Asbestos Cancer Update 2008

Health Informatics Research Group, Department of Information Studies, University of Sheffield, Sheffield, UK.

The aim of this study was to develop a tool for evaluating the quality of breast cancer information on the Internet from the perspective of patients and their families. A specific tool, Breast Cancer tool (BC tool), was developed based on the information needs of women with breast cancer and their families reported in the literature. The BC tool and other 3 generic tools (HON, IQ tool, Discern) were used to assess 40 breast cancer websites. The reliability and validity of each tool was examined and the time spent reviewing the websites was measured. The four tools were shown to have acceptable reliability (Cronbach’s alpha>0.7), convergent validity, especially the BC tool which was capable of distinguishing whether a website offers sufficient information for women and their families. However, the BC tool took more time than the other tools to use, suggesting relatively low feasibility. The results of this study reinforce the importance of developing specific tools from perspectives of patients and their family members.

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Departments of Cancer Biology and.

Oncogene-mediated signaling to the host environment induces a subset of cytokines and chemokines. The Drosophila Dac gene promotes migration of the morphogenetic furrow during eye development. Expression of the cell-fate determination factor Dachshund (DACH1) was lost in poor prognosis invasive breast cancer. Mouse embryo fibroblasts derived from Dach1(-/-) mice demonstrated endogenous Dach1 constitutively represses cellular migration. DACH1 inhibited cellular migration and invasion of oncogene (Ras, Myc, ErbB2, c-Raf)-transformed human breast epithelial cells. An unbiased proteomic analysis identified and immunoneutralizing antibody and reconstitution experiments demonstrated IL-8 is a critical target of DACH1 mediating breast cancer cellular migration and metastasis in vivo. DACH1 bound the endogenous IL-8 promoter in ChIP assays and repressed the IL-8 promoter through the AP-1 and NF-kappaB binding sites. Collectively, our data identify a pathway by which an endogenous cell-fate determination factor blocks oncogene-dependent tumor metastasis via a key heterotypic mediator.

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University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, 600 Highland Avenue K4/6 CSC, Madison, WI, 53792, USA, hhbailey@facstaff.wisc.edu.

PURPOSE: Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer. METHODS: Eligible women were treated with POH four times daily at 1,200-1,500 mg m(-2) dose(-1) on a 28-day cycle. Patients tolerating 1,200 mg m(-2) day(-1) four times daily after one cycle were dose-escalated to 1,500 mg/m(2). The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations. RESULTS: Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m(2). Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29-123 days). Median overall survival was 389 days (95% CI, 202-776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-beta1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability. CONCLUSIONS: Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.

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Breast Center, Beijing Cancer Hospital and Institute, Peking University School of Oncology, 100036 Beijing, People’s Republic of China.

In vitro studies suggest that p53 codon 72 genotype alters the apoptotic capacity of p53 protein, with the 72 arginine (R) form of wild-type p53 harboring a greater apoptosis-inducing potential than the 72 proline (P) variant. The aim of this study was to investigate whether the association between the p53 codon 72 genotype and breast cancer survival was modified by p53 gene status. In our study, we examined the p53 codon 72 genotype and p53 mutations (through exons 4-9) in paraffin-embedded specimens from 414 breast cancer patients with a median follow-up of 8.2 years. We report that the p53 codon 72 genotype was significantly associated with disease-free survival (DFS, p = 0.02) but not with disease-specific survival (DSS, p = 0.24) in the entire study population (n = 414). In contrast, the codon 72 genotype was strongly associated with both DFS (p = 0.001) and DSS (p = 0.04) among patients with a wild-type p53 tumor (n = 346), patients with the P/P variant had worse DFS and DSS than did those with the P/R or R/R variant in this subgroup of patients. More importantly, as compared with the P/R or R/R variant, the P/P variant remained an independent prognostic factor of DFS among patients with a wild-type p53 tumor (HR = 2.5; 95%CI = 1.4-4.4; p = 0.003). We conclude that the effect of p53 codon 72 genotype on breast cancer survival is dependent on p53 gene status, the P/P variant is strongly associated with poor prognosis among patients with a wild-type p53 tumor. (c) 2008 Wiley-Liss, Inc.

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School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia. mythmok@mythmok.com

Mouse mammary tumor virus (MMTV) has long been known as a causal agent of breast cancer in mice. To date, varied MMTV-like envelope gene (env) sequences have been identified in up to 74% of human breast cancers. However, the role and origin of these MMTV-like sequences in human breast cancer remain uncertain. Our study was initiated to study the integration of MMTV-like env sequences in human breast cancer. PCR screening has identified 28 (56%) Australian breast cancer specimens and 7 (87.5%) human breast cancer cell lines to be positive for MMTV-like env sequence. In the MCF-7 genome, a fragment containing an MMTV-like env sequence of approximately 1.9 kb plus a downstream rodent-like sequence of approximately 200 bp was found to be integrated into a bacterial-like beta-lactamase sequence by insertional mutagenesis. The identified MMTV-rodent fragment is present in some MCF-7 sublines but absent in the screened specimens and other cell lines. Sporadic mutations found in this fragment indicate it has multiple copies in the MCF-7 genome. Sequence analysis has identified a novel ORF of approximately 1.6 kb which is 94-99% identical to MMTV env genes. RT-PCR was performed on the MCF-7 cDNA but no MMTV-like env transcript was detected. This is the first report to reveal the locus of MMTV-like env sequence in human cells. The MMTV-like env sequence was shown to be distinct from the human endogenous retroviral sequences and is closely related to rodents. (c) 2008 Wiley-Liss, Inc.

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