Introduction: cancer and drug resistance
Cancer is a leading cause of disease worldwide with 12.7 million new cases diagnosed in 2008. At the same time, an estimation of 7.6 million cancer deaths occurred in the same year [
1]. Although cancer survival rates have been improving as a result of early diagnosis and better treatment, mortality rates remain high among patients with advanced diseases largely due to the development of drug resistance. Cytotoxic chemotherapy is commonly used for the treatment and management of cancer, particularly solid tumors. It is particularly important for patients that are refractory to or not suitable for hormonal therapy or molecular-targeted therapeutic agents and may sometimes represent the sole option for advanced or metastatic cancer [
2]. For example, the anthracyclines doxorubicin and epirubicin are widely employed as first-line chemotherapy for breast cancer patients, and the taxanes paclitaxel and docetaxel are commonly considered to be the most effective second-line options [
3-
5]. Despite their initial effectiveness as cancer systemic therapeutic agents, most conventional chemotherapeutic treatments eventually fail because of acquired drug resistance. A number of mechanisms function alone or in combination to confer resistance to cancer cells and they include amplification of cell survival signal pathways, increased DNA damage repair, and altered cellular drug uptake, efflux or metabolism [
6,
7]. The principal mechanism of action of the taxane class of drugs is disruption of microtubule dynamics and function during mitosis and thus, in essence, taxanes are mitotic inhibitors or spindle poisons. The modes of action of anthracyclines include inhibition of DNA and RNA synthesis and the creation of free radicals that damage DNA and cell membranes. However, detailed mechanisms by which taxanes and anthracyclines induce cancer cell death and how their antiproliferative functions are bypassed during the development of drug resistance remain largely undefined.
FOXO-FOXM1 axis in tumorigenesis and drug resistance
Forkhead box (Fox) proteins are multifunctional transcription factors responsible for the spatio-temporal fine-tuning of a broad repertoire of transcriptional programmes during normal development. Inevitably, deregulation of their modes of transcriptional regulation and action will lead to pathological conditions, including cancer. The forkhead box class O (FOXO) family of transcription factors (i.e., FOXO1, FOXO3a, FOXO4 and FOXO6), functioning downstream of the phosphoinositol-3-kinase (PI3K)-AKT (PKB) oncogenic signaling pathway, are central to a diversity of cellular functions including cell cycle arrest, apoptosis, development, differentiation, invasion, metabolism, migration, and resistance to oxidative stress and DNA damage [
6,
8-
11]. Hyperactivation of the PI3K-AKT cascade is a common feature in many cancers, and this ultimately leads to FOXO inactivation. Accordingly, inactivation and downregulation of FOXO proteins have been implicated in tumorigenesis and cancer progression [
8]. FOXOs, in particular FOXO3a, also function downstream of the ERK/MAPK, PI3K/Akt and IKK pathways and therefore facilitate the cross-talk between three frequently deregulated signaling cascades in most cancers. Recent evidence has shown that the cytostatic and cytotoxic effects of many anti-cancer drugs, such as paclitaxel [
12,
13], doxorubicin [
14,
15], lapatinib [
16], gefitinib [
17,
18], imatinib [
19-
21], cisplatin [
22], and tamoxifen [
8], are mediated through FOXO activation primarily via inactivation of the PI3K-AKT axis. In addition, in response to doxorubicin treatment, FOXO3a is also targeted by the stress-activated MAPKs, including JNK and p38. For example, JNK has been shown to induce FOXO3a activity and nuclear localization through repressing AKT phosphorylation and activity. Moreover, p38 phosphorylation of FOXO3a on Ser-7 also contributes to its nuclear relocalization and activation in response to doxorubicin [
23].
While the FOXO subfamily of transcription factors behave as tumor suppressors, another Forkhead subfamily member FOXM1 functions like a classic oncogene. The forkhead box protein M1 (FOXM1) transcription factor is a regulator of a wide range of biologic processes including cell cycle progression, cell differentiation, apoptosis, angiogenesis, senescence, tissue homeostasis and DNA damage repair [
8,
24]. Elevated FOXM1 expression has been documented in cancers of the liver, prostate, breast, lung and colon etc. [
8,
25]. Different gene expression profiling studies of cancers have independently and consistently identified FOXM1 as one of the most commonly upregulated genes in human solid tumors [
25-
27]. These findings point to a key role for FOXM1 in tumorigenesis. Consistent with this idea, FOXM1 has been shown to induce the expansion of stem cell compartments, resulting in the initiation of hyperplasia during tumorigenesis [
28]. Besides cancer initiation, FOXM1 also plays a part in cancer progression through promoting the acquisition of stem cell (SC) [
29,
30] and epithelial-to-mesenchymal transition (EMT) phenotypes [
31]. Accordingly, FOXM1 promotes EMT and SC compartment expansion through inducing the expression of mesenchymal/stem cell markers, including ZEB1, ZEB2, Snail2, E-cadherin, and vimentin, which will ultimately culminate in increased cell proliferation, self-renewal capacity (long-term viability), cell migration, angiogenesis and drug resistance [
31].
Additionally, FOXM1-deficient cells display polyploidy, aneuploidy, and chromosome missegregation as well as an increase in the number of DNA breaks, all of which highlighting the importance of FOXM1 in safeguarding mitosis and genomic integrity [
32,
33]. FOXM1 has also been demonstrated to play a crucial role in drug responsiveness and resistance [
8,
16,
24,
34]. For example, it has been shown that deregulated FOXM1 expression can confer resistance to chemotherapeutic drugs, such as cisplatin and epirubicin, and protect cancer cells against DNA-damage induced cell death, and disrupt mitosis/cytokinesis control [
16,
35,
36]. Recent evidence shows that the p38 MAPK-MK2 signaling axis participates in the control of E2F1 and FOXM1 expression as well as drug sensitivity in response to epirubicin [
37]. In addition, upon DNA damage, the checkpoint kinases Chk1 and Chk2 also phosphorylate and activate FOXM1, which in turn activates the expression of genes important for homologous recombination, including BRCA2, XRCC1, EXO1, PLK4, POLE2 and RFC4 [
38,
39].
In consequence, cancer cells with deregulated or overexpressed FOXM1 will be more efficient in the repair of damage DNA, thus conferring resistance to genotoxic therapeutics. FOXM1 also has a critical role in the development of endocrine resistance in breast cancer [
40]. This is primarily due to the fact that ERα is a key regulator of FOXM1 expression at the transcriptional level, and that FOXM1 also regulates ERα expression in breast cancer cells [
41]. The regulation of FOXM1 by ERα and vice versa culminates in a positive forward feeding loop that can contribute toward tumorigenesis and hormone-insensitivity in endocrine-related malignancies, such as breast cancer. Furthermore, recent evidence suggested that the anti-proliferative role of ERβ1 in the development of breast cancer is mediated through the negative regulation of FOXM1 expression via ERα [
42].
Interestingly, FOXO3a and FOXM1 have antagonistic functions in the regulation of their target genes [
43,
44], such that genes activated by FOXM1 are often repressed by FOXO3a. It has also been found that FOXM1 is a direct transcriptional target repressed by FOXO proteins and a vital downstream effector of the PI3K-AKT-FOXO axis [
7,
16,
17]. Furthermore, FOXO3a and FOXM1 not only compete for binding to the same response elements in target genes, but are also capable of regulating distinct functional gene networks. For instance, FOXM1 activates while FOXO3a represses VEGF expression to control breast cancer cell angiogenesis and migration (Fig. 1) [
44]. In addition, potential cooperation between FOXO3a and FOXM1 to regulate ERα gene transcription in breast cancer cells has also been reported [
41]. Collectively, these findings suggest that genes generally activated by FOXM1 are repressed by FOXO3a and probably by other FOXO family members and that the FOXO-FOXM1 axis can modulate cancer initiation, progression and drug resistance through regulation genes essential for cell proliferation, survival, self-renewal, migration, angiogenesis, cell cycle/checkpoint transition and DNA damage repair (Fig. 1).
Future perspectives
Given the crucial role of FOXO and FOXM1 proteins, a better understanding of the mechanisms by which FOXO and FOXM1 are regulated as well as a greater emphasis on their roles in cancer initiation, progression and drug resistance, may render these proteins crucial prognostic markers and therapeutic targets for breast cancer and other malignancies.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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