American Association for Cancer Research

July 15 Cancer Research Highlights

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Selected Articles from the July 15, 2009 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 July 15 issue of Cancer Research.


Long-lived Min Mice Develop Advanced Intestinal Cancers

Halberg et al.

Page 5768

In mouse models for intestinal cancer, progression to advanced cancer has depended on additional constitutional mutations or overt genomic instability. Halberg and colleagues report that long-lived Min mice can develop invasive adenocarcinomas that metastasize by direct extension to regional lymph nodes without overt DNA copy number variation or extensive microsatellite instability. This finding raises the possibility that age-dependent somatic recombination and/or epigenetic change can be sufficient to generate advanced intestinal cancer in the absence of sequence or chromosomal instability.
 

Ovarian Cancer Modifiers in BRCA1/2 Carriers

Rebbeck et al.

Page 5801

Mutations in BRCA1 and BRCA2 (BRCA1/2) are associated with an increased lifetime risk of developing breast and ovarian cancers. However, variation in cancer occurrence suggests that other factors influence this risk. Rebbeck and colleagues studied a cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1. In BRCA1 carriers, haplotypes in BRIP1, MRE11, and NBS1 were associated with altered ovarian cancer risk. In BRCA2 carriers, haplotypes in ATM, BARD1 BRIP1, MRE11, and RAD51 were associated with altered ovarian cancer risk. These genes interact biologically with BRCA1/2, so it is biologically plausible that these mutations modify ovarian cancer risk in women who carry BRCA1/2 mutations.


Antimyeloma Activity of NVP-BEZ235

McMillin et al.

Page 5835

PI3K/Akt/mTOR signaling mediates proliferation, survival, and drug resistance in diverse neoplasias, including multiple myeloma (MM). McMillin and colleagues report that the dual PI3K/mTOR inhibitor NVP-BEZ235 has potent in vitro activity against cells even in the presence of cytokines or accessory cells (stromal cells/osteoclasts) of the bone marrow milieu. NVP-BEZ235 has in vivo anti-MM activity and decreases the amplitude of transcriptional signatures of myc, proteasome function, and high-risk MM. This study provides a framework for simultaneous targeting of PI3K/Akt/mTOR at multiple molecular levels, as opposed to inhibition of single targets in the pathway, as a therapeutic strategy for MM.


Hsu et al.Early exposure to xenoestrogens may be linked to breast cancer risk later in adult life, suggesting that epithelial progenitor cells are susceptible and may transmit these exposure injuries through epigenetic mechanisms to their differentiated progeny. Hsu and colleagues used progenitor-containing mammospheres to study the epigenetic effects of diethylstilbestrol (DES) exposure. MicroRNA-9-3 was found to be down-regulated with repressive chromatin marks at its locus, accompanied by an aberrant increase in DNA methylation of its promoter CpG island. Functional analyses suggest that miR-9-3 plays a role in the p53-related apoptotic pathway. Promoter hypermethylation of this microRNA may be a hallmark for early breast cancer development, with restoration of its expression an option for future treatment. 


Kinome Profiling in Pediatric Brain Tumors

Sikkema et al.

Page 5987

Sikkema et al.Sikkema and colleagues used flow-through peptide microarrays to generate kinome profiles to identify potential new targets when a priori aberrant kinase signaling activity is not necessarily known. Tyrosine kinase activity profiles were obtained from 29 pediatric brain tumors using the PamChip kinome profiling system. These profiles suggest the existence of a tumor-specific kinase activity profile including CDK2 and c-Met, confirming earlier reports on activation of these kinases. Furthermore, Src kinase was found to be highly phosphorylated and the Src kinase inhibitors PP1 and dasatinib induced substantial tumor death in pediatric brain tumor cell lines. These results demonstrate the usefulness of kinase activity profiling to identify new potential targets for treatment. 


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