uPA is upregulated by high dose celecoxib in women at increased risk of developing breast cancer

NAF and plasma samples were collected in women at increased breast cancer risk before and 2 weeks after taking celecoxib 200 or 400 mg twice daily (bid). uPA, PAI-1 and PGE2 were measured before and after intervention.Celecoxib concentrations trended higher in women taking 400 mg (median 1025.0 ng/mL) compared to 200 mg bid (median 227.3 ng/mL), and in post- (534.6 ng/mL) compared to premenopausal (227.3 ng/mL) women. In postmenopausal women treated with the higher (400 mg bid) celecoxib dose, uPA concentrations increased, while PAI-1 and PGE2 decreased. In women taking the higher dose, both PAI-1 (r = -.97, p = .0048) and PGE2 (r = -.69, p = .019) in NAF and uPA in plasma (r = .45, p = .023) were correlated with celecoxib concentrations.Celecoxib concentrations after treatment correlate inversely with the change in PAI-1 and PGE2 in the breast and directly with the change in uPA in the circulation. uPA upregulation, in concert with PAI-1 and PGE2 downregulation, may have a cancer preventive effect.Cancer cell invasion and metastasis requires the degradation of the extracellular matrix (ECM) and basement membrane. This process is accomplished by several proteins, including those of the plasminogen activator (PA) system. Urokinase-type PA (uPA), which is secreted in inactive form (pro-uPA), plays a key role in ECM degradation. Pro-uPA is converted to its active form after binding to its specific surface receptor, uPAR [1,2]. In women with breast cancer, uPA appears to promote cancer invasion and metastasis [3] through degradation of the ECM, stimulation of angiogenesis, alteration in cell migration and adhesion [4], and inhibition of apoptosis [5].The total involvement of plasminogen activators in cancer, however, is not that clear. In addition to demonstrated negative effects, PAs apparently play a positive role in certain aspects of the cancer process. For example, PAs induce antiangiogenic activity in vitro and in patients with cancer [6]. Several clinical studies