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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2012, Vol. 6 Issue (4) : 376-380     DOI: 10.1007/s11684-012-0228-0
REVIEW |
Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance
Fung Zhao, Eric W.-F. Lam()
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
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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     
Corresponding Authors: Lam Eric W.-F.,Email:eric.lam@imperial.ac.uk   
Issue Date: 05 December 2012
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-012-0228-0     OR     http://academic.hep.com.cn/fmd/EN/Y2012/V6/I4/376
Fig.1  Integration of signals with FOXO and FOXM1 axis upon stimulation of chemotherapeutic drugs. Hemotherapeutic drugs have various modes of action but ultimately integrate signals with the PI3K-AKT-FOXO-FOXM1 signaling cascade. FOXO and FOXM1 then exert antagonistic functions in the regulation of target genes, which in turn control cancer-related processes including drug resistance, angiogenesis and migration.
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): 2893-2917
doi: 10.1002/ijc.25516 pmid:21351269
2 Wong ST, Goodin S. Overcoming drug resistance in patients with metastatic breast cancer. Pharmacotherapy 2009; 29(8): 954-965
doi: 10.1592/phco.29.8.954 pmid:19637949
3 Nabholtz JM. Docetaxel-anthracycline combinations in metastatic breast cancer. Breast Cancer Res Treat 2003; 79( Suppl 1): S3-S9
doi: 10.1023/A:1024369220605 pmid:12868800
4 Glück S. Adjuvant chemotherapy for early breast cancer: optimal use of epirubicin. Oncologist 2005; 10(10): 780-791
doi: 10.1634/theoncologist.10-10-780 pmid:16314288
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): 187-201
doi: 10.2174/157489208786242313 pmid:18991787
6 Gomes AR, Brosens JJ, Lam EW. Resist or die: FOXO transcription factors determine the cellular response to chemotherapy. Cell Cycle 2008; 7(20): 3133-3136
doi: 10.4161/cc.7.20.6920 pmid:18927504
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): 1256-1266
doi: 10.2174/138945011796150244 pmid:21443467
8 Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 2007; 7(11): 847-859
doi: 10.1038/nrc2223 pmid:17943136
9 Ho KK, Myatt SS, Lam EW. Many forks in the path: cycling with FoxO. Oncogene 2008; 27(16): 2300-2311
doi: 10.1038/onc.2008.23 pmid:18391972
10 Lam EW, Francis RE, Petkovic M. FOXO transcription factors: key regulators of cell fate. Biochem Soc Trans 2006; 34(Pt 5): 722-726
doi: 10.1042/BST0340722 pmid:17052182
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.e1-6
pmid:19136085
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): 49795-49805
doi: 10.1074/jbc.M309523200 pmid:14527951
13 Sunters A, Madureira PA, Pomeranz KM, Aubert M, Brosens JJ, Cook SJ, Burgering BM, Coombes RC, Lam EW. Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt. Cancer Res 2006; 66(1): 212-220
doi: 10.1158/0008-5472.CAN-05-1997 pmid:16397234
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): 670-678
doi: 10.1158/1535-7163.MCT-07-0397 pmid:18347152
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): 5886-5898
doi: 10.1128/MCB.01265-07 pmid:18644865
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): 57-68
pmid:19513552
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): 582-591
doi: 10.1158/1535-7163.MCT-08-0805 pmid:19276163
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): 3169-3179
doi: 10.1158/1535-7163.MCT-07-0507 pmid:18089711
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 BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism. Mol Cell Biol 2004; 24(22): 10058-10071
doi: 10.1128/MCB.24.22.10058-10071.2004 pmid:15509806
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): 2211-2220
doi: 10.1074/jbc.M606669200 pmid:17132628
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): 2317-2329
doi: 10.1038/sj.onc.1208421 pmid:15688014
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): 3237-3246
doi: 10.1158/1535-7163.MCT-08-0398 pmid:18852127
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): 1545-1555
doi: 10.1074/jbc.M111.284224 pmid:22128155
24 Myatt SS, Lam EW. Targeting FOXM1. Nat Rev Cancer 2008; 8(3): 242
doi: 10.1038/nrc2223-c2 pmid:18297052
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): 744-750
doi: 10.1593/neo.04277 pmid:15720800
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): 537-547
doi: 10.1016/j.ajpath.2010.10.020 pmid:21281787
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): 2129-2137
pmid:11280777
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): 9515-9526
doi: 10.1158/0008-5472.CAN-10-2173 pmid:21062979
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): 427-442
doi: 10.1016/j.ccr.2011.08.016 pmid:22014570
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): 4292-4302
doi: 10.1158/0008-5472.CAN-10-4087 pmid:21507930
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): 2296-2306
doi: 10.1002/jcb.23150 pmid:21503965
32 Laoukili J, Stahl M, Medema RH. FoxM1: at the crossroads of ageing and cancer. Biochim Biophys Acta 2007; 1775(1): 92-102
pmid:17014965
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): 126-136
doi: 10.1038/ncb1217 pmid:15654331
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): e12293
doi: 10.1371/journal.pone.0012293 pmid:20808831
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): 24-34
doi: 10.1158/1541-7786.MCR-09-0432 pmid:20068070
36 Millour J, de Olano N, Horimoto Y, Monteiro LJ, Langer JK, Aligue R, Hajji N, Lam EW. ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Mol Cancer Ther 2011; 10(6): 1046-1058
doi: 10.1158/1535-7163.MCT-11-0024 pmid:21518729
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):1189-1202
pmid:22802261
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): 1007-1016
doi: 10.1128/MCB.01068-06 pmid:17101782
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 2012Sep3. [Epub ahead of print]
doi: 10.1093/carcin/bgs167 pmid:22581827
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): 2983-2995
doi: 10.1038/onc.2010.47 pmid:20208560
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): 25167-25176
doi: 10.1074/jbc.M603906200 pmid:16809346
42 Horimoto Y, Hartman J, Millour J, Pollock S, Olmos Y, Ho KK, Coombes RC, Poutanen M, M?kel? 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): 1148-1156
doi: 10.1016/j.ajpath.2011.05.052 pmid:21763263
43 Koo CY, Muir KW, Lam EW. FOXM1: From cancer initiation to progression and treatment. Biochim Biophys Acta 2012; 1819(1): 28-37
doi: 10.1016/j.bbagrm.2011.09.004 pmid:21978825
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): 1845-1858
doi: 10.1038/onc.2011.368 pmid:21860419
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