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

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression