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View the Table of Contents for the October 1 issue of Cancer Research.
Milne et al. Page 9420
The failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk as the most likely candidate. Milne et al. carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. The authors conclude that rs744154 itself, although intronic, could be causal. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer.
Dumaz et al. Page 9483
Melanocytes require the RAS/RAF/MEK/ERK and the cAMP signaling pathways to maintain the fine balance between proliferation and differentiation. Dumaz et al. investigated how cross-talk between these pathways affects melanoma progression. The authors show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells. As a consequence, BRAF alone is responsible for signaling to MEK. However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF. This switch is accompanied by dysregulated cAMP signaling, a step that is necessary to allow CRAF to signal to MEK. Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling.
Yang et al. Page 9665
Prostaglandin E2 (PGE2), one of the major metabolites of cyclooxygenase-2 (COX-2), has been implicated in tumorigenesis and tumor progression in several human cancers including colorectal and lung. Yang et al. demonstrate that one of the PGE2 receptors, the EP4 receptor, plays an important role in metastasis in both of these tumor types. The authors show that selective antagonism of EP4 receptor signaling results in a profound reduction in lung and colon cancer metastasis. Selective antagonism of the EP4 receptor may thus represent a novel therapeutic approach for the treatment of cancer and especially its propensity to metastasize.
Page 9682
NPRL2 is one of candidate tumor suppressor genes clustered in the human chromosome 3p21.3 region. To explore its biological role, Ueda et al. analyzed the endogenous expression of the NPRL2 protein and the cellular response to cisplatin in NSCLC cell lines and found that NPRL2 expression was significantly and reciprocally correlated to cisplatin sensitivity. They also found that a combination treatment with NPRL2-nanoparticle and cisplatin significantly enhanced therapeutic efficacy and overcame cisplatin-induced resistance in vitro and in vivo. Their findings shed new light on mechanism of NPRL2 function and cisplatin resistance and implicate the translational potential of NPRL2 as a molecular marker and agent for cancer treatment and prognosis.
Page 9722
The loss-of-function mutations in tumor suppressor genes are usually very specific to cancer cells and present attractive and unique opportunities for therapeutic interventions. However, antitumor agents that target loss-of-function mutations have not been readily identified. Using the DPC4 gene in pancreatic cancer as an example, Wang et al. demonstrate the feasibility of a novel screening strategy, named Pharmacological Synthetic Lethal Screening (PSLS), for the identification of agents that selectively target cancer cells with loss-of-function mutations. After screening 19,590 compounds, the authors identified one lead compound, UA62001, which showed 4.6-fold selectivity against DPC4 deficiency in the DPC4 isogenic cell lines. A fairly good correlation between DPC4 deficiency and UA62001 sensitivity was observed in commonly used pancreatic cancer cell lines.
Page 9731
Targeting oncogenes which are preferentially expressed in tumors is an attractive strategy in anticancer therapy. Forkhead Box M1 (FoxM1) is one such oncogenic transcription factor, which is overexpressed in a number of different carcinomas, while its expression is extinguished in terminally differentiated cells. Radhakrishnan et al. report the identification of the antibiotic thiazole compound Siomycin A as an inhibitor of FoxM1 transcriptional activity. Apart from the expected decline in FoxM1 target genes, Siomycin A treatment exhibited interesting anticancer properties such as reduction in anchorage-independent cell growth and selective killing of transformed cells. These properties make Siomycin A an attractive candidate for anticancer drug development.