TY - JOUR
T1 - Alterations of the tumor suppressor gene ARLTS1 in ovarian cancer
AU - Petrocca, Fabio
AU - Iliopoulos, Dimitrios
AU - Qin, Haiyan R.
AU - Nicoloso, Milena S.
AU - Yendamuri, Say
AU - Wojcik, Sylwia E.
AU - Shimizu, Masayoshi
AU - Di Leva, Gianpiero
AU - Vecchione, Andrea
AU - Trapasso, Francesco
AU - Godwin, Andrew K.
AU - Negrini, Massimo
AU - Calin, George A.
AU - Croce, Carlo M.
PY - 2006/11/1
Y1 - 2006/11/1
N2 - ASLTS1 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 AKLTS1 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.
AB - ASLTS1 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 AKLTS1 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.
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U2 - 10.1158/0008-5472.CAN-06-2289
DO - 10.1158/0008-5472.CAN-06-2289
M3 - Article
C2 - 17079447
AN - SCOPUS:33751270220
SN - 0008-5472
VL - 66
SP - 10287
EP - 10291
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -