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Frontiers of Medicine

, Volume 6, Issue 4, pp 376–380 | Cite as

Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance

  • Fung Zhao
  • Eric W. -F. Lam
Review

Abstract

The forkhead transcription factors FOXO and FOXM1 have pivotal roles in tumorigenesis and in mediating chemotherapy sensitivity and resistance. Recent research shows that the forkhead transcription factor FOXM1 is a direct transcriptional target repressed by the forkhead protein FOXO3a, a vital downstream effector of the PI3K-AKT-FOXO signaling pathway. Intriguingly, FOXM1 and FOXO3a also compete for binding to the same gene targets, which have a role in chemotherapeutic drug action and sensitivity. An understanding of the role and regulation of the FOXO-FOXM1 axis will impact directly on our knowledge of chemotherapeutic drug action and resistance in patients, and provide new insights into the design of novel therapeutic strategy and reliable biomarkers for prediction of drug sensitivity.

Keywords

FOXO3a FOXM1 transcription factor cancer drug resistance tumorigenesis 

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References

  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127(12): 2893–2917PubMedCrossRefGoogle Scholar
  2. 2.
    Wong ST, Goodin S. Overcoming drug resistance in patients with metastatic breast cancer. Pharmacotherapy 2009; 29(8): 954–965PubMedCrossRefGoogle Scholar
  3. 3.
    Nabholtz JM. Docetaxel-anthracycline combinations in metastatic breast cancer. Breast Cancer Res Treat 2003; 79( Suppl 1): S3–S9PubMedCrossRefGoogle Scholar
  4. 4.
    Glück S. Adjuvant chemotherapy for early breast cancer: optimal use of epirubicin. Oncologist 2005; 10(10): 780–791PubMedCrossRefGoogle Scholar
  5. 5.
    Brunello A, Roma A, Falci C, Basso U. Chemotherapy and targeted agents for elderly women with advanced breast cancer. Recent Patents Anticancer Drug Discov 2008; 3(3): 187–201CrossRefGoogle Scholar
  6. 6.
    Gomes AR, Brosens JJ, Lam EW. Resist or die: FOXO transcription factors determine the cellular response to chemotherapy. Cell Cycle 2008; 7(20): 3133–3136PubMedCrossRefGoogle Scholar
  7. 7.
    Wilson MS, Brosens JJ, Schwenen HD, Lam EW. FOXO and FOXM1 in cancer: the FOXO-FOXM1 axis shapes the outcome of cancer chemotherapy. Curr Drug Targets 2011; 12(9): 1256–1266PubMedCrossRefGoogle Scholar
  8. 8.
    Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 2007; 7(11): 847–859PubMedCrossRefGoogle Scholar
  9. 9.
    Ho KK, Myatt SS, Lam EW. Many forks in the path: cycling with FoxO. Oncogene 2008; 27(16): 2300–2311PubMedCrossRefGoogle Scholar
  10. 10.
    Lam EW, Francis RE, Petkovic M. FOXO transcription factors: key regulators of cell fate. Biochem Soc Trans 2006; 34(Pt 5): 722–726PubMedGoogle Scholar
  11. 11.
    Brosens JJ, Parker MG, McIndoe A, Pijnenborg R, Brosens IA. A role for menstruation in preconditioning the uterus for successful pregnancy. Am J Obstet Gynecol 2009; 200(6):615. e1–6PubMedCrossRefGoogle Scholar
  12. 12.
    Sunters A, Fernández de Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA, Coffer PJ, Medema RH, Coombes RC, Lam EW. FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem 2003; 278(50): 49795–49805PubMedCrossRefGoogle Scholar
  13. 13.
    Sunters A, Madureira PA, Pomeranz KM, Aubert M, Brosens JJ, Cook SJ, Burgering BM, Coombes RC, Lam EW. Paclitaxelinduced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Cancer Res 2006; 66(1): 212–220PubMedCrossRefGoogle Scholar
  14. 14.
    Hui RC, Francis RE, Guest SK, Costa JR, Gomes AR, Myatt SS, Brosens JJ, Lam EW. Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells. Mol Cancer Ther 2008; 7(3): 670–678PubMedCrossRefGoogle Scholar
  15. 15.
    Hui RC, Gomes AR, Constantinidou D, Costa JR, Karadedou CT, Fernandez de Mattos S, Wymann MP, Brosens JJ, Schulze A, Lam EW. The forkhead transcription factor FOXO3a increases phosphoinositide-3 kinase/Akt activity in drug-resistant leukemic cells through induction of PIK3CA expression. Mol Cell Biol 2008; 28(19): 5886–5898PubMedCrossRefGoogle Scholar
  16. 16.
    Francis RE, Myatt SS, Krol J, Hartman J, Peck B, McGovern UB, Wang J, Guest SK, Filipovic A, Gojis O, Palmieri C, Peston D, Shousha S, Yu Q, Sicinski P, Coombes RC, Lam EW. FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer. Int J Oncol 2009; 35(1): 57–68PubMedGoogle Scholar
  17. 17.
    McGovern UB, Francis RE, Peck B, Guest SK, Wang J, Myatt SS, Krol J, Kwok JM, Polychronis A, Coombes RC, Lam EW. Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer. Mol Cancer Ther 2009; 8(3): 582–591PubMedCrossRefGoogle Scholar
  18. 18.
    Krol J, Francis RE, Albergaria A, Sunters A, Polychronis A, Coombes RC, Lam EW. The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells. Mol Cancer Ther 2007; 6(12 Pt 1): 3169–3179PubMedCrossRefGoogle Scholar
  19. 19.
    Fernández de Mattos S, Essafi A, Soeiro I, Pietersen AM, Birkenkamp KU, Edwards CS, Martino A, Nelson BH, Francis JM, Jones MC, Brosens JJ, Coffer PJ, Lam EW. FoxO3a and BCRABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism. Mol Cell Biol 2004; 24(22): 10058–10071PubMedCrossRefGoogle Scholar
  20. 20.
    Birkenkamp KU, Essafi A, van der Vos KE, da Costa M, Hui RC, Holstege F, Koenderman L, Lam EW, Coffer PJ. FOXO3a induces differentiation of Bcr-Abl-transformed cells through transcriptional down-regulation of Id1. J Biol Chem 2007; 282(4): 2211–2220PubMedCrossRefGoogle Scholar
  21. 21.
    Essafi A, Fernández de Mattos S, Hassen YA, Soeiro I, Mufti GJ, Thomas NS, Medema RH, Lam EW. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene 2005; 24(14): 2317–2329PubMedCrossRefGoogle Scholar
  22. 22.
    Fernández de Mattos S, Villalonga P, Clardy J, Lam EW. FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells. Mol Cancer Ther 2008; 7(10): 3237–3246PubMedCrossRefGoogle Scholar
  23. 23.
    Ho KK, McGuire VA, Koo CY, Muir KW, de Olano N, Maifoshie E, Kelly DJ, McGovern UB, Monteiro LJ, Gomes AR, Nebreda AR, Campbell DG, Arthur JS, Lam EW. Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin. J Biol Chem 2012; 287(2): 1545–1555PubMedCrossRefGoogle Scholar
  24. 24.
    Myatt SS, Lam EW. Targeting FOXM1. Nat Rev Cancer 2008; 8(3): 242PubMedCrossRefGoogle Scholar
  25. 25.
    Pilarsky C, Wenzig M, Specht T, Saeger HD, Grützmann R. Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. Neoplasia 2004; 6(6): 744–750PubMedCrossRefGoogle Scholar
  26. 26.
    Uddin S, Ahmed M, Hussain A, Abubaker J, Al-Sanea N, AbdulJabbar A, Ashari LH, Alhomoud S, Al-Dayel F, Jehan Z, Bavi P, Siraj AK, Al-Kuraya KS. Genome-wide expression analysis of Middle Eastern colorectal cancer reveals FOXM1 as a novel target for cancer therapy. Am J Pathol 2011; 178(2): 537–547PubMedCrossRefGoogle Scholar
  27. 27.
    Okabe H, Satoh S, Kato T, Kitahara O, Yanagawa R, Yamaoka Y, Tsunoda T, Furukawa Y, Nakamura Y. Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res 2001; 61(5): 2129–2137PubMedGoogle Scholar
  28. 28.
    Gemenetzidis E, Elena-Costea D, Parkinson EK, Waseem A, Wan H, Teh MT. Induction of human epithelial stem/progenitor expansion by FOXM1. Cancer Res 2010; 70(22): 9515–9526PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, Huang H, Xue J, Liu M, Wang Y, Sawaya R, Xie K, Yung WK, Medema RH, He X, Huang S. FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell 2011; 20(4): 427–442PubMedCrossRefGoogle Scholar
  30. 30.
    Wang Z, Park HJ, Carr JR, Chen YJ, Zheng Y, Li J, Tyner AL, Costa RH, Bagchi S, Raychaudhuri P. FoxM1 in tumorigenicity of the neuroblastoma cells and renewal of the neural progenitors. Cancer Res 2011; 71(12): 4292–4302PubMedCrossRefGoogle Scholar
  31. 31.
    Bao B, Wang Z, Ali S, Kong D, Banerjee S, Ahmad A, Li Y, Azmi AS, Miele L, Sarkar FH. Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J Cell Biochem 2011; 112(9): 2296–2306PubMedCrossRefGoogle Scholar
  32. 32.
    Laoukili J, Stahl M, Medema RH. FoxM1: at the crossroads of ageing and cancer. Biochim Biophys Acta 2007; 1775(1): 92–102PubMedGoogle Scholar
  33. 33.
    Laoukili J, Kooistra MR, Brás A, Kauw J, Kerkhoven RM, Morrison A, Clevers H, Medema RH. FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat Cell Biol 2005; 7(2): 126–136PubMedCrossRefGoogle Scholar
  34. 34.
    Chen J, Gomes AR, Monteiro LJ, Wong SY, Wu LH, Ng TT, Karadedou CT, Millour J, Ip YC, Cheung YN, Sunters A, Chan KY, Lam EW, Khoo US. Constitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer. PLoS ONE 2010; 5(8): e12293PubMedCrossRefGoogle Scholar
  35. 35.
    Kwok JM, Peck B, Monteiro LJ, Schwenen HD, Millour J, Coombes RC, Myatt SS, Lam EW. FOXM1 confers acquired cisplatin resistance in breast cancer cells. Mol Cancer Res 2010; 8(1): 24–34PubMedCrossRefGoogle Scholar
  36. 36.
    Millour J, de Olano N, Horimoto Y, Monteiro LJ, Langer JK, Aligue R, Hajji N, Lam EW. ATMand p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Mol Cancer Ther 2011; 10(6): 1046–1058PubMedCrossRefGoogle Scholar
  37. 37.
    de Olano N, Koo CY, Monteiro LJ, Pinto PH, Gomes AR, Aligue R, Lam EW. The p38 MAPK-MK2 axis regulates E2F1 and FOXM1 expression after epirubicin treatment. Mol Cancer Res 2012;10(9):1189–1202PubMedCrossRefGoogle Scholar
  38. 38.
    Tan Y, Raychaudhuri P, Costa RH. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Mol Cell Biol 2007; 27(3): 1007–1016PubMedCrossRefGoogle Scholar
  39. 39.
    Park YY, Jung SY, Jennings NB, Rodriguez-Aguayo C, Peng G, Lee SR, Kim SB, Kim K, Leem SH, Lin SY, Lopez-Berestein G, Sood AK, Lee JS. FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair. Carcinogenesis 2012 Sep 3. [Epub ahead of print] DOI: 10.1093/carcin/bgs167Google Scholar
  40. 40.
    Millour J, Constantinidou D, Stavropoulou AV, Wilson MS, Myatt SS, Kwok JM, Sivanandan K, Coombes RC, Medema RH, Hartman J, Lykkesfeldt AE, Lam EW. FOXM1 is a transcriptional target of ERalpha and has a critical role in breast cancer endocrine sensitivity and resistance. Oncogene 2010; 29(20): 2983–2995PubMedCrossRefGoogle Scholar
  41. 41.
    Madureira PA, Varshochi R, Constantinidou D, Francis RE, Coombes RC, Yao KM, Lam EW. The Forkhead box M1 protein regulates the transcription of the estrogen receptor alpha in breast cancer cells. J Biol Chem 2006; 281(35): 25167–25176PubMedCrossRefGoogle Scholar
  42. 42.
    Horimoto Y, Hartman J, Millour J, Pollock S, Olmos Y, Ho KK, Coombes RC, Poutanen M, Mäkelä SI, El-Bahrawy M, Speirs V, Lam EW. ERβ1 represses FOXM1 expression through targeting ERα to control cell proliferation in breast cancer. Am J Pathol 2011; 179(3): 1148–1156PubMedCrossRefGoogle Scholar
  43. 43.
    Koo CY, Muir KW, Lam EW. FOXM1: From cancer initiation to progression and treatment. Biochim Biophys Acta 2012; 1819(1): 28–37PubMedCrossRefGoogle Scholar
  44. 44.
    Karadedou CT, Gomes AR, Chen J, Petkovic M, Ho KK, Zwolinska AK, Feltes A, Wong SY, Chan KY, Cheung YN, Tsang JW, Brosens JJ, Khoo US, Lam EW. FOXO3a represses VEGF expression through FOXM1-dependent and-independent mechanisms in breast cancer. Oncogene 2012; 31(14): 1845–1858PubMedCrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Surgery and CancerImperial College LondonLondonUK

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