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View the Table of Contents for the June 15 issue of Cancer Research.
Machida et al. Page 6210
Hypermethylated gene promoter sequences are promising cancer markers. Such hypermethylation often marks early, pre-invasive, tumor stages. However, as shown through immunohistochemistry and in situ and liquid PCR methylation assays, hypermethylation and silencing of the pro-apoptotic gene, ASC/TMS1, is a late-stage lung cancer marker. In sputum, ASC/TMS1 hypermethylation mimics the high incidence of this change in stage III lung adenocarcinomas is seldom present in high-risk, cancer-free smokers, but is positive in 24% of clinically cancer-free individuals previously resected for stage I non-small cell lung cancer and who have very high risk for persistent or recurrent disease. Hypermethylation of ASC/TMS1 in sputum merits further study as a prognostic marker in patients resected for early-stage lung cancer.
Rossini et al. Page 6219
Some epidemiological studies have suggested a positive association between antibiotic use and risk of breast cancer. Rossini et al. evaluated the role of prolonged antibiotic treatments on tumor development in HER-2/neu proto-oncogene transgenic female mice, which spontaneously develop mammary carcinoma. The results indicated that a prolonged exposure to antibiotic determined a significantly higher risk of tumor development and an increase in ductal branching and terminal buds in comparison to controls. Further studies are critical to understand the mechanism by which antibiotic treatments influence mammary gland differentiation.
Page 6312
To explore DNA copy number alterations in high-grade serous carcinomas, Park et al. applied SNP array analysis and identified a frequently amplified region on chromosome 19p13.12. Comprehensive mRNA expression analysis of all the genes within the minimal amplicon leads to the identification of Notch3 as the candidate amplified oncogene. Furthermore, inactivation of Notch3 by both g-secretase inhibitor and Notch3-specific siRNA suppressed cell proliferation and induced apoptosis in the cell lines that overexpressed Notch3. The results suggest inactivation of Notch3 can be a potential therapeutic approach in ovarian carcinomas.
Page 6361
Optimal re-expression of most genes silenced through promoter methylation requires the sequential application of DNA methyltransferase inhibitors followed by histone deacetylase inhibitors in tumor cell cultures. Gore et al. treated patients with myelodysplastic syndrome or acute myeloid leukemia with the methyltransferase inhibitor 5-azacitidine followed by the histone deacetylase inhibitor sodium phenylbutyrate. Major responses associated with cytogenetic complete response developed in patients receiving prolonged dosing schedules of 5-azacitidine. Demethylation of p15 or CDH-1 was demonstrated only in clinical responders. This study provides the first demonstration that molecular mechanisms responsible for clinical responses to DNMT/HDAC inhibitor combinations may include reversal of aberrant epigenetic gene silencing.