The role of thrombin and its receptors in epithelial malignancies: Lessons from a transgenic mouse model and transcriptional regulation

Abstract

The otherwise well-orchestrated epithelial sheets are disrupted when they acquire the ability to overexpress the prototype mammalian thrombin receptor, human protease-activated receptor-1 (hPar1). This is exhibited by down-regulation of cell-cell contacts and alterations in cell-matrix interactions. The notion that hPar1 is one of a series of genes that is part of a malignant program stems from studies indicating that hPar1 expression directly correlates with tumor metastasis and the time-limited physiological invasion of the placenta to the uterus decidua. Our transgenic mouse model of tissue-targeted hPar1 overexpression in the mammary glands exhibits a phenotype of hyperplasia, characterized by a dense network of ductal side branching and accelerated proliferation. The transgenic mammary glands exhibit increased levels of wnt-4 and -7b, and the striking stabilization of β-catenin. This novel association between hPar1 and nuclear β-catenin may provide a key determinant in the molecular pathway of hPar1 oncogenicity. While studying the properties of hPar1 in tumor biology we demonstrated its role as a survival factor that protects cells from undergoing apoptosis. Withdrawal of the hPar1 gene leads to selective apoptosis especially in young sprouting blood vessels, whereas mature vessels remain unaffected. We also provide evidence showing that hPar1 gene overexpression in tumors stems from enhanced transcriptional activity. This is evaluated on the basis of elicited run-on transcription rate in highly metastatic vs. low metastatic cells (on a background of equal stability rates). Indeed, we have shown that the transcription factor Egr-1 induced hPar1 gene overexpression in prostate cancer. In addition, the tumor suppressor gene p53 also acts on hPar1 as one of its target genes, regulating its level of expression in the context of a given tumor. It still remains to determine the profile of individual fingerprints and specific motifs that bind to a panel of transcription factors, as well as tumor suppressor genes which are critically involved in altering hPar1 transcription levels according to the type of tumor.