الفهرس 
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Abstract
Prognostic significance of urokinase plasminogen activator inhibitor-1 in breast cancer and its correlation with different prognostic factors
Breast cancer is the most frequently diagnosed cancer in women, and the second most frequent cause of cancer death. Multiple factors that are associated with an increase in breast cancer risk have been identified.
Malignant progression of breast cancer involves aberrations in proliferation The next steps in tumorigenesis involve spontaneous mutations The tumor expansion and dissemination are an unregulated tissue remodeling processes that require the coordinated and temporal regulation of a series of adhesive, proteolytic and migratory events.
The plasminogen system is composed of an inactive proenzyme plasminogen (plg) that can be converted to plasmin by either of two plasminogen activators (PA): urokinase-type (uPA) and tissue-type (tpA) Plasminogen activators which are serine proteinases, their activity is controlled by plasminogen activator inhibitors, PAI-1 and PAI-2. Plasmin displays a broad spectrum activity, and is able to degrade many glycoproteins and proteoglycans of the extracellular matrix, as well as fibrin, and to activate other proteases such as pro-metalloproteinases. Plasmin can also activate or release growth factors from the extracellular matrix including latent transforming growth factor (TGF), basic fibroblast growth factor (BFGF) and vascular endothelial growth factor (VEGF).
Urokinase plasminogen activator (uPA) system plays a key role in cancer invasion and metastasis. PAI-1 is the most efficient inhibitor known of both tPA and uPA, and is present in plasma at nM concentration.
Plasminogen activator inhibitor (PAI-1) plays a crucial role in tumor cell adhesion, cell migration, and angiogenesis.
Because PAI-1 is an inhibitor of uPA, it might be expected to prevent invasion and metastasis. Indeed, in some model systems, overexpression of PAI-1 reduced the formation of metastases. Other studies, however, have shown that PAI-1 promotes, rather than inhibits, invasion and metastasis.
The present study aimed to determine urokinase plasminogen activator inhibitor type-1 as a prognostic marker in different subgroups of patients with different stages from I to III with breast cancer using Imubind uPA ELISA for measuring PAI-1 antigen in human plasma and correlating the level of PAI-1 with different prognostic parameters.
Moreover, the relationship between PA-1 level and the incidence of metastasis, was studied.
The study was conducted on 37 female patients with histologically proved breast carcinoma stage I, II and III with age range from 25-75 years (group I) and 10 healthy females with matched age, representing a control group (group II).
All patients were subjected to thorough clinical examination, laboratory investigations including: complete blood count (CBC), kidney function tests as, blood urea and serum creatinine, liver function tests as, SGPT and SGOT, radiological examination including: chest X-ray, abdomen pelvic ultrasound and isotopic bone scan, hormone receptor assay for estrogen and progesterone and biochemical assay of PAI-1 in plasma.
Currently, uPA and PAI-1 are the most extensively validated biological prognostic factors in breast cancer. For predicting outcome in these patients, both uPA and PAI-1 provide data that is independent of the classical prognostic factors such as nodal status, tumor size and tumor grade.
In the present study we found that the level of plasma (PAI-1) was increased in all patients with breast cancer with different stages and grades than in the control subject. The mean of PAI-1 ng/mg protein in patients with breast cancer was equal to 153.2 ng/mg protein while the mean of PAI-1 in control subjects was equal to 86.4 ng/mg protein. As a consequence studies have now been extended to the determination of PAI-1 in blood because assay of soluble components in blood rather than in tissue extracts may offer wider applications.
In our study no significant difference was found between pre and post menopausal patients reading plasma PAI-1 concentration (p > 0.05). Our finding are in accordance with Hansen et al. (1993) who showed that there was no significant difference between pre and post menopausal patients in the median value of uPA (p > 0.27) and PAI-1 (p > 0.24) and also found a highly significant correlation between low levels and long overall survival in both premenopausal (p < 0.005) and postmenopausal (p < 0.001) patients.
In our study we divided the patients into subgroups according to age, tumor size, number of lymph nodes, histological type (Grade), Hormone receptor (ER, PR), stage of tumor and menstruation status.
We found that, the level of PAI-1 is increased in all breast cancer patients by 77%. The postmenopausal patients showed higher level of PAI-1 (by 83%) compared to control.
The presence or absence of lymph node involvement also affect the plasma level of PAI-1. In lymph node positive subgroup, the increase in PAI-1 was about 69% while in lymph node negative subgroup the increase was higher 92%.
The tumor size showed no effect on the PAI-1 level in the plasma. There was no significant change in the level of PAI-1 in subgroup of patients which divided according to ER and PR. Our correlation studies indicated that, the level of PAI-1 and the stage of tumor in premenopausal subgroups was in a negative correlation. (r = - 0.545, p = 0.024)
Also we found the following correlations:
- ER was positively correlated with PR in lymph node positive (r = 0.838, p = 0.027) and negative subgroups (r = 0.588, p = 0.027) and also in premenopausal (r = 0.882, p = 0.000) and postmenopausal subgroups (r = 0.608, p = 0.004).
- Positive correlations between size of tumor and the number of lymph nodes in lymph node (positive) (r = 0.571, p = 0.004) and premenopasual subgroups (r = 0.583, p = 0.014).
- Negative correlation between the size of tumor and ER in lymph node negative (r = - 0.547, p = 0.043) and postmenopausal subgroups (r = - 0.611, p = 0.004).
- The age is positively correlated with tumor grade (r = 0.605, p = 0.022) and ER (r = 0.562, p = 0.036) in lymph node negative and negatively correlated with tumor stage in lymph node positive (r= - 0.443, p = 0.034) and ER (r = - 0.548, p = 0.023) in premenopausal subgroups.
- The stage of tumor was positively correlated with the ER (r = 0.582, p = 0.029) and PR (r = 0.568, p = 0.034) in lymph node negative subgroups.
uPA and PAI-1 are among the first tumor markers to have their clinical value confirmed. These markers can therefore be now considered for the routine assessment of prognosis in patients with nearly diagnosed breast cancer. For determining prognosis, uPA and PAI-1 are likely to be the most useful in the axillary node-negative subgroup. Approximately 70% of node-negative women are cured of their disease by surgery and radiotherapy, whereas ~30% relapse within 10 years. Current prognostic factors are not sufficiently sensitive to identify the subgroup of patients who are likely to develop recurrent disease. uPA and PAI-1 may therefore be the first biological markers to assist in the differentiation of aggressive and indolent node-negative breast cancer. In this scenario, women with node-negative disease and high concentration of uPA and PAI-1 could given adjuvant chemotherapy,