FOXM1

Forkhead box protein M1 is a is_associated_with::protein that in humans is encoded by the FOXM1 is_associated_with::gene. The is_associated_with::protein encoded by this gene is a member of the FOX family of is_associated_with::transcription factors. FOXM1 has been awarded the is_associated_with::Molecule of the Year 2010 for its growing potential as a target for cancer diagnosis and therapies.

Function
FOXM1 is known to play a key role in is_associated_with::cell cycle progression where endogenous FOXM1 expression peaks at S and G2/M phases. FOXM1-null mouse embryos were neonatal lethal as a result of the development of polyploid cardiomyocytes and is_associated_with::hepatocytes, highlighting the role of FOXM1 in mitotic division. More recently a study using transgenic/is_associated_with::knockout mouse embryonic is_associated_with::fibroblasts and human is_associated_with::osteosarcoma cells (U2OS) has shown that FOXM1 regulates expression of a large array of G2/M-specific genes, such as Plk1, is_associated_with::cyclin B2, Nek2 and is_associated_with::CENPF, and plays an important role in maintenance of chromosomal segregation and genomic stability.

Cancer link
FOXM1 gene is now known as a human proto-oncogene. Abnormal upregulation of FOXM1 is involved in the oncogenesis of is_associated_with::basal cell carcinoma, the most common human cancer worldwide. FOXM1 upregulation was subsequently found in the majority of solid human cancers including liver, breast, lung, prostate, cervix of uterus, colon, pancreas, and brain.

Isoforms
There are three FOXM1 isoforms, A, B and C. Isoform FOXM1A has been shown to be a gene transcriptional is_associated_with::repressor whereas the remaining isoforms (B and C) are both transcriptional activators. Hence, it is not surprising that FOXM1B and C isoforms have been found to be upregulated in human cancers.

Mechanism of oncogenesis
The exact mechanism of FOXM1 in cancer formation remains unknown. It is thought that upregulation of FOXM1 promotes oncogenesis through abnormal impact on its multiple roles in cell cycle and chromosomal/genomic maintenance. Aberrant upregulation of FOXM1 in primary human skin keratinocytes can directly induce genomic instability in the form of loss of heterozygosity (LOH) and copy number aberrations.

FOXM1 overexpression is involved in early events of is_associated_with::carcinogenesis in is_associated_with::head and neck is_associated_with::squamous cell carcinoma. It has been shown that is_associated_with::nicotine exposure directly activates FOXM1 activity in human oral is_associated_with::keratinocytes and induced is_associated_with::malignant transformation.

Role in stem cell fate
A recent report by the research group which first found that the over-expression of FOXM1 is associated with human cancer, showed that aberrant upregulation of FOXM1 in adult human epithelial stem cells induces a precancer phenotype in a 3D-organotypic tissue regeneration system - a condition similar to human hyperplasia. The authors showed that excessive expression of FOXM1 exploits the inherent self-renewal proliferation potential of stem cells by interfering with the differentiation pathway, thereby expanding the progenitor cell compartment. It was therefore hypothesized that FOXM1 induces cancer initiation through stem/progenitor cell expansion.

Role in epigenome regulations
Given the role in progenitor/stem cells expansion, FOXM1 has been shown to modulate the is_associated_with::epigenome. It was found that overexpression of FOXM1 "brain washes" normal cells to adopt cancer-like is_associated_with::epigenome. A number of new is_associated_with::epigenetic biomarkers influenced by FOXM1 were identified from the study and these were thought to represent is_associated_with::epigenetic signature of early cancer development which has potential for early cancer diagnosis and prognosis.

Clinical applications
Precancer initiation and multifaceted oncogenic roles of FOXM1 in a myriad of human cancers render it a highly promising biomarker for cancer diagnostics and anticancer drug development. Hence, FOXM1 gene is currently being exploited for clinical use as biomarker for cancer risk prediction, early cancer screening, molecular diagnostics/prognostics and/or companion diagnostics for personalized therapeutics.

A number of anti-tumour compounds are being developed to target FOXM1 specifically but none so far has entered clinical trials. Nevertheless, prototype drugs are currently under active research for a number of cancer types.

Interactions
FOXM1 has been shown to interact with CDH1.