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Alterations of the Tumor Suppressor Gene ARLTS1 in Ovarian Cancer

¹ Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; ² Department of Histopathology and Medical Oncology, University of Rome "La Sapienza," Sant'Andrea Hospital, Rome, Italy; ³ Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; and ⁴ Department of Experimental and Diagnostic Medicine, Interdepartment Center for Cancer Research, University of Ferrara, Ferrara, Italy

Requests for reprints: George A. Calin, Comprehensive Cancer Center, Ohio State University, 410 West 12th Avenue, Wiseman Hall, Room 441, Columbus, OH 43210. Phone: 614-292-4354; Fax: 614-292-3312; E-mail: george.calin{at}osumc.edu and Carlo M. Croce, Comprehensive Cancer Center, Ohio State University, 410 West 12th Avenue, Wiseman Hall, Room 385L, Columbus, OH 43210. E-mail: carlo.croce{at}osumc.edu.

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. (Cancer Res 2006; 66(21): 10287-91)

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