Molecular studies of squamous cell carcinoma of the head and neck (HNSCC) have demonstrated multiple genetic abnormalities such as activation of various oncogenes (Ras, Myc, epidermal growth factor receptor, and cyclin D1), tumor suppressor gene inactivation (TP53 and p16), and loss of heterozygosity at numerous chromosomal locations. Despite these observations, accurate and reliable biomarkers that predict patients at highest risk for local recurrence have yet to be defined. In an effort to identify gene expression signatures that may serve as biomarkers, we studied 41 squamous cell carcinoma tumors (25 primary and 16 locally recurrent) from various anatomical sites and 13 normal oral mucosal biopsy samples from healthy volunteers with microarray analysis using Affymetrix U133A GeneChip arrays. Differentially expressed genes were identified by calculating generalized t tests (P < 0.001) and applying a series of filtering criteria to yield a highly discriminant list of 2890 genes. Hierarchical clustering and image generation using standard software were used to visualize gene expression signatures. Several gene expression signatures were readily identifiable in the HNSCC tumors, including signatures associated with proliferation, extracellular matrix production, cytokine/chemokine expression, and immune response. Of particular interest was the association of a gene expression signature enriched for genes involved in tumor invasion and metastasis with patients experiencing locally recurrent disease. Notably, these tumors also demonstrated a marked absence of an immune response signature suggesting that modulation of tumor-specific immune responses may play a role in local treatment failure. These data provide evidence for a new gene expression-based biomarker of local treatment failure in HNSCC.

Boppart MD, Volker SE, Alexander N, Burkin DJ, Kaufman SJ. Exercise promotes ␣7 integrin gene transcription and protection of skeletal muscle. Am J Physiol Regul Integr Comp Physiol 295: R1623-R1630, 2008. First published September 10, 2008 doi:10.1152/ajpregu.00089.2008.-The ␣7␤1 integrin is increased in skeletal muscle in response to injury-producing exercise, and transgenic overexpression of this integrin in mice protects against exerciseinduced muscle damage. The present study investigates whether the increase in the ␣7␤1 integrin observed in wild-type mice in response to exercise is due to transcriptional regulation and examines whether mobilization of the integrin at the myotendinous junction (MTJ) is a key determinant in its protection against damage. A single bout of downhill running exercise selectively increased transcription of the ␣7 integrin gene in 5-wk-old wild-type mice 3 h postexercise, and an increased ␣7 chain was detected in muscle sarcolemma adjacent to tendinous tissue immediately following exercise. The ␣7B, but not ␣7A isoform, was found concentrated and colocalized with tenascin-C in muscle fibers lining the MTJ. To further validate the importance of the integrin in the protection against muscle damage following exercise, muscle injury was quantified in ␣7 Ϫ/Ϫ mice. Muscle damage was extensive in ␣7 Ϫ/Ϫ mice in response to both a single and repeated bouts of exercise and was largely restricted to areas of high MTJ concentration and high mechanical force near the Achilles tendon. These results suggest that exercise-induced muscle injury selectively increases transcription of the ␣7 integrin gene and promotes a rapid change in the ␣7␤ integrin at the MTJ. These combined molecular and cellular alterations are likely responsible for integrin-mediated attenuation of exercise-induced muscle damage. exercise; injury; repeated bout effect; tenascin-C SEVERAL CLASSES OF CELL ADHESION molecules provide mechanisms for attaching cells to each other and to their extracellular environment. These include integrins, cadherins, and members of the immunoglobulin and selectin families (23). Integrins are transmembrane heterodimers of noncovalently bound ␣-and ␤-subunits. Integrins bind to specific ligands in the extracellular matrix, form clusters, and recruit cytoskeletal and cytoplasmic proteins that stabilize the cell and provide a means for communication between the outside and inside of the cell. Eighteen ␣-subunits and 8 ␤-subunits have been characterized, and at least 24 heterodimers have been identified (46).␣7␤1 is the predominant integrin in adult skeletal muscle. The ␣7 subunit determines the specificity of ligand binding to laminin in the basal lamina surrounding individual muscle fibers, whereas the ␤1 subunit participates in linkage with actin via several subsarcolemmal proteins, including ␣-actinin, talin, vinculin, paxillin, and tensin. Several other integrin ␣-subunits are expressed in skeletal muscle in association with ␤1, including ␣1, ␣3, ␣4, ␣5, ␣6, ␣9, ␣10, ␣11, and ␣v (15,29,30,39,...

Many studies have evaluated the cancer -preventive potential of individual bioactives from tomatoes and broccoli, but few have examined them within the context of a whole food. Male Copenhagen rats were fed diets containing 10% standard tomato powder, tomato enriched with lycopene or total carotenoids, standard broccoli floret, broccoli sprouts, or broccoli enriched with indole glucosinolates or selenium for 7 days. All broccoli diets increased the activity of colon quinone reductase (NQO1). Indole glucosinolate-enriched broccoli and selenium-enriched broccoli increased hepatic NQO1 and cytochrome P450 1A activity (P < 0.05). Standard broccoli and lycopene-enriched tomato diets down-regulated prostatic glutathione S-transferase P1 mRNA expression. Different tomato diets resulted in altered hepatic accumulation of lycopene, phytofluene, and phytoene. These results demonstrate that the bioactive content of vegetables affects both tissue content of bioactives and activity of detoxification enzymes. Enhancing bioactive content of tomatoes and broccoli may enhance efficacy in the prevention of prostate cancer.

The prolyl isomerase cyclophilin A (CypA) regulates the Jak2/Stat5 pathway, which is necessary for mammary differentiation and the pathogenesis of breast cancer. In this study, we assessed the role of this isomerase during mammary gland development and erbB2-driven tumorigenesis. Genetic deletion of CypA resulted in delayed mammary gland morphogenesis and differentiation with corresponding decrease in Jak2/Stat5 activation; mammary gland cross-transplantation confirmed this defect was epithelial in nature. Analysis of mammary stem and progenitor populations revealed significant disruption of epithelial maturation. Loss of CypA in the erbB2 transgenic mouse model revealed a marked increase in mammary tumor latency that correlated with decreased Stat5 activation, associated gene expression, and reduced epithelial cell proliferation. These results demonstrate an important role for CypA in the regulation of Jak2/Stat5-mediated biology in mammary epithelium, identifying this isomerase as a novel target for therapeutic intervention. These findings reveal cyclophilin A functions in normal mammary epithelial development and ErbB2-driven mammary tumorigenesis and suggest therapies targeting cyclophilin A may be efficacious for breast cancer treatment. http://cancerres.aacrjournals.org/content/canres/78/14/3877/F1.large.jpg .