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Biochimica et Biophysica Acta 1819 (2012) 28–37 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagrm Review FOXM1: From cancer initiation to progression and treatment☆ Chuay-Yeng Koo, Kyle W. Muir, Eric W.-F. Lam ⁎ Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK a r t i c l e i n f o Article history: Received 8 August 2011 Received in revised form 20 September 2011 Accepted 21 September 2011 Available online 29 September 2011 Keywords: FOXM1 Chemotherapy Cancer Function Regulation a b s t r a c t The Forkhead box protein M1 (FOXM1) transcription factor is a regulator of myriad biological processes, including cell proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis and apoptosis. Elevated FOXM1 expression is found in cancers of the liver, prostate, brain, breast, lung, colon, pancreas, skin, cervix, ovary, mouth, blood and nervous system, suggesting it has an integral role in tumorigenesis. Recent research findings also place FOXM1 at the centre of cancer progression and drug sensitivity. In this review the involvement of FOXM1 in various aspects of cancer, in particular its role and regulation within the context of cancer initiation, progression, and cancer drug response, will be summarised and discussed. © 2011 Elsevier B.V. All rights reserved. 1. Introduction 1.1. FOXM1: a brief overview Forkhead box protein M1 (FOXM1), also formerly known as HFH11, MPP-2, WIN, and Trident, belongs to the Forkhead superfamily of transcription factors which all share an evolutionary conserved ‘winged helix’ DNA-binding domain. It regulates the expression of a plethora of target genes through binding to the consensus sequence, TAAACA [1,2]. The human FOXM1 gene, consisting of 10 exons, is mapped to chromosome 12p13-3 [1]. Of the 10 exons, exon Va (A1) and exon VIIa (A2) are alternatively spliced, giving rise to 3 distinct variants: FOXM1a, -b and -c [3]. The FOXM1a isoform is transcriptionally inactive as it harbours both the Va and VIIa exons, resulting in the disruption of the transactivation domain by the exon VIIa. However, as FOXM1a can still bind DNA it is considered to be a dominant negative regulator of other FOXM1 isoforms. On the other hand both FOXM1b, which contains neither of the two exons, and FOXM1c, which has the Va exon only, are transcriptionally active and can directly promote target gene expression in an isoform-specific manner. 1.2. FOXM1 and cancer The FOXM1 transcription factor plays an essential role in the regulation of a wide spectrum of biological processes, including cell ☆ Grant support: Cancer Research UK and Breast Cancer Campaign (E.W.-F. Lam) and Imperial College Healthcare NHS Trust – BRC Funding (E.W.-F. Lam, C.-Y. Koo). ⁎ Corresponding author at: Department of Surgery and Cancer, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. Tel.: +44 20 8383 5829. E-mail address: [email protected] (E.W.-F. Lam). 1874-9399/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagrm.2011.09.004 proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis and apoptosis. Elevated expression of FOXM1 is also observed in a multitude of malignancies, including cancers of the liver, prostate, brain, breast, lung, colon, pancreas, skin, cervix, ovary, mouth, blood and nervous system [4–18]. Genome-wide gene expression profiling of cancers has independently and consistently identified FOXM1 as one of the most commonly upregulated genes in human solid tumours [19–21]. These findings point to a principal role for FOXM1 in tumorigenesis. In addition, recent research also links FOXM1 deregulation to cancer progression and the development of cancer drug resistance. Consequently, extensive studies have been conducted to better understand the regulation and roles of FOXM1 during tumorigenesis and the development of cancer drug resistance (Fig. 1). 2. FOXM1 in tumorigenesis 2.1. Cell cycle and proliferation FOXM1 is one of a few genes shown to be upregulated during early cancer development [2,20,22–24]. The involvement of FOXM1 in the onset of tumorigenesis largely relates to its role in cell cycle progression and proliferation. FOXM1 is a key regulator for G1/S and G2/M transition, and M phase progression. Besides regulating Cdc25A expression at the G1/S checkpoint, FOXM1 also controls the transcription of Skp2 and Cks1, which are substrate-targeting subunits of the Skp1/cullin/F-box protein (SCF) complex essential for the ubiquitinylation and degradation of the cyclin-dependent kinase inhibitors (CKIs), p21 Waf1/Cip1 and p27 Kip1 [25]. It also regulates the expression of several genes, such as Cdc25B, cyclin B, Aurora B kinase, survivin, polo-like kinase 1 (PLK1) and centromere protein C.-Y. Koo et al. / Biochimica et Biophysica Acta 1819 (2012) 28–37 A (CENPA), CENPB and CENPF, involved in G2/M transition, and the maintenance of proper chromosomal stability and segregation during mitosis. Accordingly, the majority of FOXM1 depleted cells suffer delays in G2 and experience severe mitotic abnormalities upon entry into mitosis. Frequently these FOXM1-deficient cells also have mitotic spindle defects, chromosome misalignment, mitotic spindle checkpoint dysfunction as well as cytokinesis failure, resulting in the cells undergoing centrosome amplication and even endoreduplication, and eventually becoming aneuploid and polyploid [25–27]. The integral role of FOXM1 in tumorigenesis is further supported by the finding that constitutive hepatic FoxM1b expression in transgenic mice has little effect on hepatocellular carcinoma development but instead promotes cell proliferation in pre-neoplastic and early neoplastic lesions. On the contrary in conditional FoxM1 knockout mice the hepatocytes fail to proliferate and are refractory to the development of hepatic adenomas and hepatocellular carcinomas (HCC) when induced with xenobiotic liver carcinogens [28,29]. The observation of an increase in nuclear p27Kip1 as well as a reduction of Cdc25C in the FoxM1-deficient hepatocytes provides further evidence that FoxM1 cooperates with other cell cycle regulators and oncogenes to promote proliferative signals in cancer cells. These findings indicate that FOXM1 has a critical role in cell cycle progression and proliferation. As such, FOXM1 deregulation can confer proliferative advantages to cells and make them more susceptible to cellular transformation by oncogenes. FOXM1 is a cell cycle-regulated protein. Under normal conditions, its expression is restricted primarily to proliferating cells and is therefore absent in quiescent or terminally differentiated cells. Upon re-entry of resting cells into the cell cycle, FOXM1 expression is induced in late G1 and sustained throughout S, G2 and M phases. The activity of FOXM1 is further regulated by cyclin-CDK complexes in a cell cycledependent manner (Fig. 2). Accordingly, cyclin-CDK phosphorylation of FOXM1 at Thr596 in the C-terminal region recruits the transcriptional co-activator p300/CREB binding protein (CBP) to enhance its transcriptional activity at specific stages of the cell cycle [30]. Normally FOXM1 transcriptional activity is repressed by its inhibitory N-terminal region 29 in G1 and early S phases, however during G2 cyclin A-CDK complexes phosphorylate FOXM1 and relieve its autorepression enabling its transactivational activity [31]. In addition, phosphorylation of FOXM1 via Raf/ MEK/MAPK pathway also stimulates FOXM1 nuclear translocation and thereby its transcriptional activity during G2/M [32]. Paradoxically, FOXM1 is also dependent on one of its downstream targets, PLK1, for its phosphorylation and activation, thereby providing a positive feedback loop to ensure the proper temporal execution of mitotic events [33]. It is not at all surprising that FOXM1 activity is so heavily regulated by posttranscriptional modifications during the cell cycle, given its critical role in cell cycle control. 2.2. Cellular senescence Cellular senescence is a tumour-suppressing mechanism that arrests cell proliferation of potential tumours. Therefore overcoming senescence is a fundamental step in tumorigenesis. Recent studies suggest that FOXM1 also contributes to cell transformation by antagonizing cellular senescence. For example, in gastric cancer the FOXM1 gene is often inappropriately activated, whereas FOXM1 depletion can trigger the onset of p53- and p16INK4A-independent senescence of cancer cells by inducing p27Kip1 expression [34]. Further to this, premature cellular senescence is observed in embryonic fibroblasts (MEFs) derived from FoxM1-deficient mice. Moreover, early passage FoxM1 −/− MEFs display markers of cellular senescence, including irreversible cell cycle arrest, increased expression of the cellular senescence regulator p19 Arf and increased senescence-associated β-galactosidase activity [25]. In contrast, ectopic FOXM1 expression can suppress oxidative stress induced cellular senescence and the accumulation of senescence markers, p53 and p21 Waf1/Cip1, and p19Arf [35]. This ability of FOXM1 to override the cellular senescence programme is at least partially mediated by the ability of FOXM1 to induce the expression of the Polycomb group protein Bmi-1 via the oncogene c-myc [35]. Together, these findings underscore the potential importance of FOXM1 expression in cell immortalisation and human tumorigenesis. Fig. 1. Functional roles of FOXM1. FOXM1 regulates a variety of biological processes in mammalian cells through regulating the transcription of genes important for cell cycle progression, cell proliferation and survival, cell differentiation, DNA damage repair, angiogenesis, cell migration and chemotherapeutic drug response. 30 C.-Y. Koo et al. / Biochimica et Biophysica Acta 1819 (2012) 28–37 2.3. Stem cell-like self-renewal properties 3.1. Cell growth and proliferation Cancer and stem cells share a number of properties, including sustained proliferative capacity, immortality, and the ability to self-renew. Recent studies from human and mouse models have revealed that FOXM1 has a role in promoting cancer initiation through stimulating stem cell-like characteristics, including self-renewal. Accordingly, it has been shown that ectopic FOXM1 expression suppresses primary human keratinocyte terminal differentiation and induces stem cell compartment expansion, generating a hyperproliferative phenotype similar to that observed for human epithelial hyperplasia [36]. Consistently, a lung carcinogenesis study demonstrated that FoxM1 overexpression promotes Clara cell hyperplasia and can cooperate with an activated KRas to induce lung cancer in vivo [37]. Another mouse model study also showed that FoxM1 is involved in maintaining the tumorigenicity of neuroblastoma cells and the self-renewal capacity of mouse neural stem/progenitor cells [38,39]. In addition, these reports are further supported by two more mouse studies showing that FoxM1 plays a key role in maintaining stem cell renewal in vivo through inducing the expression of pluripotency genes, including Oct4, Nanog and Sox2 [38,39]. Together these findings provide convincing evidence that FOXM1 plays a central role in tumorigenesis through promoting stem cell-like properties, including cell renewal, immortalisation and sustained proliferative ability. There is ample evidence to implicate FOXM1 in cancer cell proliferation and growth following initial tumorigenesis. For example, cancer cell proliferation and tumour growth are significantly reduced in lung adenomas and colon adenocarcinomas carcinogenic mouse models when FoxM1 is deleted [6,9,10,41]. Conversely a marked increase in the proliferation, number and size of tumours of hepatocellular carcinoma (HCC), lung adenomas, prostate and colon carcinomas was observed when mice with the FoxM1 transgene were subjected to tumour induction by carcinogens [5,10,42]. Consistent with this, the depletion of FOXM1 by siRNA in various cancer cell lines (lung, prostate, liver, breast, colon and cervix) also results in a reduction in cell proliferation and anchorage-independent colony formation on soft agar. Furthermore, the phenotypic changes that accompany FOXM1 knock-down have been shown to be associated with decreased expression of cell cycle proteins, cyclin A2, cyclin B1, and Cdc25 phosphatases, and increased expression of the cell cycle inhibitors p21Waf1/Cip1 and p27Kip1 [5,6,10,11,43], suggesting that FOXM1 is needed to sustain the cell cycle programme required for continuous cancer cell proliferation and growth. Collectively, these knock-out mouse models provide crucial evidence on the proliferative roles of FOXM1 not only in tumorigenesis but also during cancer progression. Constitutive FOXM1 is crucial to tumour growth as it allows sustained growth even in conditions when nutrients are scarce. 3.2. Tissue homeostasis 3. FOXM1 in cancer progression In cancer progression tumour initiation is followed by tumour promotion. Besides its initial role in tumorigenesis, FOXM1 can also promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting tumour invasion, migration and angiogenesis [40]. To halt cancer progression, chemotherapies must ideally be administered earlier in cancer development and be targeted specifically at the disease mechanisms. In this respect, there is sufficient evidence to support the use of FOXM1 as a reliable marker for early cancer detection and a target for arresting cancer growth and progression. The functions of FOXM1 are not confined to cell proliferation. It also has important roles in embryonic and organ development as well as tissue regeneration. During embryogenesis, FOXM1 is expressed mainly in tissues of epithelial and mesenchymal origin [44]. The range of cells that require FOXM1 for embryonic development includes cardiomyocytes, hepatocytes, neuroectodermal cells and smooth muscle cells of blood vessels, intestine and oesophagus [45–47]. Accordingly, in the first FoxM1 knockout mouse model whereby the exon 3 of FoxM1 gene was disrupted by the PGK-neomycin cassette, the homozygous knockout mutants died during the perinatal period due to structural defects Fig. 2. Phosphorylation sites of FOXM1. Schematic figure showing the domain structure of FOXM1c (763aa) containing phosphorylation sites and the respective kinases involved. Post-translational modifications of FOXM1 affect mainly FOXM1 transcriptional activity, stability and subcellular localisation. Importantly, phosphorylation of FOXM1 is essential to relieve autorepression by the N-terminal Repressor Domain. Phosphorylation of FOXM1 by cyclin A/E-CDK2 complexes (T600, T611, S638), cyclin B-CDK1 (S251) and PLK1 (S730, S739) results in activation of FOXM1 transcriptional activity, while Chk2 enhances the stability of FOXM1 and transcriptionally activates FOXM1 by phosphorylation of FOXM1 at S361. Phosphorylation at confirmed sites (S331, S704) and possible unknown sites by ERK and p38 signalling pathway stimulates FOXM1 nuclear translocation. NRD = N-terminal Repressor Domain, FKH = Forkhead DNA Binding domain, TAD = Transactivation Domain. C.-Y. Koo et al. / Biochimica et Biophysica Acta 1819 (2012) 28–37 in the heart and liver [48]. Consistent with this finding, in a recent FoxM1 −/− mouse model generated by deleting the exons coding for DNA binding and transactivation domains of FoxM1, the embryos died in utero at around E18.5 days, suffering from severe abnormalities in lungs, liver, heart and in blood vessel formation [6,49]. Although the expression of FOXM1 is not usually detected in terminally differentiated adult cells, FOXM1 expression is reactivated to alter cell cycle kinetics and enhance the proliferative capacity of cells for tissue repair in the event of injury. Studies on tissue regeneration of various organs, including lung, liver and pancreas, have highlighted an essential role of FOXM1 in tissue repair [50–54]. In addition, reduced levels of Cdc25A and nuclear accumulation of the cyclin-dependent kinase inhibitor p21 Waf1/Cip1 were also observed in regenerating FoxM1-deficient hepatocytes, indicating that FOXM1 regulates cell cycle regulators to drive cell proliferation during tissue regeneration. 31 LOX2. Significantly, pulmonary metastasis in the mouse model can be prevented by the reintroduction of a peptide derived from Arf in a FOXM1 repression dependent manner, highlighting the value of targeting this pathway therapeutically. 4. FOXM1 in chemotherapy sensitivity and resistance 4.1. Cancer chemotherapy drugs and resistance Angiogenesis is a key step during cancer progression and involves the development of new blood vessels necessary for tumour growth. Strongly implicated in this process is the vascular endothelial growth factor (VEGF), which is the principal angiogenic activator produced and secreted by cancer cells. FOXM1 has a role in governing the angiogenic switch in tumours by transcriptionally activating VEGF expression through direct binding to Forkhead binding elements (FHRE) of the VEGF promoter [55–57]. Correspondingly, in breast, brain and gastric cancers, VEGF is positively associated with FOXM1 expression [56,57]. It is evident that the suppression of FoxM1 expression by RNA interference in pancreatic cancer cells results in less VEGF secretion into the culture media, as there is a failure to induce capillary tube formation when these media are applied to human umbilical vascular endothelial cells (HUVECs). Similar findings in glioblastomas, gastric carcinomas and HCC further substantiate the idea that FoxM1 is required for VEGF-induced angiogenesis in tumour cells [9,43,56,57]. Systemic chemotherapy is used to treat the majority of people diagnosed with cancer. It is also the mainstay of treatment for leukaemia and other advanced or metastatic solid cancers [63–66]. Conventional chemotherapeutics can stop these cancer cells from multiplying and spreading, but their cytotoxic function can be fairly unspecific, resulting in damage to healthy cells. As a consequence, cancer therapies have been developed recently to target specific cellular molecules involved in cancer survival, growth and progression, thus reducing the risk of damaging healthy tissue [67]. For instance, hormonal therapies are being used to target nuclear receptor signalling pathways in ‘hormone-dependent’ cancers in a way that does not disrupt normal cell biology [64]. Another such group of targeted therapeutics are the small molecule inhibitors and antibodies that target the tyrosine kinase activity of EGFRs (epidermal growth factor receptors) in breast and non-small cell lung cancer [68–70], or the BCR-ABL oncogene in chronic myeloid (myelogenous) leukaemia (CML) [71]. Despite their usefulness in the clinic, relatively little is known about the underlying mechanisms by which these chemotherapeutic drugs cause cell cycle arrest and cell death. In addition, the long-term effectiveness of most chemotherapeutic drugs is often hampered by the development of acquired drug resistance [72], in itself a major cause of cancer treatment failure. Recent research has revealed that FOXM1 plays an integral part in the determination of anti-cancer drug sensitivity and if aberrantly activated or expressed may promote the development of acquired drug resistance [40,73]. 3.4. Cancer cell migration and invasion 4.2. FOXO-FOXM1 axis in tumorigenesis and drug resistance The ability of tumour cells to invade and metastasise to the surrounding tissues is one of the hallmarks of advanced tumours. During cancer cell invasion, the degradation of the basement membrane and various components of extracellular matrix (ECM) is facilitated by a group of zinc-dependent endopeptidases, the matrix metalloproteinases (MMPs) [58,59]. Of this family, MMP-2 and MMP-9 have consistently been implicated in tumour invasion, metastasis and angiogenesis [58,59]. It has been shown that suppression of FOXM1 leads to a reduction in MMP-2 and MMP-9 expression in pancreatic cancer cells, which is associated with an overall decrease in cancer cell migration, invasion and angiogenesis [9]. A similar role for FOXM1 in the regulation of MMP-2 and MMP-9 expression as well as cell migration and invasion has also been documented in other malignancies, such as glioblastoma, colorectal carcinoma, and breast carcinoma [20,43,60]. MMP-2 expression is regulated directly by FOXM1 at the transcriptional level through a forkhead consensus site on the MMP-2 promoter [60], while FOXM1 regulates MMP-9 expression indirectly via its downstream target JNK1 [42]. In a genome-wide expression study of prostate cancers, FOXM1 was identified as one of the commonly up-regulated genes in metastatic prostate cancers, suggesting that FOXM1 is functionally involved in signalling pathways contributing to tumour metastasis [61]. A recent mouse model implicated FOXM1 in the metastasis of hepatocellular carcinoma [62]. The study demonstrated that in the absence of Arf, the mouse p19Arf tumour suppressor, FOXM1 overexpression contributes directly to metastatic behaviour by driving the epithelial–mesenchymal transition (EMT) through Akt, disrupting the rigidity of the cytoskeleton by upregulating the microtubule destabilizing protein Stathmin, and promoting the formation of pre-metastatic niches at distant organs by upregulating the lysyl oxidase collagen cross-linking proteins LOX and The FOXO Forkhead transcription factors function downstream of the PI3K-AKT(PKB) signalling cascade [40,74–77]. Hyperactivation of the PI3K-AKT pathway is a feature of many cancers, and ultimately this inactivates FOXO proteins. The cytostatic and cytotoxic effects of a variety of anti-cancer drugs [78], such as paclitaxel [79,80], doxorubicin [81], lapatinib [22], gefitinib [82,83], imatinib [84–86], and cisplatin [40,87], are dependent on FOXO activation, particularly FOXO3a. As FOXM1 is a transcriptional target repressed by FOXO proteins [82,88], it is therefore also a vital downstream effector of the PI3K-AKT-FOXO signalling axis in response to chemotherapy [89] (Fig. 3). 3.3. FOXM1 in tumour angiogenesis 4.3. Taxanes Taxanes promote the polymerisation of tubulin and induce cell death through disrupting the normal microtubule dynamics required for mitosis during cell division. Studies on breast cancer cell lines have revealed that there is a correlation between the level of FOXM1 expression and sensitivity to the taxane paclitaxel (also commonly called taxol) [90]. Specifically, FOXM1 overexpression has been shown to confer resistance to paclitaxel, whereas depletion of FOXM1 by siRNA or an ARF (alternate reading frame)-derived peptide FOXM1 inhibitor (ARF26–44) can increase the sensitivity of breast cancer cells to the drug [90]. The regulation of FOXM1 expression by FOXO3a may play a key role in the determination of taxane sensitivity and resistance, given that FOXO3a also mediates the cytotoxic function of paclitaxel [79,80]. Accordingly, paclitaxel has also been shown to induce FOXO3a expression and activity to trigger cell death in breast cancer cells, and this is achieved partly through inducing the expression of the pro-apoptotic BH3-only BCL-2 family member Bim [79,80]. Further work shows that paclitaxel can 32 C.-Y. Koo et al. / Biochimica et Biophysica Acta 1819 (2012) 28–37 activate FOXO3a through the stress-activated MAPK JNK in breast cancer cells [80,91]. Activated JNK has been shown to promote FOXO3a activity by at least three distinct mechanisms. Firstly, JNK can repress the inhibitory PI3K-AKT pathway-dependent phosphorylation of FOXO3a [80]. Secondly, JNK can directly phosphorylate and activate FOXO proteins [92]. Finally, JNK can also phosphorylate and inhibit the FOXO-sequestering chaperone protein 14-3-3 [91]. These findings clearly suggest that the JNK-FOXO axis integrates the taxane signals with FOXM1 to determine drug sensitivity by reducing FOXM1 activity. Despite the fact that the exact mechanism by which FOXM1 modulates taxane resistance remains undefined, it is likely that it could relate to its role as a transcriptional regulator of genes involved in G2 and mitosis [40]. not in MCF-7 cells and the expression of a constitutively active mutant FOXM1 in cisplatin sensitive MCF-7 cells also confers resistance, whereas silencing of FOXM1 can resensitise the resistant cells to the drug. Such data strongly imply that FOXM1 can promote resistance through enhancing DNA damage repair, therefore suggesting that targeting FOXM1 is a viable strategy in circumventing acquired cisplatin resistance. Concordantly, the FOXM1 inhibitor thiostrepton induces cell death and proliferative arrest in the cisplatin resistant cells through the down-regulation of FOXM1 resistance-promoting activities. Together these findings point to a novel mechanism of acquired cisplatin resistance in breast cancer cells, centred on the induction of FOXM1. In this context, the AKT-FOXO signalling cascade provides a link between the cellular response to cisplatin and FOXM1 expression. 4.4. Cisplatin and other platinum-based compounds 4.5. Anthracyclines Cisplatin (also called cisplatinum, or cis-diamminedichloroplatinum (II)/CDDP) is a very potent and widely used chemotherapy agent for the treatment of a broad range of cancers, including sarcomas, testicular cancer, small cell lung cancer, ovarian cancer, colorectal cancer, lymphomas and germ cell tumours. Like other platinum-based compounds, the cytotoxicity of cisplatin derives from platinum-adducts formed on genomic DNA, resulting in DNA damage and cell death [93,94]. It has been reported that in colon carcinoma cells, cisplatin treatment results in FOXO3a dephosphorylation at AKT sites, nuclear translocation and activation [84]. By contrast, the depletion of FOXO3a using siRNA can rescue sensitive colon carcinoma cells from cisplatin-induced cell death [84]. Such data suggest that FOXO3a is a key mediator of the cytotoxic effects of cisplatin in colon cancer cells and that this occurs through cisplatin induced FOXO3a AKT-site dephosphorylation and nuclear re-localisation. Consistent with this notion, the small molecule AKT inhibitor API-2/triciribine, which is currently under clinical assessment, can resensitise the resistant colon cancer cells to cisplatin [84]. There is also recent evidence that FOXM1 may be associated with cisplatin resistance and the DNA damage repair response [95]. A comparison of FOXM1 expression in cisplatin sensitive and resistant MCF-7 breast cancer cells reveals that FOXM1 is down-regulated in the sensitive cells but is maintained or induced in the resistant cells [95]. Furthermore, cisplatin treatment activates DNA damage repair in the resistant MCF-7-CISR but Anthracyclines (also called anthracycline antibiotics), including daunorubicin (Daunomycin), doxorubicin (Adriamycin) and epirubicin, represent a broad class of commonly used chemotherapeutic agents with a wide spectrum of anti-tumour activities and as such form the standard treatment for a range of cancers [96]. Anthracyclines function primarily as DNA intercalators, which block DNA and RNA synthesis to induce DNA damage and cell death. These drugs also trigger cell death through inducing DNA cleavage by topoisomerase IIA, resulting in the fragmentation of genomic DNA. Notably, cancer cells are susceptible to cell death induced by DNA damaging drugs, such as anthracycline. Recent research has demonstrated that FOXM1 expression levels are critical determinants of the cellular response to anthracyclines [97]. Analysis of epirubicin sensitive and resistant MCF-7 breast carcinoma cells reveals that FOXM1 levels are higher in the resistant MCF-7-EPIR cells [97]. Additionally, FOXM1 expression is induced in the resistant cells but down-regulated in the sensitive cells by epirubicin. Further to this, overexpression of FOXM1 in sensitive MCF-7 can confer epirubicin resistance, whereas depletion of FOXM1 by siRNA can resensitise MCF-7-EPI R cells to the drug. The repression of FOXM1 expression by epirubicin in the drug responsive cancer cells has been shown to be mediated through p53 induction, which in turn represses E2F activity by activating the retinoblastoma pRB proteins and down-regulating E2F- Fig. 3. Regulation of FOXM1 at the transcriptional level. Schematic representation of FOXM1 transcription regulation by ER (oestrogen receptor), FOXO and E2F. ERα modulates FOXM1 transcription by binding to the oestrogen responsive element (ERE) upstream of FOXM1 promoter when it is activated by oestrogen (E2). FOXM1 is a downstream target of EGFR/HER2-PI3K-AKT-FOXO pathway. The interaction of FOXO with the putative Forkhead response element (FHRE) causes the negative regulation of FOXM1 transcription. E2F positively regulates FOXM1 transcription by binding to E2F element (E2FE) proximal to the FOXM1 gene promoter. Upon treatment with genotoxic drugs, p53 and p21Cip1 activation prevent the phosphorylation of pRB-E2F complexes, resulting in a lack of free E2F molecules being recruited to E2FE and thus, FOXM1 repression. ATM also regulates E2F activity, which in turn affects FOXM1 regulation in response to DNA damage. C.-Y. Koo et al. / Biochimica et Biophysica Acta 1819 (2012) 28–37 1 expression. Therefore the regulation of FOXM1 expression by epirubicin appears to be primarily mediated at the transcriptional level through an E2F-site on the FOXM1 promoter [97]. Interestingly, p53 expression is lost in the epirubicin-resistant MCF-7-EPIR breast cancer cells, further suggesting that the tumour-suppressor protein p53 mediates the cytotoxic effects of epirubicin through targeting FOXM1. Accordingly, reintroduction of p53 into p53-deficient cells not only restores epirubicin sensitivity but also FOXM1 expression control, confirming that the loss of p53 contributes towards the deregulation of FOXM1 expression and thus, the development of epirubicin resistance [97]. In agreement, a recent study also showed that the anthracycline daunorubicin can repress FOXM1 expression through the sequential activation of p53, the cyclin-dependent kinase inhibitor p21Cip1 and pRB in a number of cancer cell lines, including MCF-7 [98]. Intriguingly, FOXM1 and E2F1 levels can be down-regulated by epirubicin in MCF-7 cells depleted of p21 Cip1, indicating that epirubicin can also repress E2F activity and FOXM1 expression through mechanisms independent of p21 Cip1. There is also evidence that besides p53, the DNA damage-sensing kinase Ataxia-telangiectasia mutated (ATM) contributes towards modulating epirubicin sensitivity by regulating FOXM1 expression [97]. Indeed, ATM is overexpressed in the drug resistant MCF-7-EPIR cells and its expression enhances E2F activity in response to epirubicin treatment. Interestingly, the levels of DNA damage sustained by the MCF-7EPIR cells after epirubicin treatment are significantly reduced when compared with the drug sensitive MCF-7 cells, as revealed by the γH2AX staining. Additionally MCF7 cells treated with the ATM inhibitor KU-55933 and siRNA show the abolition of E2F-1 and FOXM1 induction upon epirubicin treatment. Together these data suggest that ATM induces E2F1 expression, which in turn, activates E2F-dependent FOXM1 expression in response to DNA damaging agents, and that this interaction can promote DNA repair. FOXM1 has also been shown to be phosphorylated by checkpoint kinase 2 (CHK2), in response to DNA damage, on serine 361, which increases FOXM1 protein stability enabling it to promote expression of DNA repair genes [51]. As CHK2 functions directly downstream of ATM in DNA damage response, it is predicted that the induction of FOXM1 expression by ATM may also occur through post-translational mechanisms in response to anthracyclines [51]. Collectively, these findings suggest that genotoxic chemotherapeutic agents, such as epirubicin, trigger the activation of p53 and ATM, which converge on E2F to control FOXM1 expression, in turn controlling DNA damage repair and cell survival [97]. The finding that ATM activates and that p53 represses FOXM1 expression may have important implications for the diagnosis and treatment of drug resistant cancers, as the development of epirubicin resistance can be due to the loss of p53 function and/or an increase in ATM expression and activity. The induction of FOXM1 by ATM in response to anthracycline-induced DNA damage may represent a pre-emptive response that can counter DNA damage as well as promote the proliferation and survival of normal cells, but it can also be usurped by cancer cells to develop a survival programme to resist the cytotoxic effects of these drugs. Since FOXM1 is a transcriptional target of FOXO proteins, FOXOs, in particular FOXO3a, can also play a part in regulation of FOXM1 expression in response to anthracycline exposure. In chronic myelogenous (or myeloid) leukaemia (CML) cells, doxorubicin promotes the expression and nuclear accumulation of FOXO3a, wherein it can repress FOXM1 and induce cell death [81,99]. Thus within this context, FOXM1 repression can also be linked to the action of anthracyclines via FOXO3a. In addition, the expression and activity of ATM have also been suggested to be upregulated by FOXO3a in response to oxidative stress and chemotherapeutic drug treatment [100,101], and this may add a further layer of complexity to the already complicated web of FOXM1 regulation by genotoxic therapeutic drugs. Furthermore, these genotoxic chemotherapeutic drugs have also been shown to induce the accumulation of reactive oxygen species (ROS), which can in turn activate FOXM1 in a negative feedback loop to activate genes, including Superoxide Dismutase 33 (MnSOD), Catalase, and Peroxiredoxin 3 (PRDX3), whose products are involved in antagonizing oxidative stress [102]. This negative feedback regulation of FOXM1 by ROS may be hijacked by tumour cells to evade the cytotoxic effects of chemotherapeutic drugs and to promote survival of resistant clones. 4.6. Anti-EGFR/HER2 molecular targeted therapeutics Trastuzumab, lapatinib and gefitinib are examples of molecular targeted therapeutics which have been used in the clinic to treat cancers with EGFR and/or HER2 overexpression or mutation. Trastuzumab (Herceptin®) is a humanised monoclonal HER2 antibody used in breast cancers with HER2 overexpression. Lapatinib (GW572016) is a small molecule dual tyrosine kinase inhibitor (TKI) of HER2 and EGFR approved for the treatment of HER2-positive advanced or metastatic breast cancer patients, whereas gefitinib (also called Iressa® or ZD1839) is a selective EGFR TKI [103,104] used in the treatment of lung adenocarcinoma with EGFR mutations as well as in pre-clinical studies of breast cancer overexpressing EGFR and HER2. Deregulated and/or overexpressed EGFR and HER2 leads to constitutive activation of the downstream PI3K-Akt signalling pathway that modulates the activities of transcription factors, including FOXO3a and FOXM1. As with paclitaxel, FOXM1 is a key cellular target for trastuzumab [90], lapatinib and gefitinib, and again when aberrantly expressed, it confers resistance to these drugs to breast cancer cells [90]. These anti-EGFR/HER2 therapeutics have also been demonstrated to mediate cytotoxic and cytostatic functions in breast cancer through activation of FOXO3a [82,105], which ultimately links EGFR/HER2-PI3K-AKT signalling with FOXM1. Consistently, the depletion of FOXO3a expression using siRNA rescues sensitive breast carcinoma cells from the proliferative arrest and FOXM1 down-regulation induced by gefitinib [82]. Importantly, reintroduction of a constitutively active FOXO3a in the resistant EGFR-expressing MDA-MB-231 breast cancer cells partially restores the anti-proliferative gefitinib response [83]. These findings establish FOXM1 as a downstream mediator of the proliferative signals from the EGFR/HER2-PI3KAKT-FOXO signalling pathway as well as a principal determinant of anti-EGFR/HER2 therapeutics sensitivity. Studies on the regulation of VEGF expression and angiogenesis by the TKI lapatinib in breast cancer cells have shown that VEGF expression is activated by FOXM1 through a FHRE at the gene promoter level, but negatively regulated by FOXO3a through the same FHRE in response to lapatinib [55]. The subsequent evaluation of the regulation of the VEGF gene by FOXO3a and FOXM1 in breast cancer cells reveals that FOXO3a can potentially regulate FOXM1 target gene expression, through at least three mechanisms (Fig. 4). Firstly, activated FOXO3a can displace FOXM1 from the FHRE of target gene promoters. Secondly, FOXO3a can recruit histone deacetylases (HDACs) to the target promoters to induce chromatin condensation and the exclusion of transcription factors, including FOXM1. Furthermore, FOXO3a can regulate target gene expression indirectly via repressing FOXM1 expression. These mechanisms may represent universal means by which FOXO3a negatively regulates FOXM1 target gene expression. Thus, such studies provide novel understanding of the complex mechanisms by which FOXM1 and FOXO transcription factors cooperatively control transactivation of common target genes containing forkhead binding sites [55]. 4.7. Endocrine therapy Oestrogen is a mitogen for normal and malignant breast epithelial cells and exerts its effects primarily through two nuclear hormone receptors ERα and ERβ [106,107]. Hormonal therapy is the preferred treatment for about two-thirds of all breast cancer patients who express ERα. ERα-positive cancers are commonly treated with anti-oestrogens, including tamoxifen and fulvestrant (ICI182780; Faslodex), or aromatase inhibitors [108,109], which can induce G1/S phase cell cycle arrest and, in some cases, cell death [110]. Expression of ERα expression in 34 C.-Y. Koo et al. / Biochimica et Biophysica Acta 1819 (2012) 28–37 breast cancer cells is regulated by FOXM1 at the transcription level [8]. Respectively, ERα has also been shown to regulate FOXM1 expression through an oestrogen response element (ERE) on its promoter [111]. Moreover a cDNA microarray also identified FOXM1 as an oestrogenresponsive gene in breast cancer cells [112]. As FOXM1 is a transcriptional target of ERα and ERα also regulates FOXM1 expression this creates a positive feedback transcriptional loop. This may account for the remarkable association between ERα and FOXM1 mRNA levels observed in breast cancer patient samples [111]. In addition, endocrine therapy resistance is also associated with aberrantly high FOXM1 expression in breast cancer cells. Recently, one of the ERβ isoforms, ERβ1, was demonstrated to repress FOXM1 expression through targeting ERα to reduce cell proliferation in breast cancer, providing a mechanism through which breast cancer cells may become resensitised to endocrine therapy [113]. Collectively, these findings suggest that FOXM1 is central to the proliferative function of oestrogen and is intimately associated with ER signalling in breast cancer cells. As such, deregulated FOXM1 expression may contribute to breast cancer endocrine therapy resistance. 4.8. Potential therapeutic agents targeting FOXM1 Collectively, there is overwhelming evidence pointing to FOXM1 dysregulation as a major cause of tumorigenesis and drug resistance, suggesting that targeting FOXM1 activity in malignant cells is a promising strategy for cancer treatment [73]. A high through-put screen for potential FOXM1 inhibitors identified a thiazole compound, Siomycin A [114]. Further experiments confirmed that Siomycin A treated cells have a decrease in FOXM1 transcriptional activity, leading to a reduction in FOXM1 target genes such as Cdc25B, Survivin and CENPB. The antitumour effects of Siomycin A include reduced anchorage-independent growth and an increase in cell death [114]. Interestingly, another thiazole compound, thiostrepton is also able to repress the transcriptional activity and downregulate the mRNA and protein levels of FOXM1 in cancer cells [115]. As with Siomycin A, thiostrepton can also cause breast cancer cells to undergo proliferative arrest and apoptosis. Furthermore, breast cancer cells treated with thiostrepton become less migratory and invasive, which are also functional attributes of FOXM1 downregulation [115]. The exact mechanism of action of both Siomycin A and thiostrepton is as yet undefined, but could be related to the ability of most thiazole antibiotics to function as proteasome inhibitors [116]. It is also noteworthy that both thiazoles do not exert any anti-growth or apoptotic effects on untransformed cells, thus making them extremely attractive molecules for further development into specific therapeutics against cancer and in particular against the development of drug resistance [115,116]. 5. Conclusion and future perspectives Ongoing studies of FOXM1 have provided a fascinating perspective on its role and regulation in cancer development and drug resistance. The FOXM1 transcription factor plays a central role in the regulation of a multitude of cellular functions, including cell proliferation, cell survival, and immortalisation, which are essential for tumorigenesis. An understanding of the FOXM1 function and how it is regulated will undoubtedly provide new clues in deciphering the mechanisms of tumorigenesis and cancer progression. Recently emerging evidence reveals that FOXM1 also has a significant role in cancer drug resistance. Concordantly, the latest studies demonstrate that FOXM1 expression level is an important determinant of sensitivity to breast cancer chemotherapeutic drugs, such as herceptin [90], gefitinib [82], lapatinib [22], paclitaxel [90] and cisplatin [95]. As a consequence, elucidation of the role and regulation of FOXM1 will ultimately impact directly on our understanding of cancers and drug resistance in the clinic, and provide new avenues for novel therapeutic targets. Moreover, study of the role and Fig. 4. Mechanisms of action of FOXO3a and FOXM1 in regulation of target gene promoter activity. In cycling cancer cells, FOXM1 binds to FHRE of target genes and activates their transcription. In response to chemotherapy and cellular stress, FOXO3a inhibits FOXM1-dependent transcription through at least 3 mechanisms: A) Activated FOXO3a is recruited to FHRE of target gene promoter to displace FOXM1, resulting in repression of target gene activity. B) The interaction of FOXO3a with FHRE recruits HDACs that repress gene transcription by inducing chromatin condensation. This reduces the accessibility of transcription factors such as FOXM1 to bind the gene promoters and activate gene transcription. C) FOXO3a can also bind to FHRE of FOXM1 gene to repress FOXM1 expression, which indirectly regulates the transactivation of FOXO3a and FOXM1 containing the common FHRE sites. C.-Y. Koo et al. / Biochimica et Biophysica Acta 1819 (2012) 28–37 regulation of FOXM1 may also lead to identification of reliable molecular markers for cancers that will allow early detection and treatment of pre-malignant lesions. In this context, FOXM1 could also be an important biomarker for identifying patients who respond better to current treatment modalities. 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