Regulation of human protease-activated receptor 1 (hPar1) gene expression in breast cancer by estrogen

A pivotal role is attributed to the estrogenreceptor (ER) pathway in mediating the effect of estrogen in breast cancer progression. Yet the precise mechanisms of cancer development by estrogen remain poorly understood. Advancing tumor categorization a step forward, and identifying cellular gene fingerprints to accompany histopathological assessment may provide targets for therapy as well as vehicles for evaluating the response to treatment. We report here that in breast carcinoma, estrogen may induce tumor development by eliciting protease-activated receptor-1 (PAR1) gene expression. Induction of PAR1 was shown by electrophoretic mobility shift assay, luciferase reporter gene driven by the hPar1 promoter, and chromatin-immunoprecipitation analyses. Functional estrogen regulation of hPar1 in breast cancer was demonstrated by an endothelial tube-forming network. Notably, tissue-microarray analyses from an established cohort of women diagnosed with invasive breast carcinoma exhibited a significantly shorter disease-free (P 0.006) and overall (P 0.02) survival of patients that were positive for ER and PAR1, compared to ER-positive but PAR1-negative patients. We propose that estrogen transcriptionally regulates hPar1, culminating in an aggressive gene imprint in breast cancer. While ER patients are traditionally treated with hormone therapy, the presence of PAR1 identifies a group of patients that requires additional treatment, such as anti-PAR1 biological vehicles or chemotherapy.—Salah, Z., Uziely, B., Jaber, M., Maoz, M., Cohen, I., Hamburger, T., Maly, B., Peretz, T., B.-S, R. Regulation of human protease-activated receptor 1 (hPar1) gene expression in breast cancer by estrogen

The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis

During the metastasis process, tumor cells invade the blood circulatory system directly from venous capillaries or indirectly via lymphatic vessels. Understanding the relative contribution of each pathway and identifying the molecular targets that affect both processes is critical for reducing cancer spread. Methionine aminopeptidase 2 (MetAp2) is an intracellular enzyme known to modulate angiogenesis. In this study, we investigated the additional role of MetAp2 in lymphangiogenesis. A histological staining of tumors from human breast-cancer donors was performed in order to detect the level and the localization of MetAp2 and lymphatic capillaries. The basal enzymatic level and activity in vascular and lymphatic endothelial cells were compared, followed by loss of function studies determining the role of MetAp2 in lymphangiogenesis in vitro and in vivo. The results from the histological analyses of the tumor tissues revealed a high MetAp2 expression, with detectable sites of co-localization with lymphatic capillaries. We showed slightly reduced levels of the MetAp2 enzyme and MetAp2 mRNA expression and activity in primary lymphatic cells when compared to the vascular endothelial cells. The genetic and biochemical manipulation of MetAp2 confirmed the dual activity of the enzyme in both vascular and lymphatic remodulation in cell function assays and in a zebrafish model. We found that cancer-related lymphangiogenesis is inhibited in murine models following MetAp2 inhibition treatment. Taken together, our study provides an indication that MetAp2 is a significant contributor to lymphangiogenesis and carries a dual role in both vascular and lymphatic capillary formation. Our data suggests that MetAp2 inhibitors can be effectively used as anti-metastatic broad-spectrum drugs

Democratic leaders and the democratic peace: The operational codes of Tony Blair and Bill Clinton

Do the beliefs of leaders make a significant difference in determining if democracies are peaceful and explaining why democracies (almost) never fight one another? Our comparisons of Prime Minister Tony Blair and President Bill Clinton reveal that both leaders view democracies as more friendly than nondemocracies, and they have significantly less cooperative beliefs toward the latter than toward the former, a difference that extends to the behavior of their respective governments during the Kosovo conflict. We also find that individual differences in the operational codes of the two leaders matter in the management of conflict with nondemocracies; the leaders exhibit opposite leadership styles and behavior associated with the domestic political culture of the two states. Overall, these results support the dyadic version of the democratic peace and suggest that the conflict behavior of democratic states depends upon the beliefs and calculations of their leaders in dealing with nondemocracies. © 2006 International Studies Association