title: FoxM1 down-regulation leads to inhibition of proliferation, migration and invasion of breast cancer cells through the modulation of extra-cellular matrix degrading factors.
abstract: Forkhead box M1 (FoxM1) transcription factor is known to play important role in human cancers which, in part, is mediated by its ability to modulate cell cycle regulatory proteins as well as genes involved in cell proliferation and differentiation. In breast cancer, FoxM1 down-regulation is increasingly being recognized as an important mechanism for the targeted activity of anti-cancer agents. However, the mechanistic insight in support of the role of FoxM1 in aggressive breast cancer is poorly understood. We have tested the biological consequence of FoxM1 down-regulation and up-regulation in breast cancer cell lines and found that the down-regulation of FoxM1 in MDA-MB-231 and SUM149 cells by siRNA approach inhibited cell growth, clonogenicity, migration, and invasion. We also found decreased expression of CDK2 and E2F1 with concomitant increase in p21 and p27 proteins, suggesting an important role of FoxM1 in cell cycle progression. In contrast, over-expression of FoxM1 by cDNA transfection, in breast cancer cells (SUM102 and SKBR3) expressing low levels of FoxM1, resulted in increased cell proliferation, migration, and invasion. Moreover, down-regulation of FoxM1 inhibited the expression of many factors that are involved in the degradation of extra cellular matrix and angiogenesis such as uPA, uPAR, MMP-2, MMP-9, and vascular endothelial growth factor (VEGF) as well as inhibited the activity of MMP-9 and VEGF. Interestingly, over-expression of uPA by cDNA transfection abrogated the cellular effects that were observed by the down-regulation of FoxM1. Taken together, these results suggest the potential application of FoxM1 down-regulation as a novel approach for the treatment of aggressive breast cancer.
authors.affiliation: Department of Pathology, Barbara Ann Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Dejuan
authors.initials: D
authors.lastname: Kong
authors.forename: Shadan
authors.initials: S
authors.lastname: Ali
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.forename: Raza
authors.initials: R
authors.lastname: Ali
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D055293:Receptors, Urokinase Plasminogen Activator; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D014568:Urokinase-Type Plasminogen Activator; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9