The mechanism by which gastroesophageal reflux promotes metaplasia→dysplasia→ carcinoma is unknown. The aim of the study is to determine if repeated exposure to acid and bile confers a tumorigenic phenotype in a telomerase (hTERT)-immortalized benign Barrett’s cell line, BAR-T. BAR-T cells were exposed to acid (pH 4) (A) and bile salt (200µM glycochenodeoxycholic acid) (B) daily for 5 min up to 65+ wks. The control cells were grown in parallel without any A or B treatment. Cell morphology, proliferation, transformation, and molecular changes in the gene expression for COX-2, TC22, p53 and p53 target genes were analyzed at 8–12 wks intervals. At 46 wks BAR-T cells exposed to (A+B) showed distinct phenotypic changes: forming clusters and acini, and at 65 wks displayed foci in monolayer, and formed distinct colonies in soft agar. Untreated cells did not show any such changes. In A+B treated BAR-T cells, COX-2 mRNA increased 10-20-fold, TC22 mRNA increased by 2-3-fold at 22 – 65 wks, p53, MDM2, PERP and p21mRNA increased 2.5-, 6.4-, 4- and 2.6- fold respectively when compared to untreated cells at 34 weeks. However, at 58 wks onward, there was a sharp decline of p53 and its target genes to the baseline level. At 65 weeks A+B treated BAR-T cells formed tumor in nude mice whereas untreated cells did not. We demonstrate a novel in-vitro model of transformation of a benign Barrett’s cell line following repeated exposure to A+B over the course of 65 wks.

TOPORS is the first example of a protein with both ubiquitin and SUMO-1 E3 ligase activity and has been implicated as a tumor suppressor in several different malignancies. To gain insight into the cellular role of TOPORS, a proteomic screen was performed to identify candidate sumoylation substrates. The results indicate that many of the putative substrates are involved in chromatin modification or transcriptional regulation. Transfection studies confirmed mammalian Sin3A as a sumoylation substrate for TOPORS. These findings suggest that TOPORS may function as a tumor suppressor by regulating mSin3A and other proteins involved in chromatin modification.

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Murine double minute 4 (MDM4) shares significant structural homology with murine double minute 2 (MDM2) and interacts and regulates transcriptional activity of the tumor suppressor p53. In tumors with wild-type p53, there is often overexpression of MDM2 or MDM4 leading to functional inactivation of p53. A single-nucleotide polymorphism (SNP) in the promoter of human MDM2 (SNP309) was shown to associate with increased MDM2 expression and increased risk of cancer. This study evaluated the association of a SNP in human MDM4 (C>T) with age of onset of breast cancer in two independent cohorts. In cohort 1 of 675 patients, the average age of diagnosis for women with estrogen receptor (ER)-positive and ER-negative breast cancers was 53.2 and 48 years, respectively. In this cohort, homozygous variant (TT) carriers developed ER-negative carcinomas at an earlier age than homozygous wild-type (CC) or heterozygous (TC) such that the age at diagnosis was accelerated by 5.0 years (P = 0.018). This association was validated in a second cohort of breast cancer patients (n = 148), where TT carriers with ER-negative cancer developed the disease 3.8 years earlier than CC carriers (P = 0.006). The effect was more pronounced in Caucasians with ER-negative ductal carcinomas with TT homozygotes developing disease 7.5 years (P = 0.031) and 6.2 years (P = 7 x 10(-5)) earlier than CC carriers in cohorts 1 and 2, respectively. No association was seen in ER-positive ductal cancers suggesting that the SNP in MDM4 only has a functional association in ER-negative breast cancer.

Purpose This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma (HCC) patients. Methods In the phase I part, advanced HCC patients were dose-escalated on foretinib (30–60 mg) once daily (QD) using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival. Results The MTD of foretinib was established as 30 mg QD. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg QD in the first-line setting, foretinib demonstrated promising anti-tumor activity. According to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), the objective response rate was 22.9%, the disease stabilization rate 82.9% and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS. Conclusion Foretinib demonstrated promising anti-tumor activity and good tolerability in the first-line setting in Asian advanced HCC patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib.