Background:
Stromal fibroblasts contribute to breast cancer (BC) progression. The thrombin (extrinsic) clotting pathway is upregulated in cancer and associated with metastasis.

Material and Methods:
Our aim was to determine if stromal expression of thrombin pathway components thrombin and Tissue Factor (TF) and their receptors PAR1 and PAR2 are upregulated in invasive BC and associated with aggressive subtypes.

Stromal expression was determined by immunohistochemistry in two cohorts and correlated with clinicopathological variables.

PROSPECTIVE STUDY: Early BC (n=182), ductal carcinoma in-situ (DCIS, n=35) and normal breast tissue (n=93).

ARCHIVED TISSUE: BCs (n=84) from 2001/02 study with 69 months median follow up.

Result:
PROSPECTIVE: TF was increased in DCIS vs normal and further increased in BC vs DCIS (p<0.01). Thrombin, PAR1 and PAR2 were increased in cancer and DCIS vs normal (p<0.01). In BC, TF and thrombin were increased in HER2 receptor positive (HER2+ve, p<0.01) and correlated with increasing proliferation (Ki67 expression, p<0.001). TF was increased in oestrogen receptor negative (ER-ve, p=0.02) and high grade BC (p<0.001). PAR1 and PAR2 correlated with KI67 and were increased in high grade BC (p<0.01, all). PAR1 was increased in ER-ve (p<0.01) and PAR2 in HER2+ve (p<0.01).

ARCHIVED: As with prospective study, PAR1 was increased in ER-ve (p<0.01) and PAR2 in HER2+ve (p<0.01). PAR1 expression correlated with reduced overall (p=0.02) and recurrence free (p=0.07) survival.

Conclusion:
Stromal thrombin pathway upregulation is associated with aggressive BC subtypes and reduced survival and provides a novel therapeutic target.