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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

VEGF-A

tissue factor

breast cancer

protease-activated receptors

Publikations- och innehållstyp

art (ämneskategori)

ref (ämneskategori)