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 promigratory, invasive and proangiogenic 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 is unknown. Here, we provide the 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 vascular endothelial growth factor (VEGF)-A was determined by immunohistochemistry 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 coexpressed (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 coexpression 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 the 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.
Section of Surgery, Department of Clinical Sciences, Lund University, Lund, Sweden.
Lisa
L
Rydén
Dorthe
D
Grabau
Florence
F
Schaffner
Per-Ebbe
PE
Jönsson
Wolfram
W
Ruf
Mattias
M
Belting
D000230:Adenocarcinoma / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D044464:Receptor, PAR-2 / Q000378:metabolism*; D015398:Signal Transduction; D013548:Sweden; D013925:Thromboplastin / Q000378:metabolism*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D044464:Receptor, PAR-2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D013925:Thromboplastin