title: Regulation of human protease-activated receptor 1 (hPar1) gene expression in breast cancer by estrogen.
abstract: 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.
authors.affiliation: Sharett Institute of Oncology, Hadassah-Hebrew University Hospital, P.O. Box 12000, Jerusalem 91120, Israel.
authors.forename: Zaidoun
authors.initials: Z
authors.lastname: Salah
authors.forename: Beatrice
authors.initials: B
authors.lastname: Uziely
authors.forename: Mohammad
authors.initials: M
authors.lastname: Jaber
authors.forename: Miriam
authors.initials: M
authors.lastname: Maoz
authors.forename: Irit
authors.initials: I
authors.lastname: Cohen
authors.forename: Tamar
authors.initials: T
authors.lastname: Hamburger
authors.forename: Bella
authors.initials: B
authors.lastname: Maly
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
authors.forename: Rachel
authors.initials: R
authors.lastname: Bar-Shavit
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D004247:DNA; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D004967:Estrogens / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D044463:Receptor, PAR-1 / Q000235:genetics*
chemical_list: D017931:DNA Primers; D004967:Estrogens; D044463:Receptor, PAR-1; D004247:DNA