Abstract
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.
Highlights
ARLTS1 [ADP ribosylation factor-like 11 (ARL11)] is a recently identified tumor suppressor gene described in association with familial cancers: a Trp149Stop (G446A) variant (MUT) leading to premature termination of translation was identified in cancer kindreds displaying various combinations of breast, ovarian, prostate, gastric, and lung carcinomas, melanomas, and B-cell chronic lymphocytic leukemias
In the present study, we showed the tumor suppressor function of ARLTS1 in ovarian cancer and we investigated the biological importance of the Trp149Stop polymorphism in both ovarian and breast cancer models
We previously described the methylation of a predicted promoter as the cause of reduced or absent ARLTS1
Summary
ARLTS1 [ADP ribosylation factor-like 11 (ARL11)] is a recently identified tumor suppressor gene described in association with familial cancers: a Trp149Stop (G446A) variant (MUT) leading to premature termination of translation was identified in cancer kindreds displaying various combinations of breast, ovarian, prostate, gastric, and lung carcinomas, melanomas, and B-cell chronic lymphocytic leukemias (B-CLL; ref. 1). The Trp149Stop variant frequency is similar in control cases and patients with sporadic cancers [1], and it was shown that. Ovarian cancer is the most lethal of gynecologic malignancies in the United States with f23,000 new cases and >15,000 deaths estimated for 2006 [10], and hereditary breast and ovarian cancers are among the most commonly encountered adult genetic diseases [11]. We showed that ARLTS1 is frequently down-regulated in ovarian primary tumors and cell lines and restoration of its expression by adenoviral ARLTS1 or by the demethylating agent 5-AZA-2-deoxycytidine (5-AZA) effectively induced apoptosis in vitro and suppressed ovarian cancer tumorigenicity in nude mice. No similar effects on ovarian cancer cells constitutively expressing the ARLTS1 protein have been observed. We showed that ARLTS1 Trp149Stop polymorphism greatly reduced the protein apoptotic function in ovarian and breast cancer cell lines
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
