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

Wenyi Qin,Ferdinando Mannello,George Rottinghaus,John E Hewett,Yin-Chieh Chen,Edward R Sauter,John T Flynn,Beth Kliethermes,Weizhu Zhu

doi:10.1186/1471-2407-8-298

Abstract

BackgroundWhile increased urokinase-type plasminogen activator (uPA) expression in breast cancer tissue is directly associated with poor prognosis, recent evidence suggests that uPA overexpression may suppress tumor growth and prolong survival. Celecoxib has been shown to have antiangiogenic and antiproliferative properties. We sought to determine if uPA, PA inhibitor (PAI)-1 and prostaglandin (PG)E2 expression in nipple aspirate fluid (NAF) and uPA and PGE2 expression in plasma were altered by celecoxib dose and concentration in women at increased breast cancer risk.MethodsNAF 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.ResultsCelecoxib 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.ConclusionCelecoxib 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.

Highlights

While increased urokinase-type plasminogen activator expression in breast cancer tissue is directly associated with poor prognosis, recent evidence suggests that uPA overexpression may suppress tumor growth and prolong survival
We previously reported that PGE2, a small lipid associated with breast tumor development, decreased in proportion to circulating celecoxib concentration in postmenpausal women taking the 400 mg twice daily dose [18]
We previously observed that uPA and PA inhibitor (PAI)-1 are concentrated in nipple aspirate fluid (NAF) compared to plasma [22]

Summary

Introduction

While increased urokinase-type plasminogen activator (uPA) expression in breast cancer tissue is directly associated with poor prognosis, recent evidence suggests that uPA overexpression may suppress tumor growth and prolong survival. 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. Several clinical studies have shown associations between high tissue-type PA expression and activity and a favorable prognosis in breast cancer [7]. In a mouse mammary cancer model, induced uPA expression delayed tumor progression and had antiangiogenic and antiproliferative effects. Tumors expressing proteolytically inactive uPA mutants grew faster than tumors overexpressing proteolytically active uPA, suggesting that the inhibitory actions were mediated by uPA's protease activity [8]

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