BRCA1 promoter methylation is a marker of better response to anthracycline-based therapy in sporadic TNBC.

The aim of the current study was to investigate the role of BRCA1 gene aberrations in sporadic triple-negative breast cancer (TNBC) and its impact on anthracycline-based therapy. BRCA1 promoter methylation was analyzed in 70 TNBC and compared with the clinical and pathologic characteristics. As a control group, we used 70 patients with non-TNBC. BRCA1 promoter methylation was observed in 65.2 % of patients and was similar in both groups. BRCA1 promoter methylation was associated with decreased intensity of BRCA1 protein expression (P = 0.002) and significant increase of median disease-free survival (DFS) of TNBC patients receiving adjuvant anthracycline-based chemotherapy (P = 0.001). Multivariate analysis revealed that BRCA1 promoter methylation remains a favorable factor in regard to DFS (HR 0.224; 95 % CI 0.092-0.546, P = 0.001) in TNBC after adjustment for other prognostic factors. In contrast, in non-TNBC, BRCA1 promoter methylation was not associated with any clinical and pathologic parameters. BRCA1 promoter methylation is a common mechanism of BRCA1 gene aberration in sporadic breast cancer and is predictive for better response to anthracycline-based therapies.

Inflammation and Barrett's carcinogenesis.

Barrett's esophagus (BE) is one of the most common premalignant lesions in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. Esophageal adenocarcinoma (EA) develops through progression from BE to low- and high-grade dysplasia (LGD/HGD) and to adenocarcinoma. It is widely accepted that inflammation can increase cancer risk, promoting tumor progression. Therefore, inflammation is regarded as the seventh hallmark of cancer. In recent years, the inflammation-cancer connection of Barrett's carcinogenesis has been intensively studied, unraveling genetic abnormalities. Besides genetic alterations, inflammation is also epigenetically linked to loss of protein expression through transcriptional silencing via promoter methylation. Key mediators linking inflammation and Barrett's carcinogenesis include reactive oxygen species (ROS), NFκB, inflammatory cytokines, prostaglandins, and specific microRNAs (miRNAs). Therefore, the decipherment of molecular pathways that contain these and novel inflammatory key mediators is of major importance for diagnosis, therapy, and prognosis. The detailed elucidation of the signaling molecules involved in Barrett's carcinogenesis will be important for the development of pharmaceutical inhibitors. We herein give an overview of the current knowledge of the inflammation-mediated genetic and epigenetic alterations involved in Barrett's carcinogenesis. We highlight the role of oxidative stress and deregulated DNA damage checkpoints besides the NFκB pathway.

Trichostatin A causes p53 to switch oxidative-damaged colorectal cancer cells from cell cycle arrest into apoptosis.

Many studies aim at improving therapeutic efficacy by combining strategies with oxidative stress-inducing drugs and histone deacetylase (HDAC) inhibitors in colorectal cancer. As p53 and p21(WAF1) are essential in oxidative stress-induced DNA damage, we investigated epigenetic regulation of p21(WAF1) promoter. Firstly, HCT116 p53(+)/(+) and p53(-)/(-) colorectal cancer cells were treated with H(2)O(2) for 6 hrs and 24 hrs (early/late response). Chromatin immunoprecipitation revealed transcriptional transactivation of p21(WAF1) in HCT116 p53(+)/(+) cells as shown by increased binding of p53 and acetylated H4 around two p21(WAF1) promoter sites, the responsible element (RE) and the Sp1 site, while both proteins bound preferentially on the RE. Interestingly, H3 was not involved, suggesting H4-specific transactivation of the p21(WAF1) promoter. H(2)O(2) addition resulted in G(2)/M arrest of both HCT116 cell lines without significant cell death. To investigate whether a HDAC inhibitor strengthens G(2)/M arrest, we pretreated cells with Trichostatin A (TSA). In HCT116 p53(+)/(+) cells, we found (i) remarkably increased acetylated H4 around both p21(WAF1) promoter regions, especially at the Sp1 site; (ii) increased acetylation of p53 at lysines 320 and 382;(iii) displacement of HDAC1 from the Sp1 site, thus inhibiting its repression effect and increasing p53 binding.p53 seems to trigger H4-acetylation around the p21(WAF1) promoter because there was nearly no H4 acetylation in HCT116 p53(-)/(-) cells. For the first time we show that there is a time-dependent TSA mode of action with increased p53-dependent histone H4 acetylation at the p21(WAF1) promoter in early response, and decreased acetylation in late response. Reduced p53-triggered transactivation of p21(WAF1) in late response allows cells to re-enter cell cycle, and TSA causes p53 to simultaneously induce apoptosis.

Practice of pancakarma in Western countries - a german experience.

Ayurveda is gaining popularity in European countries. Because of the unique curative properties, Pancakarma is being sought by many. However, there are some limitations in its application to western people. These points are highlighted in this article.