Purpose: Cell signaling pathways include a complex myriad of interconnected factors from the membrane to the nucleus, such as erbB family receptors and the phosphoinositide-3-kinase/Akt/ mTOR and Ras-Raf-ERK cascades, which drive proliferative signals, promote survival, and regulate protein synthesis. Experimental Design: To find pivotal factors in these pathways, which provide prognostic information in malignancies, we studied 103 human breast tumors with an immunohistochemical profile, including total and phosphorylated (p) proteins: human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor, extracellular signal-regulated kinase 1/2, Akt, 4E-binding protein 1 (4EBP1), eukaryotic initiation factor 4E, phosphorylated ribosomal protein S6 kinase 1, phosphorylated ribosomal protein S6, and Ki67.Western blot and reverse lysate protein arrays were also done in a subset of tumors. Results: Significantly, activation of the phosphoinositide-3-kinase/Akt/mTOR cascade was detected in a high proportion of tumors (41.9%). Tumors with HER2 overexpression showed higher p-Akt as compared with negative tumors (P < 0.001). Levels of p-Akt correlated with the downstream molecules, p-4EBP1 (P = 0.001) and p-p70S6K (P = 0.05). Although 81.5% of tumors expressed p-4EBP1, in 16.3% of these tumors, concomitant activation of the upstream factors was not detected. Interestingly, p-4EBP1 was mainly expressed in poorly differentiated tumors (P < 0.001) and correlated with tumor size (P < 0.001), presence of lymph node metastasis (P = 0.002), and locoregional recurrences (P = 0.002). Coexpression of p-4EBP1 and p-eIF4G correlated with a high tumor proliferation rate (P = 0.012). Conclusion: In this study, p-4EBP1was the main factor in signaling pathways that associate with prognosis and grade of malignancy in breast tumors. Moreover, p-4EBP1 was detected in both HER2-positive and HER2-negative tumors. This factor seems to be a channeling point at which different upstream oncogenic alterations converge and transmit their proliferative signal, modulating protein translation.Human tumors are characterized by their great heterogeneity and histopathologic variability. Currently, >250 malignant tumors and thousands of subtypes and histologic variants have been described. Nevertheless, the classic pathologic criteria, such as tumor size, grade of malignancy, and metastatic dissemination, are generally the most relevant prognostic factors in cancer. In addition to the variability of histopathologic subtypes, molecular study of tumors is even more complex. In all malignant tumors, at least six genetic alterations should affect the main mechanisms of cellular transformation, including growth factor and cell signaling pathways, the cell cycle, apoptosis, and mechanisms implicated in cellular invasiveness, and angiogenesis (1 -3). Overall, >350 genes associated with cancer have been identified, representing >1% of the human genome (4).Studies using cDNA expression arrays have detected hundreds of genetic alterations w...

No abstract

Synovial sarcoma (SS) accounts for 5%-10% of all soft tissue sarcomas. It is a well-defined soft tissue neoplasm with biphasic and monophasic histologic subtypes and unknown histogenesis. It usually occurs in the extremities, especially the thigh-knee region of young adults. Recurrences are frequent and distant metastasis developed in approximately half of the patients. SSs are characterized by a recurrent nonrandom chromosomal translocation, t(X; 18) (p11; q11), which is considered the primary genetic event in more than 90% of cases. Only 4 cases of cutaneous and subcutaneous SSs have been published in the literature so far. We report a case of primary subcutaneous SS in the forearm of a young woman and discuss the histopathologic differential diagnosis with other similar neoplasms. This is the first reported case of primary cutaneous SS showing immunoreactivity for TLE1 in the nuclei of neoplastic cells, supporting the use of this marker for diagnosis of this rare cutaneous neoplasm.

No abstract

Summary Melanoma is the most aggressive skin tumour, being the leading cause of death from skin cancer. Its incidence has increased more rapidly than for any of the top 10 cancers. A low percentage of patients with metastasis (meaning it has spread to other parts of the body) survive over one year after diagnosis, due to the lack of efficient therapy. Not all melanomas are the same, they can vary in how aggressive they are (how quickly they develop and potentially spread) and in their appearance. The authors of this study, from Spain, studied cultured (grown in the lab from a sample) melanoma cells with different aggressiveness features and patients with different types of melanoma lesions. They aimed to find metabolic markers in melanoma that could predict the evolution of the disease. Cellular metabolism is the set of chemical reactions that occur in living organisms in order to maintain life. It is known that the metabolism of cancer cells is different from that of normal cells since they grow and divide rapidly, needing high‐energy supply. In this context, the authors found that proteins (enzymes) related with energy production are altered. These proteins are: the ATP synthase (β‐F1‐ATPase), the heat‐shock protein 60 (HSP60), the glycolytic glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) and the pyruvate kinase M2 (PKM2). These proteins provide the bioenergetic signature (BEC index=β‐F1‐ATPase/HSP60/GAPDH ratio) of cancer. A reduction in BEC index correlates with the aggressiveness of cultured melanoma cells and tumours and worse overall survival in melanoma patients. The authors conclude that the level of metabolic enzymes and BEC status are markers of (indicators of) melanoma stage (how adavanced it is, e.g. if it has spread and by how much) and overall survival in melanoma patients.