Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.

BackgroundTight junction proteins in the cell organize paracellular permeability and they play a critical role in apical cell-to-cell adhesion and epithelial polarity. Claudins are major integral membrane proteins of tight junctions, especially Claudin 1, 4, and 7, which are known as the impermeability Claudins. In this study, we investigated the importance of loss of Claudin 1, 4, and 7 expression, and their relation to tumor progression in colorectal cancer patients.Material/MethodsLoss of Claudin 1, 4, and 7 expression was examined by immunohistochemical method in 70 patients diagnosed with colorectal cancer. Cases with loss of Claudin expression in <1/3 of tumor cells were classified as mild loss, whereas cases with loss of Claudin expression ≥1/3 of tumor cells were classified as moderate-to-marked loss in order to evaluate the relation between loss of Claudin 1, 4, and 7 expression and clinicopathologic data.ResultsThe severe suppression of Claudin 1, 4, and 7 expression was found to be significantly related to the depth of tumor invasion, positive regional lymph nodes, histological grade, lymphovascular invasion, perineural invasion, and lymphocytic response. Additionally, severity of loss in Claudin 4 expression was found to have a relation with distant metastasis.ConclusionsClaudin 1, 4, and 7 are important building blocks of paracellular adhesion molecules. Their decreased expression in colorectal cancer seems to have critical effects on cell proliferation, motility, invasion, and immune response against the tumor.

It has been reported previously that: 1) normal breast epithelial cells that are CD24-/44+ express higher levels of stem/progenitor cell associated genes; 2) cancer cells that have undergone epithelial to mesenchymal transition display CD24-/44+ cell surface expression, a marker for breast cancer stem cells; 3) loss of E-cadherin is a preliminary step in epithelial to mesenchymal transition; and 4) vimentin is a marker of mesenchymal phenotype.We hypothesized that stem cell subpopulations would be more frequent in metastatic than in primary tumors. Therefore we assessed by immunohistochemical analysis, tissue microarrays containing tissue from primary and associated metastatic breast cancers for expression of CD24, CD44, E-cadherin and vimentin to evaluate candidate cancer-initiating cell populations in breast cancer subtypes and metastatic lesions. The occurrence of CD24-/44+ and CD24+/44- cells did not differ in primary vs matched lymph node or distant and locoregional metastatic lesions; E-cadherin expression was decreased in primary vs lymph node metastases (P=0.018) but not decreased in distant and locoregional metastases relative to primary tumor, while vimentin, was more frequently expressed in lymph node and distant and locoregional metastases (P=0.013, P=0.004) than in matched primary cancers. Thus, the frequency of CD24-/44+ cells does not differ in metastases relative to the primary breast cancer but differs by tumor stage and subtype.

BackgroundHMGB1, the most important member of the high mobility group box protein family, is a nuclear protein with different functions in the cell; it has a role in cancer progression, angiogenesis, invasion, and metastasis development. We studied the expression of HMGB1 and whether it is a prognostic factor in colorectal carcinoma.Material/MethodsThe study included 110 cases that were histopathologically diagnosed with colorectal carcinoma from the tissue samples acquired by surgical resection and biopsy in Antalya Education and Research Hospital between 2008 and 2012. HMGB1 expression was examined via immunohistochemical method.ResultsHMGB1 expression was evaluated as negative in 32 (44.4%) of the patients and as positive in 40 (55.6%) patients. There was no relation between the HMGB1 expression and sex, age, tumor invasion depth, and histological type. However, a significant relation was detected between the HMGB1 expression and lymph node status, metastasis status, and stage (p:<0.001, p:<0.001, p:<0.001, respectively). Similar results were obtained for the relations between the HMGB1 and histological grade, perineural invasion, lymphovascular invasion, and lymphocytic response (p<0.001, p<0.001, p<0.001, and p<0.001, respectively).ConclusionsThe results of our study demonstrate that HMGB1 overexpression has a significant role in tumor progression (especially migration of tumor cells) and tumor ability to metastasize in colorectal cancers; thus, it corroborates the idea that it might be an important prognostic factor.

To compare various graft materials in the rabbit model, including autologous cartilage, dermal tissue, fat, and AlloDerm (a cadaver-derived material).Methods: Twenty-five New Zealand white rabbits were used. Equally sized autogenous (fat, fascia, cartilage, and dermal) grafts and AlloDerm were implanted into subcutaneous dorsal pockets on the rabbits. Animals were killed 1, 2, 3, and 4 months after surgery. The grafts were examined microscopically for thickness, resorption, fibrosis, neovascularization, inflammation, eosinophilia, and the presence of multinucleated giant cells or microcysts. Results:The cartilage grafts revealed excellent viability with no resorption. The fascial grafts showed negli-gible volume loss. The dermal grafts developed epidermoid cysts. The AlloDerm grafts demonstrated graft thickening at 1 month and total resorption at 3 and 4 months. The fat grafts demonstrated 30% to 60% partial resorption. Conclusions:The major disadvantage of using an autogenous fat graft was partial resorption, whereas cyst formation was observed with dermal grafts. AlloDerm caused tissue reaction and resorption. The best graft material was cartilage, with a low absorption rate, good biocompatibility, and minimal tissue reaction or fibrosis, followed by fascia, with a minimal shrinkage capacity and tissue reaction.