PAR1 Action in Tumor Development and Metastasis.
Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor that is not
expressed in normal breast epithelia, but is up-regulated in invasive breast carcinomas.
In the present study, we found that matrix metalloprotease-1 (MMP-1) activates the
PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a
cell-penetrating lipopeptide `pepducin', P1pal-7, ... read morea potent inhibitor of cell viability
in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7
significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the
lungs by up to 88%. Consistently, biochemical analysis of xenograft tumors treated with
P1pal-7 or MMP-1 inhibitor demonstrated attenuated Akt activity. Dual therapy with
P1pal-7 and taxotere inhibited the growth of MDA-MB-231 xenografts by 95%. The
correlation of PAR1 with invasive breast carcinoma and its ability to promote migration
and invasion has been well documented. We have observed that ectopic expression of PAR1
in MCF-7 breast carcinoma cells induces a fibroblast-like morphological change and a
corresponding enhancement of migration and invasion. Transcriptional profiling by
genechip analysis revealed that PAR1 expression promotes the expression of mesenchymal
proteins such as vimentin, laminin, and integrin, and down-regulates epithelial proteins
such as E-cadherin, claudin, zona occludens and cytokeratin. PAR1 expression also
induced a concerted shift in the expression of ErbB family of receptors and ligands,
promoting the constitutive activity of EGFR/HER2 signaling. Together, these observations
suggest that PAR1 and EGFR cooperatively induce Epithelial-to-Mesenchymal Transition
(EMT) in breast carcinoma cells. This proposed mechanism is supported by empirical
evidence from the NCI-60 panel of breast carcinoma cells, which demonstrate 100%
correlation of PAR1 expression with EGFR expression and EMT status. We have demonstrated
that PAR1 blockade induces apoptosis and chemosensization in the primary tumor, and
inhibits metastasis to the lungs. Furthermore, we found that PAR1 induces EMT to promote
breast cancer invasion and metastasis. Together, our results suggest that PAR1 is a
critical target of breast cancer pathogenesis that can be exploited by novel inhibitors
as exemplified by the pepducin technology.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Biochemistry.
Advisors: Lidija Covic, and Akiko Hata.
Committee: Athan Kuliopulos, and Larry Feig.
Keyword: Biochemistry.read less
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