August 15 Cancer Research Highlights

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Selected Articles from the August 15, 2007 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Cancer Research is published. Click on the article title to view the complete article.

View the Table of Contents for the August 15 issue of Cancer Research.

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Mouse Diaphonous-1 Contributes to Myeloid Malignancies

Peng et al.

Page 7565

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Refinement of Neu Phosphorylation Sites Required for Metastatic Mammary Tumor Induction

Schade et al.

Page 7579

ErbB-2 overexpression and amplification occurs in 15% to 30% of human invasive breast carcinomas associated with poor clinical prognosis. Previously, Schade and colleagues demonstrated that four ErbB-2/Neu tyrosine-autophosphorylation sites within the cytoplasmic tail of the receptor recruit distinct adaptor proteins and are sufficient to mediate signal transduction in vitro. These Grb2 (Neu-YB) and Shc (Neu-YD) binding sites can induce mammary tumorigenesis and metastasis. The role of other sites of phosphorylation is unknown. The authors now show that transgenic mice bearing the two other ErbB-2 autophosphorylation sites (Neu-YC and Neu-YE) developed metastatic mammary tumors. Their findings indicate that activation of distinct Neu-coupled signaling pathways has an important impact on the biological behavior of Neu-induced tumors.

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Metatstatic Hepatocellular Carcinoma Model Demonstrates Effect of p53 Loss

Chen et al.

Page 7589

Hepatocellular carcinoma (HCC) patients frequently present with disease that has metastasized to other regions of the liver, the portal vein, lymph nodes, or lungs, leading to poor prognoses. Chen and coauthors have described a metatstatic HCC model generated after the somatic introduction of the mouse polyoma virus middle T antigen to mice combined with liver-specific deletion of p53. They demonstrate a novel cell autonomous effect of p53 loss of function on HCC metastasis. Their data illustrate a new model system amenable for the analysis of HCC metastasis and the role of p53 in those processes.

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OSU-A9 Shows Promise for Prostate Cancer Therapy

Weng et al.

Page 7815

Indole-3-carbinol has emerged as a promising chemopreventive agent due to its in vivo efficacy in various animal models. However, it exhibits weak antiproliferative potency, and is unstable in an acidic milieu. Weng and colleagues used indole-3-carbinol as a lead to develop potent antitumor/chemopreventive agents with improved chemical stability and efficacy. This effort culminated in the identification of OSU-A9 {[1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol}, which is resistant to acid-catalyzed condensation and exhibits 100-fold higher apoptosis-inducing activity than the parent compound. The authors concluded that the ability of OSU-A9 to target multiple components of cancer cell survival signaling with high potency portends its clinical value in prostate cancer therapy.

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Pulmonary P450 Metabolism of NNK Is Required for Tumorigenesis 

Weng et al.

Page 7825

Critical to mechanisms of chemical carcinogenesis and the design of chemopreventive strategies is whether procarcinogen bioactivation in an extrahepatic target tissue, e.g., the lung, is essential for tumor formation. Weng and colleagues generated a novel triple-transgenic mouse model, with the NADPH-cytochrome P450 reductase (Cpr) gene deleted in a lung-specific and doxycycline-inducible fashion (lung-Cpr-null). Using this model, the authors confirmed the essential role of pulmonary P450-mediated metabolic activation in NNK-induced lung cancer, and this mouse model should be applicable to studies on other procarcinogens that require P450-mediated metabolic activation.

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Circulating IGFBP-1 Levels Predict Pancreatic Cancer

Wolpin et al.

Page 7923

Considerable evidence supports a link between hyperinsulinemia and the subsequent risk of pancreatic cancer. Using the resources of four large prospective cohort studies, Wolpin and colleagues assessed whether prediagnostic plasma levels of IGFBP-1 were associated with the subsequent risk of developing pancreatic cancer. The authors found that individuals in the lowest quartile of circulating IGFBP-1 experienced a greater than two-fold increase in the risk of pancreatic cancer when compared to participants in the three highest quartiles of plasma IGFBP-1, thus providing a much needed indicator of risk and, potentially, a tool for early detection.

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