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View the Table of Contents for the April 15 issue of Cancer Research.
Ding et al. Page 4095
The discovery of molecular markers to detect a precancerous state before histological atypia would have profound implications in the prevention of breast cancer and in the management of women at high risk of developing carcinoma. The Polycomb group protein, EZH2, can cause malignant transformation of the mammary epithelium and has been associated with poor survival in breast and other malignancies. Ding et al. report that EZH2 protein expression is elevated in morphologically normal breast epithelium in the vicinity of ductal carcinoma in situ. Notably, increased EZH2 protein expression, detected by immunohistochemistry, marked morphologically normal breast epithelium at risk for developing carcinoma as early as 12 years prior to the diagnosis of cancer. EZH2 expression was also elevated in histologically benign breast tissues from women carrying BRCA1 mutations who have up to an 85% lifetime risk of developing breast cancer. This study supports a role of EZH2 as a potential marker for detecting preneoplastic lesions of the breast in vivo before evident histological atypia, as well as a possible target for preventative intervention.
Sasai et al. Page 4215
Activation of the Sonic Hedgehog (Shh) pathway increases expression of Gli1 and causes medulloblastoma in Ptc1+/–p53–/– mice. To develop new therapies against medulloblastoma, it is important to propagate tumor cells. Sasai et al. found that the Shh pathway is suppressed in cultured tumor cells and is not activated when those cells are transplanted in vivo. In one case, tumor cells showed high levels of Gli1 but this was a consequence of gene amplification. In contrast, the authors found that the Shh pathway remains active in cells directly transplanted from medulloblastomas and those cells provide a useful system for testing antitumor agents.
Page 4368
NAD-dependent protein deacetylases or sirtuins control the acetylation state and the activity of important tumor suppressor proteins and oncoproteins. Heltweg et al. report identification of a novel compound, cambinol, which inhibits the activity of two members of the human sirtuin family, SIRT1 and SIRT2, and induces hyperacetylation of their relevant cellular targets including p53, BCL6, and tubulin. Cambinol sensitizes cells to chemotherapy in a p53-independent fashion and exhibits activity as a single agent in BCL6-expressing lymphoma cell lines in vitro and in mouse xenografts. These findings suggest that inhibitors of SIRT1/SIRT2 may constitute novel anticancer agents.
Page 4503
Nitric oxide–donating aspirin (NO-ASA) is a novel chemopreventive agent. To explore its effect in the prevention of pancreatic cancer, Ouyang et al. used the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) in a Syrian golden hamster model. Compared to controls, NO-ASA reduced the incidence of pancreatic cancer by 88.9% and its multiplicity by 94%; conventional aspirin had no significant effect. NO-ASA arrested the transition from PanIN2 to PanIN3 and carcinoma, achieving its effect through changes in ductal cell kinetics, and suppression of NF-κB activation and COX-2 expression. NO-ASA shows significant promise as a chemopreventive agent against pancreatic cancer and merits further evaluation.