Epigenetic inactivation of the potential tumor suppressor gene FOXF1 in breast cancer.
The expression of several members of the FOX gene family is known to be altered in a variety of cancers. We show that in breast cancer, FOXF1 gene is a target of epigenetic inactivation and that its gene product exhibits tumor-suppressive properties. Loss or downregulation of FOXF1 expression is associated with FOXF1 promoter hypermethylation in breast cancer cell lines and in invasive ductal carcinomas. Methylation of FOXF1 in invasive ductal carcinoma (37.6% of 117 cases) correlated with high tumor grade. Pharmacologic unmasking of epigenetic silencing in breast cancer cells restored FOXF1 expression. Re-expression of FOXF1 in breast cancer cells with epigenetically silenced FOXF1 genes led to G(1) arrest concurrent with or without apoptosis to suppress both in vitro cell growth and in vivo tumor formation. FOXF1-induced G(1) arrest resulted from a blockage at G(1)-S transition of the cell cycle through inhibition of the CDK2-RB-E2F cascade. Small interfering RNA-mediated depletion of FOXF1 in breast cancer cells led to increased DNA re-replication, suggesting that FOXF1 is required for maintaining the stringency of DNA replication and genomic stability. Furthermore, expression profiling of cell cycle regulatory genes showed that abrogation of FOXF1 function resulted in increased expression of E2F-induced genes involved in promoting the progression of S and G(2) phases. Therefore, our studies have identified FOXF1 as a potential tumor suppressor gene that is epigenetically silenced in breast cancer, which plays an essential role in regulating cell cycle progression to maintain genomic stability.
Lo
Pang-Kuo
PK
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Lee
Ji Shin
JS
Liang
Xiaohui
X
Han
Liangfeng
L
Mori
Tsuyoshi
T
Fackler
Mary Jo
MJ
Sadik
Helen
H
Argani
Pedram
P
Pandita
Tej K
TK
Sukumar
Saraswati
S
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004261:DNA Replication; D050684:E2F Transcription Factors / Q000378:metabolism; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D016160:Retinoblastoma Protein / Q000378:metabolism
D050684:E2F Transcription Factors; C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors; D016160:Retinoblastoma Protein; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2