Review
FOXM1: From cancer initiation to progression and treatment☆

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Abstract

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.

Highlights

► The FOXM1 transcription factor is a regulator of a broad range of biological processes. ► Elevated and deregulated FOXM1 expression is found in a wide spectrum of cancers. ► FOXM1 also plays a central role in cancer initiation, progression and anti-cancer drug resistance. ► This review summarises the role and regulation of FOXM1 in various aspects of cancer.

Introduction

Forkhead box protein M1 (FOXM1), also formerly known as HFH-11, 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.

The FOXM1 transcription factor plays an essential role in the regulation of a wide spectrum of biological processes, including cell 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], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [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], [20], [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).

Section snippets

Cell cycle and proliferation

FOXM1 is one of a few genes shown to be upregulated during early cancer development [[2], [20], [22], [23], [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

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

Cancer chemotherapy drugs and resistance

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], [64], [65], [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

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

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    ☆

    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).

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