A pivotal role is attributed to the estrogen-receptor (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 (PAR(1)) gene expression. Induction of PAR(1) was shown by electrophoretic mobility shift assay, luciferase reporter gene driven by the hPar(1) 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 PAR(1), compared to ER-positive but PAR(1)-negative patients. We propose that estrogen transcriptionally regulates hPar(1), culminating in an aggressive gene imprint in breast cancer. While ER(+) patients are traditionally treated with hormone therapy, the presence of PAR(1) identifies a group of patients that requires additional treatment, such as anti-PAR(1) biological vehicles or chemotherapy.