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Evidence for tissue factor phosphorylation and its correlation with protease activated receptor expression and the prognosis of primary breast cancer.

Rydén, Lisa LU ; Grabau, Dorthe LU ; Schaffner, Florence; Jönsson, Per-Ebbe LU ; Ruf, Wolfram and Belting, Mattias LU (2010) In International Journal of Cancer 126(10). p.2330-2340
Abstract
Tissue factor (TF)-mediated protease activated receptor (PAR)-2 signaling is associated with a pro-migratory, invasive and pro-angiogenic phenotype in experimental models of breast cancer, and has been mechanistically coupled to phosphorylation of the TF cytoplasmic domain (pTF). However, the clinical relevance of these findings are unknown. Here, we provide first in vivo evidence of TF phosphorylation in experimental as well as clinical breast cancer tumors. pTF was demonstrated in MDA-MB-231 xenografts and in tumors from the MMTV-PyMT transgene model of spontaneous murine breast adenocarcinoma. Tumors from PAR-2-deficient transgenic mice were negative for pTF, thus linking pTF to PAR-2 signaling. The clinical correlation between TF, pTF,... (More)
Tissue factor (TF)-mediated protease activated receptor (PAR)-2 signaling is associated with a pro-migratory, invasive and pro-angiogenic phenotype in experimental models of breast cancer, and has been mechanistically coupled to phosphorylation of the TF cytoplasmic domain (pTF). However, the clinical relevance of these findings are unknown. Here, we provide first in vivo evidence of TF phosphorylation in experimental as well as clinical breast cancer tumors. pTF was demonstrated in MDA-MB-231 xenografts and in tumors from the MMTV-PyMT transgene model of spontaneous murine breast adenocarcinoma. Tumors from PAR-2-deficient transgenic mice were negative for pTF, thus linking pTF to PAR-2 signaling. The clinical correlation between TF, pTF, PAR-1, PAR-2, and VEGF-A was determined by IHC on tumors from a cohort of 172 consecutive primary breast cancer patients with a median follow-up time of 50 months. In 160 evaluable patient tumors, pTF was associated with TF (p=0.01) and cancer cell expression of PAR-1 (p=0.001), PAR-2 (p=0.014) and VEGF-A (p=0.003) using chi(2) test. PAR-2 and VEGF-A were co-expressed (p=0.013) and associated with a more aggressive phenotype. Interestingly, all patients experiencing recurrences had tumors expressing pTF and PAR-2, and pTF alone as well as co-expression of pTF and PAR-2 were significantly correlated with shorter recurrence-free survival (log rank test, p=0.04 and p=0.02, respectively). This study provides first evidence to link PAR-2 expression and TF phosphorylation to clinical data in human breast cancer. In conjunction with experimental tumor models, these data support an important role of TF-PAR-2 signaling in breast cancer recurrence. (c) 2009 UICC. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
VEGF-A, tissue factor, breast cancer, protease-activated receptors
in
International Journal of Cancer
volume
126
issue
10
pages
2330 - 2340
publisher
John Wiley & Sons
external identifiers
  • wos:000276928700007
  • pmid:19795460
  • scopus:77951209407
ISSN
0020-7136
DOI
10.1002/ijc.24921
language
English
LU publication?
yes
id
c60d899b-c9c0-4897-87f8-6f1400a20b44 (old id 1500813)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19795460?dopt=Abstract
date added to LUP
2009-11-04 11:11:05
date last changed
2018-07-15 03:22:19
@article{c60d899b-c9c0-4897-87f8-6f1400a20b44,
  abstract     = {Tissue factor (TF)-mediated protease activated receptor (PAR)-2 signaling is associated with a pro-migratory, invasive and pro-angiogenic phenotype in experimental models of breast cancer, and has been mechanistically coupled to phosphorylation of the TF cytoplasmic domain (pTF). However, the clinical relevance of these findings are unknown. Here, we provide first in vivo evidence of TF phosphorylation in experimental as well as clinical breast cancer tumors. pTF was demonstrated in MDA-MB-231 xenografts and in tumors from the MMTV-PyMT transgene model of spontaneous murine breast adenocarcinoma. Tumors from PAR-2-deficient transgenic mice were negative for pTF, thus linking pTF to PAR-2 signaling. The clinical correlation between TF, pTF, PAR-1, PAR-2, and VEGF-A was determined by IHC on tumors from a cohort of 172 consecutive primary breast cancer patients with a median follow-up time of 50 months. In 160 evaluable patient tumors, pTF was associated with TF (p=0.01) and cancer cell expression of PAR-1 (p=0.001), PAR-2 (p=0.014) and VEGF-A (p=0.003) using chi(2) test. PAR-2 and VEGF-A were co-expressed (p=0.013) and associated with a more aggressive phenotype. Interestingly, all patients experiencing recurrences had tumors expressing pTF and PAR-2, and pTF alone as well as co-expression of pTF and PAR-2 were significantly correlated with shorter recurrence-free survival (log rank test, p=0.04 and p=0.02, respectively). This study provides first evidence to link PAR-2 expression and TF phosphorylation to clinical data in human breast cancer. In conjunction with experimental tumor models, these data support an important role of TF-PAR-2 signaling in breast cancer recurrence. (c) 2009 UICC.},
  author       = {Rydén, Lisa and Grabau, Dorthe and Schaffner, Florence and Jönsson, Per-Ebbe and Ruf, Wolfram and Belting, Mattias},
  issn         = {0020-7136},
  keyword      = {VEGF-A,tissue factor,breast cancer,protease-activated receptors},
  language     = {eng},
  number       = {10},
  pages        = {2330--2340},
  publisher    = {John Wiley & Sons},
  series       = {International Journal of Cancer},
  title        = {Evidence for tissue factor phosphorylation and its correlation with protease activated receptor expression and the prognosis of primary breast cancer.},
  url          = {http://dx.doi.org/10.1002/ijc.24921},
  volume       = {126},
  year         = {2010},
}