQ (2013) IKBKE phosphorylation and inhibition of FOXO3a: a mechanism of IKBKE oncogenic function. PLoS One 8(5):e63636. doi: 10.1371/journal.pone.0063636 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Lin H, Dai T, Xiong H, Zhao X, Chen X, Yu C, Li J, Wang X, Song L (2010) Unregulated miR-96 induces cell proliferation in human breast cancer by downregulating transcriptional factor FOXO3a. PLoS One 5(12):e15797. doi: 10.1371/journal.pone.0015797 PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Guo Y, Liu H, Zhang H, Shang C, Song Y (2012) miR-96 regulates FOXO1-mediated cell apoptosis in bladder cancer. Oncol Lett 4(3):561–565. doi: 10.3892/ol.2012.775 PubMedCentralPubMedGoogle Scholar
  28. 28.
    Segura MF, Hanniford D, Menendez S, Reavie L, Zou X, Alvarez-Diaz S, Zakrzewski J, Blochin E, Rose A, Bogunovic D, Polsky D, Wei J, Lee P, Belitskaya-Levy I, Bhardwaj N, Osman I, Hernando E (2009) Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci USA 106(6):1814–1819. doi: 10.1073/pnas.0808263106 PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Guttilla IK, White BA (2009) Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. J Biol Chem 284(35):23204–23216. doi: 10.1074/jbc.M109.031427 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Myatt SS, Wang J, Monteiro LJ, Christian M, Ho KK, Fusi L, Dina RE, Brosens JJ, Ghaem-Maghami S, Lam EW (2010) Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer. Cancer Res 70(1):367–377. doi: 10.1158/0008-5472.CAN-09-1891 PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Wu Z, Sun H, Zeng W, He J, Mao X (2012) Upregulation of MircoRNA-370 induces proliferation in human prostate cancer cells by downregulating the transcription factor FOXO1. PLoS One 7(9):e45825. doi: 10.1371/journal.pone.0045825 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Pei H, Jin Z, Chen S, Sun X, Yu J, Guo W (2014) MiR-135b promotes proliferation and invasion of osteosarcoma cells via targeting FOXO1. Mol Cell Biochem. doi: 10.1007/s11010-014-2281-2 Google Scholar
  33. 33.
    Yang XW, Shen GZ, Cao LQ, Jiang XF, Peng HP, Shen G, Chen D, Xue P (2014) MicroRNA-1269 promotes proliferation in human hepatocellular carcinoma via downregulation of FOXO1. BMC Cancer 14(1):909. doi: 10.1186/1471-2407-14-909 PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Zhao Z, Qin L, Li S (2015) miR-411 contributes the cell proliferation of lung cancer by targeting FOXO1. Tumour Biol J Int Soc Oncodev Biol Med. doi: 10.1007/s13277-015-4425-8 Google Scholar
  35. 35.
    Ho KK, Myatt SS, Lam EW (2008) Many forks in the path: cycling with FoxO. Oncogene 27(16):2300–2311. doi: 10.1038/onc.2008.23 PubMedCrossRefGoogle Scholar
  36. 36.
    Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, Place RF, Pookot D, Majid S, Igawa M, Dahiya R (2007) Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene 26(55):7647–7655. doi: 10.1038/sj.onc.1210572 PubMedCrossRefGoogle Scholar
  37. 37.
    Shiota M, Song Y, Yokomizo A, Kiyoshima K, Tada Y, Uchino H, Uchiumi T, Inokuchi J, Oda Y, Kuroiwa K, Tatsugami K, Naito S (2010) Foxo3a suppression of urothelial cancer invasiveness through Twist1, Y-box-binding protein 1, and E-cadherin regulation. Clin Cancer Res Off J Am Assoc Cancer Res 16(23):5654–5663. doi: 10.1158/1078-0432.CCR-10-0376 CrossRefGoogle Scholar
  38. 38.
    Su B, Gao L, Baranowski C, Gillard B, Wang J, Ransom R, Ko HK, Gelman IH (2014) A genome-wide RNAi screen identifies FOXO4 as a metastasis-suppressor through counteracting PI3K/AKT signal pathway in prostate cancer. PLoS One 9(7):e101411. doi: 10.1371/journal.pone.0101411 PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Zhang H, Pan Y, Zheng L, Choe C, Lindgren B, Jensen ED, Westendorf JJ, Cheng L, Huang H (2011) FOXO1 inhibits Runx2 transcriptional activity and prostate cancer cell migration and invasion. Cancer Res 71(9):3257–3267. doi: 10.1158/0008-5472.CAN-10-2603 PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, Hollstein PE, MacCollin M, Cichowski K (2006) A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10(6):459–472. doi: 10.1016/j.ccr.2006.10.003 PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    de Keizer PL, Packer LM, Szypowska AA, Riedl-Polderman PE, van den Broek NJ, de Bruin A, Dansen TB, Marais R, Brenkman AB, Burgering BM (2010) Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Res 70(21):8526–8536. doi: 10.1158/0008-5472.CAN-10-1563 PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Yoo SY, Kwon SM (2013) Angiogenesis and its therapeutic opportunities. Mediators Inflamm 2013:127170. doi: 10.1155/2013/127170 PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Furuyama T, Kitayama K, Shimoda Y, Ogawa M, Sone K, Yoshida-Araki K, Hisatsune H, Nishikawa S, Nakayama K, Ikeda K, Motoyama N, Mori N (2004) Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J Biol Chem 279(33):34741–34749. doi: 10.1074/jbc.M314214200 PubMedCrossRefGoogle Scholar
  44. 44.
    Abid MR, Shih SC, Otu HH, Spokes KC, Okada Y, Curiel DT, Minami T, Aird WC (2006) A novel class of vascular endothelial growth factor-responsive genes that require forkhead activity for expression. J Biol Chem 281(46):35544–35553. doi: 10.1074/jbc.M608620200 PubMedCrossRefGoogle Scholar
  45. 45.
    Daly C, Wong V, Burova E, Wei Y, Zabski S, Griffiths J, Lai KM, Lin HC, Ioffe E, Yancopoulos GD, Rudge JS (2004) Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev 18(9):1060–1071. doi: 10.1101/gad.1189704 PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Potente M, Urbich C, Sasaki K, Hofmann WK, Heeschen C, Aicher A, Kollipara R, DePinho RA, Zeiher AM, Dimmeler S (2005) Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Investig 115(9):2382–2392. doi: 10.1172/JCI23126 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Kim SY, Yoon J, Ko YS, Chang MS, Park JW, Lee HE, Kim MA, Kim JH, Kim WH, Lee BL (2011) Constitutive phosphorylation of the FOXO1 transcription factor in gastric cancer cells correlates with microvessel area and the expressions of angiogenesis-related molecules. BMC Cancer 11:264. doi: 10.1186/1471-2407-11-264 PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Yalcin S, Marinkovic D, Mungamuri SK, Zhang X, Tong W, Sellers R, Ghaffari S (2010) ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(−/−) mice. EMBO J 29(24):4118–4131. doi: 10.1038/emboj.2010.292 PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C, Armstrong SA, Passegue E, DePinho RA, Gilliland DG (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128(2):325–339. doi: 10.1016/j.cell.2007.01.003 PubMedCrossRefGoogle Scholar
  50. 50.
    Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S, Wang D, Feng J, Yu L, Zhu WG (2010) Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 12(7):665–675. doi: 10.1038/ncb2069 PubMedCrossRefGoogle Scholar
  51. 51.
    Wang F, Marshall CB, Yamamoto K, Li GY, Plevin MJ, You H, Mak TW, Ikura M (2008) Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53. J Mol Biol 384(3):590–603. doi: 10.1016/j.jmb.2008.09.025 PubMedCrossRefGoogle Scholar
  52. 52.
    You H, Yamamoto K, Mak TW (2006) Regulation of transactivation-independent proapoptotic activity of p53 by FOXO3a. Proc Natl Acad Sci USA 103(24):9051–9056. doi: 10.1073/pnas.0600889103 PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Bouchard C, Lee S, Paulus-Hock V, Loddenkemper C, Eilers M, Schmitt CA (2007) FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev 21(21):2775–2787. doi: 10.1101/gad.453107 PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Renault VM, Thekkat PU, Hoang KL, White JL, Brady CA, Kenzelmann Broz D, Venturelli OS, Johnson TM, Oskoui PR, Xuan Z, Santo EE, Zhang MQ, Vogel H, Attardi LD, Brunet A (2011) The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor. Oncogene 30(29):3207–3221. doi: 10.1038/onc.2011.35 PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ 3rd, Emanuel BS, Rovera G, Barr FG (1993) Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 5(3):230–235. doi: 10.1038/ng1193-230 PubMedCrossRefGoogle Scholar
  56. 56.
    Davis RJ, D’Cruz CM, Lovell MA, Biegel JA, Barr FG (1994) Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res 54(11):2869–2872PubMedGoogle Scholar
  57. 57.
    Xia SJ, Holder DD, Pawel BR, Zhang C, Barr FG (2009) High expression of the PAX3-FKHR oncoprotein is required to promote tumorigenesis of human myoblasts. Am J Pathol 175(6):2600–2608. doi: 10.2353/ajpath.2009.090192 PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Linardic CM (2008) PAX3-FOXO1 fusion gene in rhabdomyosarcoma. Cancer Lett 270(1):10–18. doi: 10.1016/j.canlet.2008.03.035 PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Mercado GE, Xia SJ, Zhang C, Ahn EH, Gustafson DM, Lae M, Ladanyi M, Barr FG (2008) Identification of PAX3-FKHR-regulated genes differentially expressed between alveolar and embryonal rhabdomyosarcoma: focus on MYCN as a biologically relevant target. Genes Chromosomes Cancer 47(6):510–520. doi: 10.1002/gcc.20554 PubMedCrossRefGoogle Scholar
  60. 60.
    Lagutina I, Conway SJ, Sublett J, Grosveld GC (2002) Pax3-FKHR knock-in mice show developmental aberrations but do not develop tumors. Mol Cell Biol 22(20):7204–7216PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Keller C, Arenkiel BR, Coffin CM, El-Bardeesy N, DePinho RA, Capecchi MR (2004) Alveolar rhabdomyosarcomas in conditional Pax3: Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev 18(21):2614–2626. doi: 10.1101/gad.1244004 PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Fredericks WJ, Galili N, Mukhopadhyay S, Rovera G, Bennicelli J, Barr FG, Rauscher FJ 3rd (1995) The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3. Mol Cell Biol 15(3):1522–1535PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Borkhardt A, Repp R, Haas OA, Leis T, Harbott J, Kreuder J, Hammermann J, Henn T, Lampert F (1997) Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene 14(2):195–202. doi: 10.1038/sj.onc.1200814 PubMedCrossRefGoogle Scholar
  64. 64.
    Hillion J, Le Coniat M, Jonveaux P, Berger R, Bernard OA (1997) AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. Blood 90(9):3714–3719PubMedGoogle Scholar
  65. 65.
    Dobson CL, Warren AJ, Pannell R, Forster A, Rabbitts TH (2000) Tumorigenesis in mice with a fusion of the leukaemia oncogene Mll and the bacterial lacZ gene. EMBO J 19(5):843–851. doi: 10.1093/emboj/19.5.843 PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    So CW, Cleary ML (2002) MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function. Mol Cell Biol 22(18):6542–6552PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    So CW, Cleary ML (2003) Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood 101(2):633–639. doi: 10.1182/blood-2002-06-1785 PubMedCrossRefGoogle Scholar
  68. 68.
    Sugita S, Arai Y, Tonooka A, Hama N, Totoki Y, Fujii T, Aoyama T, Asanuma H, Tsukahara T, Kaya M, Shibata T, Hasegawa T (2014) A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. Am J Surg Pathol 38(11):1571–1576. doi: 10.1097/PAS.0000000000000286 PubMedCrossRefGoogle Scholar
  69. 69.
    Solomon DA, Brohl AS, Khan J, Miettinen M (2014) Clinicopathologic features of a second patient with Ewing-like sarcoma harboring CIC-FOXO4 gene fusion. Am J Surg Pathol 38(12):1724–1725. doi: 10.1097/PAS.0000000000000335 PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, Johnson NA, Severson TM, Chiu R, Field M, Jackman S, Krzywinski M, Scott DW, Trinh DL, Tamura-Wells J, Li S, Firme MR, Rogic S, Griffith M, Chan S, Yakovenko O, Meyer IM, Zhao EY, Smailus D, Moksa M, Chittaranjan S, Rimsza L, Brooks-Wilson A, Spinelli JJ, Ben-Neriah S, Meissner B, Woolcock B, Boyle M, McDonald H, Tam A, Zhao Y, Delaney A, Zeng T, Tse K, Butterfield Y, Birol I, Holt R, Schein J, Horsman DE, Moore R, Jones SJ, Connors JM, Hirst M, Gascoyne RD, Marra MA (2011) Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476(7360):298–303. doi: 10.1038/nature10351 PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Trinh DL, Scott DW, Morin RD, Mendez-Lago M, An J, Jones SJ, Mungall AJ, Zhao Y, Schein J, Steidl C, Connors JM, Gascoyne RD, Marra MA (2013) Analysis of FOXO1 mutations in diffuse large B-cell lymphoma. Blood 121(18):3666–3674. doi: 10.1182/blood-2013-01-479865 PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Pellicano F, Scott MT, Helgason GV, Hopcroft LE, Allan EK, Aspinall-O’Dea M, Copland M, Pierce A, Huntly BJ, Whetton AD, Holyoake TL (2014) The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors. Stem Cells 32(9):2324–2337. doi: 10.1002/stem.1748 PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, Nakao S, Motoyama N, Hirao A (2010) TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463(7281):676–680. doi: 10.1038/nature08734 PubMedCrossRefGoogle Scholar
  74. 74.
    Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, Herzog S, Ramezani-Rad P, Jumaa H, Muller MC, Hofmann WK, Hochhaus A, Ye BH, Agarwal A, Druker BJ, Shah NP, Melnick AM, Muschen M (2011) BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J Exp Med 208(11):2163–2174. doi: 10.1084/jem.20110304 PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, Ferraro F, Mercier F, Singh H, Brumme KM, Acharya SS, Scholl C, Tothova Z, Attar EC, Frohling S, DePinho RA, Armstrong SA, Gilliland DG, Scadden DT (2011) AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 146(5):697–708. doi: 10.1016/j.cell.2011.07.032 PubMedCrossRefGoogle Scholar
  76. 76.
    Santamaria CM, Chillon MC, Garcia-Sanz R, Perez C, Caballero MD, Ramos F, de Coca AG, Alonso JM, Giraldo P, Bernal T, Queizan JA, Rodriguez JN, Fernandez-Abellan P, Barez A, Penarrubia MJ, Vidriales MB, Balanzategui A, Sarasquete ME, Alcoceba M, Diaz-Mediavilla J, San Miguel JF, Gonzalez M (2009) High FOXO3a expression is associated with a poorer prognosis in AML with normal cytogenetics. Leuk Res 33(12):1706–1709. doi: 10.1016/j.leukres.2009.04.024 PubMedCrossRefGoogle Scholar
  77. 77.
    Gargini R, Cerliani JP, Escoll M, Anton IM, Wandosell F (2015) Cancer stem cell-like phenotype and survival are coordinately regulated by Akt/FoxO/Bim pathway. Stem Cells 33(3):646–660. doi: 10.1002/stem.1904 PubMedCrossRefGoogle Scholar
  78. 78.
    Smit L, Berns K, Spence K, Ryder WD, Zeps N, Madiredjo M, Beijersbergen R, Bernards R, Clarke RB (2015) An integrated genomic approach identifies that the PI3K/AKT/FOXO pathway is involved in breast cancer tumor initiation. Oncotarget. doi: 10.18632/oncotarget.6354 Google Scholar
  79. 79.
    Prabhu VV, Allen JE, Dicker DT, El-Deiry WS (2015) Small-molecule ONC201/TIC10 targets chemotherapy-resistant colorectal cancer stem-like cells in an Akt/Foxo3a/TRAIL-dependent manner. Cancer Res 75(7):1423–1432. doi: 10.1158/0008-5472.CAN-13-3451 PubMedCrossRefGoogle Scholar
  80. 80.
    Tenbaum SP, Ordonez-Moran P, Puig I, Chicote I, Arques O, Landolfi S, Fernandez Y, Herance JR, Gispert JD, Mendizabal L, Aguilar S, y Cajal SR, Schwartz S Jr, Vivancos A, Espin E, Rojas S, Baselga J, Tabernero J, Munoz A, Palmer HG (2012) Beta-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med 18(6):892–901. doi: 10.1038/nm.2772 PubMedCrossRefGoogle Scholar
  81. 81.
    Arques O, Chicote I, Puig I, Tenbaum SP, Argiles G, Dienstmann R, Fernandez N, Caratu G, Matito J, Silberschmidt D, Rodon J, Landolfi S, Prat A, Espin E, Charco R, Nuciforo P, Vivancos A, Shao W, Tabernero J, Palmer HG (2015) Tankyrase inhibition blocks Wnt/beta-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. doi: 10.1158/1078-0432.CCR-14-3081 Google Scholar
  82. 82.
    Sisci D, Maris P, Cesario MG, Anselmo W, Coroniti R, Trombino GE, Romeo F, Ferraro A, Lanzino M, Aquila S, Maggiolini M, Mauro L, Morelli C, Ando S (2013) The estrogen receptor alpha is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness. Cell Cycle 12(21):3405–3420. doi: 10.4161/cc.26421 PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Storz P, Doppler H, Copland JA, Simpson KJ, Toker A (2009) FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases. Mol Cell Biol 29(18):4906–4917. doi: 10.1128/MCB.00077-09 PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Feng X, Wu Z, Wu Y, Hankey W, Prior TW, Li L, Ganju RK, Shen R, Zou X (2011) Cdc25A regulates matrix metalloprotease 1 through Foxo1 and mediates metastasis of breast cancer cells. Mol Cell Biol 31(16):3457–3471. doi: 10.1128/MCB.05523-11 PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Li Y, Yu J, Du D, Fu S, Chen Y, Yu F, Gao P (2013) Involvement of post-transcriptional regulation of FOXO1 by HuR in 5-FU-induced apoptosis in breast cancer cells. Oncol Lett 6(1):156–160. doi: 10.3892/ol.2013.1352 PubMedCentralPubMedGoogle Scholar
  86. 86.
    Sunters A, Fernandez de Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA, Coffer PJ, Medema RH, Coombes RC, Lam EW (2003) FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem 278(50):49795–49805. doi: 10.1074/jbc.M309523200 PubMedCrossRefGoogle Scholar
  87. 87.
    Essafi A, Fernandez de Mattos S, Hassen YA, Soeiro I, Mufti GJ, Thomas NS, Medema RH, Lam EW (2005) Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene 24(14):2317–2329. doi: 10.1038/sj.onc.1208421 PubMedCrossRefGoogle Scholar
  88. 88.
    Yang JY, Hung MC (2011) Deciphering the role of forkhead transcription factors in cancer therapy. Curr Drug Targets 12(9):1284–1290PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Chen Q, Ganapathy S, Singh KP, Shankar S, Srivastava RK (2010) Resveratrol induces growth arrest and apoptosis through activation of FOXO transcription factors in prostate cancer cells. PLoS One 5(12):e15288. doi: 10.1371/journal.pone.0015288 PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Roy SK, Srivastava RK, Shankar S (2010) Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal 5:10. doi: 10.1186/1750-2187-5-10 PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Valis K, Prochazka L, Boura E, Chladova J, Obsil T, Rohlena J, Truksa J, Dong LF, Ralph SJ, Neuzil J (2011) Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner. Cancer Res 71(3):946–954. doi: 10.1158/0008-5472.CAN-10-2203 PubMedCrossRefGoogle Scholar
  92. 92.
    Han CY, Cho KB, Choi HS, Han HK, Kang KW (2008) Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells. Carcinogenesis 29(9):1837–1844. doi: 10.1093/carcin/bgn092 PubMedCrossRefGoogle Scholar
  93. 93.
    Hui RC, Francis RE, Guest SK, Costa JR, Gomes AR, Myatt SS, Brosens JJ, Lam EW (2008) Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells. Mol Cancer Ther 7(3):670–678. doi: 10.1158/1535-7163.MCT-07-0397 PubMedCrossRefGoogle Scholar
  94. 94.
    Hui RC, Gomes AR, Constantinidou D, Costa JR, Karadedou CT, Fernandez de Mattos S, Wymann MP, Brosens JJ, Schulze A, Lam EW (2008) The forkhead transcription factor FOXO3a increases phosphoinositide-3 kinase/Akt activity in drug-resistant leukemic cells through induction of PIK3CA expression. Mol Cell Biol 28(19):5886–5898. doi: 10.1128/MCB.01265-07 PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, Majumder PK, Baselga J, Rosen N (2011) AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19(1):58–71. doi: 10.1016/j.ccr.2010.10.031 PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Lin A, Piao HL, Zhuang L, Sarbassov DD, Ma L, Gan B (2014) FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacological inhibition of the PI3K-AKT pathway. Cancer Res. doi: 10.1158/0008-5472.CAN-13-1729 Google Scholar
  97. 97.
    Ramanathan B, Jan KY, Chen CH, Hour TC, Yu HJ, Pu YS (2005) Resistance to paclitaxel is proportional to cellular total antioxidant capacity. Cancer Res 65(18):8455–8460. doi: 10.1158/0008-5472.CAN-05-1162 PubMedCrossRefGoogle Scholar
  98. 98.
    Goto T, Takano M, Hirata J, Tsuda H (2008) The involvement of FOXO1 in cytotoxic stress and drug-resistance induced by paclitaxel in ovarian cancers. Br J Cancer 98(6):1068–1075. doi: 10.1038/sj.bjc.6604279 PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Asada S, Daitoku H, Matsuzaki H, Saito T, Sudo T, Mukai H, Iwashita S, Kako K, Kishi T, Kasuya Y, Fukamizu A (2007) Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Cell Signal 19(3):519–527. doi: 10.1016/j.cellsig.2006.08.015 PubMedCrossRefGoogle Scholar
  100. 100.
    Matkar S, Sharma P, Gao S, Gurung B, Katona BW, Liao J, Muhammad AB, Kong XC, Wang L, Jin G, Dang CV, Hua X (2015) An epigenetic pathway regulates sensitivity of breast cancer cells to HER2 inhibition via FOXO/c-Myc axis. Cancer Cell 28(4):472–485. doi: 10.1016/j.ccell.2015.09.005 PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Wang W, Li NN, Du Y, Lv FF, Lin GQ (2013) FoxO3a and nilotinib-induced erythroid differentiation of CML-BC cells. Leuk Res 37(10):1309–1314. doi: 10.1016/j.leukres.2013.07.001 PubMedCrossRefGoogle Scholar
  102. 102.
    Szydlowski M, Kiliszek P, Sewastianik T, Jablonska E, Bialopiotrowicz E, Gorniak P, Polak A, Markowicz S, Nowak E, Grygorowicz MA, Prochorec-Sobieszek M, Szumera-Cieckiewicz A, Malenda A, Lech-Maranda E, Warzocha K, Juszczynski P (2015) FOXO1 activation is an effector of SYK and AKT inhibition in tonic BCR signal-dependent diffuse large B-cell lymphomas. Blood. doi: 10.1182/blood-2015-06-654111 PubMedGoogle Scholar

Copyright information

© Springer International Publishing 2015

Authors and Affiliations

  • Alexandra Coomans de Brachène
    • 1
  • Jean-Baptiste Demoulin
    • 1
    Email author
  1. Duve Institute, MEXP-UCL 74.30Université catholique de LouvainBrusselsBelgium

Personalised recommendations