Purpose: The biological effect of interleukin-6 (IL-6) signaling in oral squamous cell carcinoma (OSCC) and whether IL-6 receptor (IL-6R)-mediated signaling can be a therapeutic target for OSCC are unclear. The aim of this study was to investigate the effects of inhibition of IL-6R-mediated signaling on OSCC progression and to evaluate the availability of tocilizumab, a humanized antihuman IL-6R antibody, as a therapeutic agent for OSCC. Experimental Design: We evaluated expression levels of IL-6 and IL-6R in 58 OSCC tissues and 4 OSCC cell lines by real-time quantitative reverse transcription-PCR and/ or immunohistochemstry. We investigated the effects of tocilizumab on OSCC growth in vitro and in xenografts. Xenografts were analyzed by immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (pSTAT3), Ki-67, and CD31, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was done. Results: Expression levels of IL-6 at both mRNA and protein levels in OSCC tissues were significantly higher than those in normal mucosal tissues. In addition, OSCC cell lines expressed higher levels of both IL-6 and IL-6R mRNA than did HaCaT keratinocytes. Tocilizumab significantly reduced in vivo growth of SAS cells with a drastic reduction of STAT3 phosphorylation in tumor cells in mice. Inhibition of IL-6 signaling significantly decreased vascular endothelial growth factor mRNA expression in SAS, and microvessel density and vessel diameter in SAS tumors in tocilizumab-treated mice. Conclusions: Therapeutic approaches targeting IL-6R by tocilizumab may be effective for OSCC treatment by at least inhibiting angiogenesis. (Clin Cancer Res 2009;15(17):5426-34)

These findings suggest that HIF-1alpha was closely linked to an aggressive phenotype in breast cancer. It may be useful to study the expression of HIF-1alpha using immunohistochemical analysis for better understanding of the tumor characteristics of breast cancer.

Estrogen receptor (ER) a plays a crucial role in normal breast development and has also been linked to mammary carcinogenesis and clinical outcome in breast cancer patients. However, the molecular mechanisms controlling the expression of ERa are as yet not fully understood. Gene amplification is one of the important factors regulating protein expression. Recent studies on the amplification of the ESR1 gene, which encodes ERa, have presented conflicting data. Using fluorescence in situ hybridization and real-time quantitative polymerase chain reaction analysis, we examined the ESR1 status in a series of breast cancer tissues and analyzed its clinical importance. ESR1 gene amplification and gain were found in 22.6 and 11.3% of samples, respectively, as determined by three-dimensional fluorescence in situ hybridization assay. Moreover, ESR1 amplification and amplification plus gain were significantly negatively correlated with tumor size, number of positive lymph nodes, negative ERa, and positive human epidermal growth factor receptor 2 status. It has also been shown that ESR1 amplification strongly correlates with higher expression levels of ER protein and that patients with ESR1 amplification in their tumors apparently experience longer disease-free survival than those without. Our data suggest that ESR1 amplification might prove to be helpful in selecting patients who may potentially benefit from endocrine

Tumor stiffness evaluated by EG bears predictive potential for response to neoadjuvant chemotherapy. Stiffness evaluated by EG may be recognized as a clinically significant tumor characteristic, comparable to other data obtained by functional imaging techniques.

FBXW7 is a cell cycle regulatory gene that ubiquitinates positive cell cycle regulators such as c-Myc and cyclin E, allowing for cell cycle exit. Defects in the FBXW7 gene that lead to cell cycle re-entry and expedite the G1-S transition is thought to be one of the causes of cancer development. However, its clinical importance for breast cancer patients remains undetermined. This prompted us to investigate its expression level in breast cancer patients to establish its clinical significance. The expression level of FBXW7 mRNA was assessed in 186 cases of primary invasive breast cancer. Correlations between FBXW7 mRNA expression and clinicopathological factors, prognoses and immunohistochemical expression levels of Ki-67, FBXW7, c-Myc and cyclin E were analyzed. In vitro investigation of FBXW7 gene silencing in a breast cancer cell line was conducted. FBXW7 mRNA was expressed at significantly lower levels in patients with high histological grade and hormone receptor-negative tumors. Patients with lower FBXW7 mRNA expression had a poorer prognosis for breast cancer-specific survival than those with higher expression. A high Ki-67 labeling index and positive cyclin E protein expression were significantly correlated with lower FBXW7 mRNA expression. In vitro, silencing FBXW7 enhanced expression of c-Myc and cyclin E proteins and upregulated both cell proliferation and G1-S transition. In breast cancer, reduced FBXW7 mRNA expression may have independent prognostic potential through the enhanced function of cell cycle regulatory proteins. (Cancer Sci 2011; 102: 439-445) R ecent studies have revealed that the ubiquitin-proteasome system plays many important roles in human carcinogenesis, such as in cell cycle progression, apoptosis, signal transmission and DNA repair. Frequent deregulation of E3 ligase components in breast cancer has led to their investigation as oncogenes or tumor suppressor genes. Major examples are the amplification and overexpression of Mdm2 and Skp2, mutation of BRCA1 in familial breast cancer and, more recently discovered, mutation and loss of expression of FBXW7 (F-box and WD repeat domain-containing 7).(1,2) FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligases and regulates positive cell cycle regulators such as c-Myc, cyclin E, c-JUN, Aurora A and Notch, molecules commonly implicated in many cancers (3) including breast cancer.(4,5) c-Myc is a transcription factor and has a crucial role in deciding whether or not mammalian cells divide. Cyclin E coordinates S-phase entry from either G1 or quiescence (G0), and constitutive expression of cyclin E leads to genomic instability. One notable function of FBXW7 is induction of cell cycle exit (to G0-phase) by c-Myc degradation, whereas cell cycle re-entry (G0 to G1) is regulated by p27 and its F-box regulator Skp2. Therefore, altered expression of FBXW7 is hypothesized to cause carcinogenesis and cancer development. (6,7) FBXW7 was first linked to carcinogenesis when mutations in FBXW7 were found in the brea...