Association of uPA and PAI-1 tumor levels and 4G/5G variants of PAI-1 gene with disease outcome in luminal HER2-negative node-negative breast cancer patients treated with adjuvant endocrine therapy

Abstract

BackgroundThe aim of this study was to evaluate the prognostic potential of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) tumor tissue levels and examine the association between these biomarkers and classical prognostic factors in early node-negative luminal breast cancer patients. The clinical value of 4G/5G variants of PAI-1 gene was evaluated.Patients and methodsThis study involved 81 node-negative, estrogen receptor-positive and/or progesterone receptor-positive and human epidermal growth factor receptor 2-negative operable breast cancer patients who underwent radical surgical resection and received adjuvant endocrine therapy. Determination of uPA and PAI-1 concentrations in the breast cancer tissue extracts was performed using FEMTELLE® uPA/PAI-1 ELISA. An insertion (5G)/deletion (4G) polymorphism at position − 675 of the PAI-1 gene was detected by PCR-RFLP analysis.ResultsOur research showed that patients with uPA tumor tissue levels higher than 3 ng/mg of protein had significantly reduced disease-free survival (DFS) and overall survival (OS) when compared to patients with uPA tumor tissue levels lower or equal to 3 ng/mg of protein. Patients with PAI-1 tumor tissue levels higher than 14 ng/mg of protein had significantly decreased OS in comparison with patients with PAI-1 tumor tissue levels lower or equal to 14 ng/mg of protein. ROC analysis confirmed the uPA and PAI-1 discriminative potential for the presence/absence of relevant events in these patients and resulted in higher cut-off values (5.65 ng/mg of protein for uPA and 27.10 ng/mg of protein for PAI-1) than standard reference cut-off values for both biomarkers. The prognostic importance of uPA and PAI-1 ROC cut-off values was confirmed by the impact of uPA higher than 5.65 ng/mg of protein and PAI-1 higher than 27.10 ng/mg of protein on poorer DFS, OS and event-free survival (EFS).We observed that patients with dominant allele in PAI-1 genotype (heterozygote and dominant homozygote, − 675 4G/5G and − 675 5G/5G) had significantly increased DFS, OS and EFS when compared with patients with recessive homozygote genotype (− 675 4G/4G).ConclusionOur study indicates that uPA and PAI-1 tumor tissue levels and 4G/5G variants of PAI-1 gene might be of prognostic significance in early node-negative luminal HER2-negative breast cancer patients treated with adjuvant endocrine therapy.

A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target?

“…Indeed, uPA and PAI-1 are among the most highly induced proteins in several migratory or invasive tumor cell types. Even though some studies failed to show a correlation between elevated levels of PAI-1 and poor clinical prognosis [ 100 , 101 , 102 ], PAI-1 has been established as one of the most reliable biomarkers and prognostic markers in many cancer types, including breast [ 103 , 104 , 105 , 106 ], ovarian [ 107 ], bladder [ 108 , 109 ], colon [ 110 ], renal [ 111 ] and non-small cell lung cancers [ 112 ].…”

SERPINE1 Overexpression Promotes Malignant Progression and Poor Prognosis of Gastric Cancer

“…Previous literature have indicated that SERPINE1 had pro-angiogenic, growth and migration stimulation and anti-apoptotic activity, all of which were targeted at promoting tumor growth, cancer cell survival and metastasis [ 18 ]. SERPINE1 has been proven to be the most reliable biological and prognostic marker for a variety of cancers, including breast cancer [ 19 – 21 ], ovarian cancer [ 22 ], bladder cancer [ 23 , 24 ], colon cancer [ 25 ], kidney cancer [ 26 ] and non-small cell lung cancer [ 27 ].…”

MiR145-5p inhibits proliferation of PMVECs via PAI-1 in experimental hepatopulmonary syndrome rat pulmonary microvascular hyperplasia

“…Plasminogen activator inhibitor-1 (PAI-1), also known as endothelial plasminogen activator inhibitor or serpin E1, is a protein that in humans is encoded by the SERPINE1 gene (de Faria et al, 2019). PAI-1 is a serine protease inhibitor that functions as the principal inhibitor of urokinase (uPA) and tissue plasminogen activator (tPA), activators of fibrinolysis and plasminogen (Jevric et al, 2019). The other PAI, PAI-2, is secreted by the placenta and only present during pregnancy.…”