Alterations of the tumor suppressor gene ARLTS1 in ovarian cancer.
ARLTS1 is a tumor suppressor gene initially described as a low-penetrance cancer gene: a truncated Trp149Stop (MUT) polymorphism is associated with general familial cancer aggregation and, particularly, high-risk familial breast cancer. DNA hypermethylation has been identified as a mechanism of ARLTS1 expression down-regulation in lung carcinomas and B-cell chronic lymphocytic leukemia. We found that, in the majority of ovarian carcinomas (61.5%) and in a significant proportion of ovarian and breast cancer cell lines (45%), ARLTS1 is strongly down-regulated due to DNA methylation in its promoter region. After ARLTS1 restoration by adenoviral transduction, only the negative TOV-112 and the homozygously mutated (MUT) MCF7 cells, but not the OV-90 cells expressing a normal ARLTS1 product, underwent apoptosis and inhibition of cell growth. Furthermore, ARLTS1 reexpression significantly reduced the tumorigenic potential of TOV-112 in nude mice. On the contrary, the ARLTS1-MUT induced significantly lower levels of apoptosis in infected cells and reduced in vivo tumorigenesis only partially, supporting the hypothesis that Trp149Stop polymorphism is retained in the general population and predisposes to cancer because of a reduction, but not full loss, of normal ARLTS1 function.
Petrocca
Fabio
F
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Iliopoulos
Dimitrios
D
Qin
Haiyan R
HR
Nicoloso
Milena S
MS
Yendamuri
Say
S
Wojcik
Sylwia E
SE
Shimizu
Masayoshi
M
Di Leva
Gianpiero
G
Vecchione
Andrea
A
Trapasso
Francesco
F
Godwin
Andrew K
AK
Negrini
Massimo
M
Calin
George A
GA
Croce
Carlo M
CM
D020727:ADP-Ribosylation Factors / Q000235:genetics*; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D000077209:Decitabine; D015536:Down-Regulation; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology
D000077209:Decitabine; D020727:ADP-Ribosylation Factors; C500039:ARL11 protein, human; D001374:Azacitidine