FOXM1 gene is now known as a humanproto-oncogene.[11] Abnormal upregulation of FOXM1 is involved in the oncogenesis ofbasal cell carcinoma, the most common human cancer worldwide.[12] The upregulation of both FOXM1 and its targets has been found in the majority of solid human cancers[13] including liver,[14] breast,[15] lung,[16] prostate,[17] cervix of uterus,[18] colon,[19] and brain.[20]
There are three FOXM1isoforms in humans, A, B and C. Isoform FOXM1A has been shown to be a genetranscriptionalrepressor whereas the remaining isoforms (B and C) are both transcriptionalactivators. Hence, it is not surprising that FOXM1B and C isoforms have been found to be upregulated in human cancers.[9]
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.[21]
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.[23]
Given the role in progenitor/stem cells expansion,[23] FOXM1 has been shown to modulate theepigenome. It was found that overexpression of FOXM1 "brain washes" normal cells to adopt cancer-likeepigenome.[24] A number of newepigenetic biomarkers influenced by FOXM1 were identified from the study and these were thought to representepigenetic signature of early cancer development which has potential for early cancer diagnosis and prognosis.[24]
^Korver W, Roose J, Heinen K, Weghuis DO, de Bruijn D, van Kessel AG, Clevers H (December 1997). "The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization".Genomics.46 (3):435–42.doi:10.1006/geno.1997.5065.hdl:2066/25040.PMID9441747.S2CID25093788.
^Laoukili J, Kooistra MR, Brás A, Kauw J, Kerkhoven RM, Morrison A, Clevers H, Medema RH (February 2005). "FoxM1 is required for execution of the mitotic programme and chromosome stability".Nat. Cell Biol.7 (2):126–36.doi:10.1038/ncb1217.PMID15654331.S2CID11732068.
^Myatt SS, Lam EW (November 2007). "The emerging roles of forkhead box (Fox) proteins in cancer".Nat. Rev. Cancer.7 (11):847–59.doi:10.1038/nrc2223.PMID17943136.S2CID1330189.
^Chan DW, Yu SY, Chiu PM, Yao KM, Liu VW, Cheung AN, Ngan HY (July 2008). "Over-expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis".J. Pathol.215 (3):245–52.doi:10.1002/path.2355.PMID18464245.S2CID30137454.
^Douard R, Moutereau S, Pernet P, Chimingqi M, Allory Y, Manivet P, Conti M, Vaubourdolle M, Cugnenc PH, Loric S (May 2006). "Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer".Surgery.139 (5):665–70.doi:10.1016/j.surg.2005.10.012.PMID16701100.
^Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Aldape KD, Xie TX, Pelloski CE, Xie K, Sawaya R, Huang S (April 2006). "FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells".Cancer Res.66 (7):3593–602.CiteSeerX10.1.1.321.4506.doi:10.1158/0008-5472.CAN-05-2912.PMID16585184.
