Regulation of human protease-activated receptor 1 (hPar1) gene expression in breast cancer by estrogen
Date
2012-01-30
Authors
Salah, Zaidoun
Uziely, Beatrice
Jaber, Mohammad
Maoz, Miriam
Cohen, Irit
Hamburger, Tamar
Maly, Bella
Peretz, Tamar
Bar-Shavit, Rachel
Journal Title
Journal ISSN
Volume Title
Publisher
Federation of American Societies for Experimental Biology
Abstract
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.
Description
Keywords
thrombin , tumor , ERE , tissue microarray