American Association for Cancer Research

June 15 Cancer Research Highlights

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Selected Articles from the June 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 June 15 issue of Cancer Research.


PTEN Silencing of Survivin

Guha et al.

Page 4954

Survivin is a regulator of cell proliferation and cell viability in tumors and a promising therapeutic target. The regulation of survivin expression in cancer is not understood and whether endogenous tumor suppression contributes to this pathway is uncertain. Guha and colleagues show that the PTEN tumor suppressor, one of the most frequently subverted pathways in cancer, acutely silences survivin reporter gene expression via direct binding of FOXO transcription factors to the proximal survivin promoter. Conversely, loss of PTEN increases survivin levels and inhibits apoptosis. Therefore, survivin is a target of PTEN and this pathway may be required for efficient tumor suppression in humans.
 

15q25 Variants and Lung Cancer

Wu et al.

Page 5065

Recent genome-wide association studies mapped a lung cancer susceptibility locus to chromosome 15q25 in Caucasians. However, the reported SNPs are extremely rare in Asians and might not be causative variants in this population. Wu and colleagues conducted two-stage case-control studies with 3,565 lung cancer cases and 3,456 controls in Chinese populations to investigate SNPs on 15q25 associated with lung cancer susceptibility, using a haplotype-tagging SNP approach. Four novel SNPs (rs2036534C>T, rs667282C>T, rs12910984G>A, and rs6495309T>C) in the CHRNA3-CHRNA4-CHRNA5 gene cluster on 15q25 were identified to be associated with lung cancer risk and smoking behavior; among them, the rs6495309T>C SNP in the CHRNA3 promoter was shown to be functionally relevant. This study highlights differences in genetic markers that may exist among different ethnic populations.


Gleevec, a Candidate Drug for Human Schwannomas

Mukherjee et al.

Page 5099

A subset of neurofibromatosis type 2 (NF2)–associated vestibular schwannomas have accelerated growth patterns that often require intervention in the form of radiosurgery or microneurosurgery. Mukherjee and colleagues report that platelet-derived growth factor receptor and c-Kit, two molecular targets of Gleevec, are activated in schwannoma specimens. Furthermore, they show that Gleevec applied to a human NF2-null schwannoma cell line increased apoptosis and decreased proliferation and anchorage-independent growth. These antitumorigenic effects are correlated with inhibition of these targeted receptors and their downstream signaling pathways. Lack of in vivo models prevents extension of these in vitro studies. These data suggest further investigation of Gleevec, currently used to treat a variety of cancers in the clinic, for human schwannomas. 


The MUC1 oncoprotein is overexpressed in ~ 90% of human breast cancers, making it a potential therapeutic target; however, effective agents against MUC1 have yet to be identified. Raina and colleagues have identified a MUC1 inhibitor that directly blocks oligomerization, and thereby function, of the transforming MUC1-C subunit. The MUC1 inhibitor selectively confers death of breast carcinoma cells overexpressing MUC1 and, in multiple breast tumor xenograft models, induces complete regression with no recurrence occurring after treatment is stopped. These findings demonstrate that inhibition of MUC1-C can be effective in the treatment of human breast tumor xenografts in nude mice. 


Changes in DNA Methylation Precede Immortalization

Novak et al.

Page 5251

Novak et al.The temporal changes of DNA during human carcinogenesis are not completely understood. Using an isogenic human mammary epithelial cell model system of malignant progression, Novak and colleagues show that DNA methylation changes occur early during transformation, in a stepwise manner coincident with overcoming defined proliferation barriers to cell immortalization. A majority of the hundreds of early changes are also seen in breast cancer cells, thereby providing a bank of epigenetic biomarkers that may prove valuable in breast cancer risk assessment. DNA methylation changes in the HOXA gene cluster are illustrative, with many changes occurring prior to malignant transformation. The results presented in this study support an epigenetic progenitor model of cancer. 


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