June 1 Cancer Research Highlights

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Selected Articles from the June 1, 2006 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 1 issue of Cancer Research.

Abl Kinase Drives Invasion in EGFR, Src Deregulated Breast Cancer Cells

Constitutive signaling by Abl kinases drives development of several leukemias. However, the involvement of Abl kinases in solid tumor development and/or progression has not been investigated. Srinivasan et al. demonstrate that Abl kinases are constitutively activated in breast cancer cells downstream of deregulated EGFR, HER-2, and Src kinases, and dramatically promote breast cancer cell invasion. These data suggest that pharmacological inhibitors targeted against Abl kinases may potentially be useful in preventing breast cancer progression in patients whose tumors harbor activated Abl kinases.

MEN1 Reins in CDK2 Activity, Suppresses G₀/G₁ to S Transition

Multiple endocrine neoplasia type 1 (MEN1), an inherited tumor syndrome affecting pancreatic islets, results from mutation of the tumor suppressor gene Men1. However, how Men1 regulates islet cell proliferation is poorly understood. Schnepp et al. report that Men1 represses cyclin-dependent kinase 2 (CDK2) activity and suppresses G0/G1 to S-phase transition, and that Men1 excision in mice quickly leads to increased islet cell proliferation. These studies uncover a crucial role for Men1 in regulating CDK2 and islet cell proliferation, and suggest the CDK2 pathway as a target for therapeutic intervention against MEN1 endocrine tumors.

CSK Hit on c-Jun Squelches AP-1 Activity, Cell Transformation

The tumor suppressor protein COOH-terminal Src kinase (CSK) catalyzes a C-terminal tail phosphorylation reaction on Src and thereby restrains Src’s activity and oncogenic potential. However, CSK also inhibits transcriptional activation of activator protein-1 (AP-1). Zhu et al. have shown that CSK phosphorylates c-Jun directly and the phosphorylation of c-Jun by CSK promotes ubiquitin-dependent degradation of c-Jun, thereby inhibiting AP-1 activity and cell transformation independent of Src inhibition. These results indicated that a novel function of CSK controls cell proliferation under normal growth conditions and may have implications for CSK loss of function in carcinogenesis.

Grape Seed Extract Acts on Promoters to Inhibit Aromatase in Breast Tumors

Aromatase, estrogen synthetase, is expressed at higher levels in breast cancer. Kijima et al. show that grape seed extract (GSE) inhibits aromatase activity and reduces tumor growth in an aromatase-positive breast cancer xenograft mouse model. More excitingly, GSE also is found to selectively suppress aromatase expression by down-regulation of the promoters that drive its expression in breast tumors. These results demonstrate that GSE is potentially useful in the prevention/treatment of hormone-dependent breast cancer via inhibition of aromatase activity as well as its expression. Both pre- and postmenopausal women may benefit from the intake of GSE because of its anti-aromatase expression activity.

Paxillin Stabilizes c-Jun to Enhance Cell Transformation

Paxillin is a substrate for the oncogenic tyrosine kinase v-Src that is found in v-Src transformed cells. Paxillin transduces activation signals from receptor tyrosine kinases to downstream mitogen-activated protein kinase (MAPK), such as c-Jun N-terminal kinases (JNKs), suggesting that paxillin may be involved in cell transformation and tumor development. The authors establish stably transfected si-paxillin cells and show that knockdown of paxillin suppresses cell transformation through ubiqutin-dependent c-Jun degradation. These results suggest that paxillin is an excellent candidate target molecule for development of new chemopreventive and therapeutic drugs.