HighlightsMolecular Cancer

Research

GSK-3 Activity in Melanoma

Kubic et al.______________Page 1065

The serine/threonine kinase GSK-3 isinvolved in a wide range of cellularprocesses but has been overlooked for themost part as a participant in melanomabecause both isoforms are predominantlyphosphorylated at N-terminal epitopes andtherefore thought to be inactive. However,Kubic and colleagues report that thesekinases are active in melanoma and thatthey behave as oncogenes. One mechanismthat GSK-3 promotes with respect to thetumor cell is through the directphosphorylation and maintenance ofPAX3, a developmental protein known tosupport cellular growth and migration inmelanocytes. This study may provide afoundation for new therapeutic strategiesto target melanoma.

Novel Mechanisms of EwingSarcoma Chemoresistance

Robin et al. _____________Page 1098

Ewing sarcoma is a pediatric cancer of thebone and soft tissues. Robin and colleaguesshow that the DNA repair protein andtranscriptional coactivator, EYA3, isoverexpressed in Ewing sarcoma andmediates chemoresistance, which ispredictive of poor prognosis. EYA3 isupregulated downstream of EWS/FLI1, themajor oncogenic fusion that drives thedisease through its ability to repress theEYA3 targeting miR-708. Inhibition ofEYA3 and overexpression of miR-708 bothsensitize Ewing sarcoma cells to DNA-damaging chemotherapies. This study isthe first to show that EYA contributes tochemoresistance and to demonstrate a rolefor an EWS/FLI1/miR-708/EYA3 axis inEwing sarcoma.

Ligand Binding PromotesCDK-DependentPhosphorylation

Held et al. ______________Page 1120

Estrogen receptor-α (ERα)phosphorylation patterns encode biologicand clinical differences that underscore thevariable response of breast cancers toendocrine therapy. Held and colleaguesshow by Western and mass spectrometrythat phosphorylation of hinge domainresidues Ser294 and Ser305 differentiateligand-dependent from ligand-independentERα activation. Ser294 is induced byligand (estradiol) and phosphorylated bycyclin-dependent kinases (CDK), whereasligand suppresses growth factor–inducedSer305 phosphorylation. These resultssuggest that determining the ERαphosphorylation status at Ser294/Ser305will improve the clinical value of ER as abreast cancer biomarker and point to a newtargeting opportunity for selective CDKinhibitors to treat ERα-overexpressingbreast cancers.

August 2012 • Volume 10 • Number 8 Selected Articles from This Issue

A Journal of the Molecular and Cellular Biology of Cancer www.aacrjournals.org993

SDF-1 and CXCR4 Are Required for Tumor Cell Intravasation

Jin et al.___________________________Page 1021

The formation of tumor metastases is still not completely understood.Recent publications suggest that the expression of chemokines andtheir receptors by tumor and/or stromal cells can affect this process.Using a coculture model of breast carcinoma cells and culturedendothelial cells, Jin and colleagues observed that expression of SDF-1and CXCR4 induces angiogenic effects in endothelial cells, augmentstumor cell proliferation, and fosters interaction between both cell types,which eventually leads to transendothelial migration. They concludethat the SDF-1/CXCR4 axis is important for tumor cell intravasation.Their data demonstrate that inhibition of CXCR4 could be an optionin the treatment of breast cancer.

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