August 15 Cancer Research Highlights

Between 5% and 10% of women who survive a first primary breast cancer will subsequently develop a second primary cancer in the contralateral breast. The Women’s Environment, Cancer, and Radiation Epidemiology Study was designed to identify genetic and environmental determinants of contralateral breast cancer (CBC). ATM, a serine threonine kinase, is a key regulator of cellular pathways, protecting cells from malignant transformation that can result from exposure to genotoxic agents such as ionizing radiation. Mutations in ATM have been implicated in breast cancer risk. Concannon and colleagues screened for ATM mutations in the 2,105 study participants and identified 240 distinct sequence variants. Only 15 were observed in > 1% of subjects. Among the rare variants, deleterious alleles resulting in loss of ATM function were associated with a nonsignificant increase in risk of CBC. However, four of the 15 common variants were individually associated with a significantly decreased risk of CBC, suggesting that some alleles of ATM may exert an antineoplastic effect. 

 

The mammalian target of rapamycin (mTOR) is an ATP and nutrient sensor that contributes to the control of cell size and cell cycle progression through translational regulation. Of mTOR’s effectors, eIF4E has been implicated in tumorigenesis but the role of S6 Kinase (S6K1) has not been identified. Nakamura and colleagues genetically and pharmacologically manipulated mTOR, eIF4E, and S6K and monitored its effects on the transformed phenotype of human glioma cell lines and transformed human astrocytes. The authors found that suppression of mTOR was sufficient to inhibit the growth of these cells in soft agar, an assay of transformation. Furthermore, S6K1, but not eIF4E, rescued growth in soft agar from rapamycin-mediated suppression. In vivo, S6K1 suppression in intracranially implanted glioma xenografts resulted in reduced intracranial tumor growth. These results are the first direct demonstration of S6K1’s importance in supporting tumor growth in vitro and in vivo and define a role for the mTOR-S6K1 pathway as a mediator of glial cell transformation.

One of the key regulators of intracellular signal transduction is the Ras family of proteins. Ras proteins are guanine nucleotide–binding proteins and are activated by guanine nucleotide exchange factors that stimulate GDP/GTP exchange. Approximately 15% of human malignancies express mutant Ras proteins that are constitutively GTP-loaded and unresponsive to extracellular stimuli. The spatial organization of K-Ras proteins into nanoclusters on the plasma membrane is essential for high-fidelity signal transduction. Shalom-Feuerstein and colleagues show that K-Ras.GTP recruits Galectin-3 (Gal-3) from the cytosol to the plasma membrane where it becomes an integral nanocluster component, and that the cytosolic concentration of Gal-3 determines the magnitude of K-Ras.GTP nanoclustering and signal output. The authors also show that the regulation of K-Ras nanocluster formation and signal output by Gal-3 depends on the integrity of the Gal-3 hydrophobic pocket. These results show that Gal-3, which is overexpressed in a number of human malignancies, affects K-Ras signal output and represents potential oncogenic subversion of plasma membrane nanostructure.