PAR Genes: Molecular Probes to Pathological Assessment in Breast Cancer Progression

Departments of Oncology, Hadassah-University Hospital P.O. Box 12000, Jerusalem 91120, Israel.
Pathology Research International 01/2011; 2011(8):178265. DOI: 10.4061/2011/178265
Source: PubMed


Taking the issue of tumor categorization a step forward and establish molecular imprints to accompany histopathological assessment is a challenging task. This is important since often patients with similar clinical and pathological tumors may respond differently to a given treatment. Protease-activated receptor-(1) (PAR(1)), a G protein-coupled receptor (GPCR), is the first member of the mammalian PAR family consisting of four genes. PAR(1) and PAR(2) play a central role in breast cancer. The release of N-terminal peptides during activation and the exposure of a cryptic internal ligand in PARs, endow these receptors with the opportunity to serve as a "mirror-image" index reflecting the level of cell surface PAR(1&2)-in body fluids. It is possible to use the levels of PAR-released peptide in patients and accordingly determine the choice of treatment. We have both identified PAR(1) C-tail as a scaffold site for the immobilization of signaling partners, and the critical minimal binding site. This binding region may be used for future therapeutic modalities in breast cancer, since abrogation of the binding inhibits PAR(1) induced breast cancer. Altogether, both PAR(1) and PAR(2) may serve as molecular probes for breast cancer diagnosis and valuable targets for therapy.

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Available from: Hagit Turm, Apr 09, 2014
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    ABSTRACT: The aim of this study was to investigate the associations of matrix metalloprotease-1 (MMP-1) and its receptor protease-activated receptor-1 (PAR-1) coexpression with the clinicopathological characteristics and prognosis of patients with prostate cancer (PCa). Immunohistochemistry was performed to detect the expression changes of MMP-1 and PAR-1 proteins in 180 pairs of human PCa tissues and matched non-cancerous prostate tissues. Then, the associations of combined MMP-1 and PAR-1 expression with selected clinicopathological characteristics and patient prognosis were evaluated. Both MMP-1 and PAR-1 proteins were positively localized in cytoplasm of tumor cells in PCa tissues. Compared with non-cancerous prostate tissues, MMP-1 (PCa vs. Normal: 4.15 ± 1.28 vs. 2.37 ± 1.16, P < 0.001) and PAR-1 (PCa vs. Normal: 3.71 ± 1.21 vs. 1.55 ± 1.12, P < 0.001) protein expression were both significantly upregulated. More interestingly, the expression levels of MMP-1 in PCa tissues were positively correlated with those of PAR-1 significantly (Spearman correlation coefficient r = 0.88, P < 0.001). In addition, the coexpression of MMP-1 and PAR-1 (MMP-1-high/PAR-1-high) in PCa tissues was significantly associated with the higher Gleason score (P < 0.001), the presence of metastasis (P < 0.001) and the advanced pathological stage (P = 0.009). Furthermore, both univariate and multivariate analyses showed that MMP-1-high/PAR-1-high expression was an independent predictor for both unfavorable overall survival and biochemical recurrence-free survival. These findings confirmed for the first time that the upregulation of MMP-1 protein combined with the overexpression of PAR-1 protein may contribute to the malignant progression of PCa. More importantly, MMP-1/PAR-1 axis may be a negative prognostic factor for patients with PCa.
    No preview · Article · Jun 2014 · Medical Oncology