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View the Table of Contents for the February 1 issue of Cancer Research
Page 681
Estrogen plays a prominent role in the development of human breast cancer. Genetically engineered mouse models offer an opportunity to dissect and understand underlying molecular mechanisms and their relevance in the development of breast cancer. A new mouse model was developed to explore the contribution of aberrant expression of the Estrogen Receptor alpha (ERα) in the etiology of mammary cancer. Deregulated ERα expression resulted in the development of ductal hyperplasia and ductal carcinoma in situ (DCIS) lesions that resemble those found in humans both histologically and molecularly. These mice will facilitate in vivo genetic studies of ERα action in mammary carcinogenesis, treatment and prevention.
Page 805
Conducting a candidate gene linkage study in brothers with prostate cancer, Larson et al. defined a linkage interval in the fragile histidine triad gene (FHIT) on chromosome 3p14.2. The signal was strongest in a subset of families with multiple affected brothers and was consistent with a recessive model of inheritance. Subsequent association testing revealed a SNP in intron 5 of FHIT strongly associated with disease risk. This approach, combining plausible candidates with the usual genome-wide markers to cover the genome, may hold promise for the design of future linkage studies of cancer risk.
Page 913
Tumor progression is dependent on the availability of a vascular network that accommodates the nutrient requirements of the proliferating tumor. Although angiogenic sprouting is thought to be the principle mechanism by which vascular expansion occurs, Lu and Schroit present evidence that tumors generate their blood supply by co-opting latent, red-cell–deficient blood vessels. These vessels are then progressively mobilized to red-cell–rich patent vessels by a mechanism that is largely independent of endothelial cell proliferation. These data indicate that mobilization of a pre-existing latent vasculature to patency plays an important role in tumor development.
Page 982
Selective COX-2 inhibitors are promising therapeutic agents in epithelial malignancies, including pancreatic cancer. To explore the effects of COX-2 inhibitors on COX-2 negative pancreatic tumors, Eibl et al. conducted a composite in-vitro and in-vivo study. The COX-2 inhibitor nimesulide reduced the growth of COX-2 positive, but stimulated the growth of COX-2 negative pancreatic cancer in xenograft models. The tumor-promoting effect was accompanied by an increase in angiogenesis and mediated by the nuclear receptor PPAR-γ. These findings support the notion that molecular profiling of pancreatic tumors for the presence of COX-2 may be warranted prior to considering COX-2 inhibitors as therapeutic agents.
Page 1027
The RSKs (also called p90 ribosomal S6 kinase) are protein kinases that are highly expressed in many breast cancers. Smith et al. have identified the first specific, small-molecule inhibitor for this important family of serine/threonine protein kinases. The RSK inhibitor, called SL0101, was discovered in a screen of extracts obtained from plants of rare genera. SL0101 specifically blocks RSK activity both in vitro and in living cells. Remarkably, it inhibits the proliferation of breast cancer cells but not of normal cells. RSK is therefore an important new drug target for breast cancer, and SL0101 is the lead compound for a novel class of chemotherapeutic agents.