Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe.
Expression of the forkhead transcription factor FoxM1 correlates with proliferative status in a variety of normal and transformed cell types. Elevated expression of FoxM1 has been noted in both hepatocellular carcinoma and basal cell carcinoma. However, whether FoxM1 expression is essential for the viability of transformed cells is unknown. We report here that the expression of FoxM1 is significantly elevated in primary breast cancer. Microarray analysis shows that FoxM1 regulates genes that are essential for faithful chromosome segregation and mitosis, including Nek2, KIF20A, and CENP-A. Loss of FoxM1 expression generates mitotic spindle defects, delays cells in mitosis, and induces mitotic catastrophe. Time-lapse microscopy indicates that depletion of FoxM1 generates cells that enter mitosis but are unable to complete cell division, resulting in either mitotic catastrophe or endoreduplication. These findings indicate that FoxM1 depletion causes cell death due to mitotic catastrophe and that inhibiting FoxM1 represents a therapeutic strategy to target breast cancer.
Wonsey
Diane R
DR
Department of Discovery Medicine, Wyeth Research, Cambridge, Massachusetts, USA. Diane_Wonsey@dfci.harvard.edu
Follettie
Maximillian T
MT
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D018385:Centrosome; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008938:Mitosis; D009690:Nucleic Acid Conformation; D011003:Ploidies; D034741:RNA, Small Interfering / Q000235:genetics; D008941:Spindle Apparatus / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D014157:Transcription Factors