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Nipple Aspirate Fluid Expression of Urokinase-Type Plasminogen Activator, Plasminogen Activator Inhibitor-1, and Urokinase-Type Plasminogen Activator Receptor Predicts Breast Cancer Diagnosis and Advanced Disease

From the Department of Surgery (WQ, WZ, CW-M, ERS), University of Missouri, Columbia, Missouri.

Correspondence: Address correspondence and reprint requests to: Edward R. Sauter, MD, PhD, Department of Surgery, University of Missouri-Columbia, M588 Health Sciences Center, One Hospital Drive, Columbia, MO 65212; Fax: 573-884-4585; E-mail: sautere{at}health.missouri.edu

	ABSTRACT

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Background: Tumor expression of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and uPA receptor (uPAR) are breast cancer prognostic factors. Less is known about their usefulness in breast cancer diagnosis. Nipple aspirate fluid (NAF) is secreted into the breast duct and collected noninvasively, making it potentially useful both in breast cancer diagnosis and prognosis. We determined the association of uPA, PAI-1, and uPAR levels in NAF with breast cancer (1) detection and (2) advanced disease.

Methods: A total of 88 NAF specimens were collected from women with or without breast cancer, and uPA, PAI-1, and uPAR expression were measured by enzyme-linked immunosorbent assay.

Results: uPA and uPAR were independent predictors of cancer presence; uPAR was also an independent predictor of advanced disease stage. Higher PAI-1 expression in breast cancer that was found with univariate analysis was not observed after logistic regression was applied.

Conclusions: NAF evaluation of uPA, uPAR, and, perhaps, PAI-1 (significant only in univariate analysis) may provide useful breast cancer diagnostic and prognostic information.

Key Words: Urinary plasminogen activator • Plasminogen activator inhibitor • Nipple aspirate fluid • Breast cancer

	INTRODUCTION

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Breast cancer is the most common malignancy in US women. Cancer cell invasion and metastasis require the degradation of the extracellular matrix and basement membrane. This process is accomplished by several proteins, including those of the plasminogen activator system. High levels of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and uPA receptor (uPAR) in tumor tissue correlate with poor patient prognosis in many different human cancers,¹ including endometrial,² ovarian,³ colon,⁴ lung,⁵ stomach,⁶ and renal.⁷ It was first reported in 1988 that increased uPA levels in primary breast tumor tissue were associated with a poor prognosis.⁸ It later became evident that high tumor levels of PAI-1 and uPAR also predicted an adverse outcome.^9,10 In a more recent study, levels of uPA, PAI-1, and uPAR in 2780 patients with breast cancer directly correlated with relapse-free and overall survival.¹¹ In a pooled analysis of 8377 breast cancer patients, higher uPA and PAI-1 levels in tumor tissue were confirmed to directly relate to a worse prognosis.¹² In addition, patients with high uPA and PAI-1 levels benefit more from adjuvant chemotherapy than those with low levels.¹³ Levels of uPA, PAI-1, and uPAR in breast tumors are now considered by many to be appropriate for the routine assessment of prognosis in patients with newly diagnosed breast cancer.¹⁴

NAF is a physiologic fluid secreted from the breast ductal system, the source of the vast majority of breast cancers. NAF collection is safe and noninvasive. It can be obtained reliably in both pre- and postmenopausal women.¹⁵ We have found that secreted proteins in NAF, such as prostate-specific antigen¹⁶ and basic fibroblast growth factor,¹⁷ are associated with breast cancer. There is compelling evidence that uPA, PAI-1, and uPAR are secreted proteins. The objectives of this study were to determine whether uPA, PAI-1, and uPAR expression in NAF are associated with (1) the presence of breast cancer and (2) advanced breast cancer.

	PATIENTS AND METHODS

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Subjects
Eighty-eight specimens from 80 subjects (NAF was obtained from both breasts in 8 subjects) were collected for the study after institutional review board approval and informed consent were obtained. Women ranged in age from 23 to 83 years (median, 51 years). Premenopausal women ranged in age from 23 to 53 years (median, 43 years); postmenopausal women ranged in age from 36 to 83 years (median, 58.5 years). Exogenous hormones were used in five postmenopausal women, two of whom had cancer, whereas the other three were cancer free. If cancer was present, NAF samples were taken from the breast with cancer. Of the eight patients from whom bilateral NAF samples were taken, five had bilateral breast cancer, one had no cancer, and three had one breast with cancer and the other breast without cancer.

Women were recruited by using local media and flyers in our breast evaluation clinics. For women with breast cancer, all specimens were collected before or in conjunction with definitive treatment. A total of 87.5% of the subjects were white, 10% were black, and 2.5% were other races; 42.5% were premenopausal. We initially evaluated 56 samples—24 from subjects with and 32 from subjects without breast cancer—to determine whether uPA, PAI-1, and/or uPAR were associated with the presence of breast cancer. To determine whether these markers were associated with advanced disease, we next assessed whether one or more of the markers were associated with disease stage, tumor size, nodal status, or distant disease spread. The second analysis included the initial 24 samples with cancer, plus an additional 26 samples from women with pathologically confirmed ductal carcinoma-in-situ (DCIS) or invasive breast cancer. For both analyses, the women were categorized as having breast cancer (DCIS or invasive) or not.

Aspiration Technique
A trained physician or nurse clinician aspirated nipple fluid noninvasively by using a modified breast pump.¹⁵ The nipple was cleansed with alcohol. A warm, moist cloth was placed on the breast after the alcohol evaporated. The cloth was removed after 2 minutes, and the subject massaged her breast with both hands while the plunger of the syringe was withdrawn to the 7-mL level or until she experienced discomfort. Aspiration was repeated on the opposite breast, if present. Fluid in the form of droplets was collected in capillary tubes. Fluid generally was not pooled, unless it welled up from multiple ducts and made separation by duct impossible. The quantity of fluid varied from 1 to 200 µL.

If keratin plugs rather than NAF were obtained after suctioning was completed, the plugs were removed with an alcohol swab, and suctioning was repeated. Occasionally, this procedure was repeated two or three times to remove all of the plugs, and fluid was then routinely obtained.

Enzyme-Linked Immunosorbent Assay
The uPA, PAI-1, and uPAR enzyme-linked immunosorbent assay kits were obtained from American Diagnostica, Inc. (Greenwich, CT). Levels of uPA, uPAI-1, and uPAR were determined according to the kit manufacturer’s instructions. Briefly, 100 µL of standard, sample, and blank were pipetted into the microplate wells that were coated with mouse monoclonal antibodies specific for uPA, PAI-1, and uPAR, respectively, and incubated overnight at 4°C. A washing procedure was performed four times to remove unbound proteins. Enzyme-linked antibodies specific for each factor were added to the wells and incubated for 1 hour at room temperature. The wells were washed again, and 100 µL of diluted enzyme conjugate (streptavidin-conjugated horseradish peroxidase) was pipetted into the wells, incubated for 1 hour at room temperature, and then washed again. Substrate reagent (100 µL) was added to each well, followed by a stop solution (.5 M of sulfuric acid). Absorbance values were measured at 450 nm for uPA, uPAI-1, and uPAR by using a microplate reader. The detection limits were 10 pg/mL for uPA, 50 pg/mL for PAI-1, and .1 ng/mL for uPAR. To standardize uPA, uPAI-1, and uPAR expression, total NAF protein was measured for each sample with a bovine serum albumin protein assay kit (Pierce Chemicals, Rockford, IL).

Statistical Analysis
Statistical analysis was conducted on uPA, uPAI-1, and uPAR after controlling for total protein, because our experience in the past has indicated that this approach provides more comparable results from sample to sample, given the variance in NAF total protein. The Mann-Whitney ranked sum test (underlying assumptions for parametric testing were not met) was applied to determine whether the measured values from the cancer-free group differed significantly from those of the cancer-positive group. Similarly, for the T (tumor size), N (nodal status), M (distant metastases present or absent), and stage categories, uPA, PAI-1, and uPAR were compared by using either the Mann-Whitney ranked sum test (for only two groups) or the Kruskal-Wallis analysis of variance on ranks (for more than two groups). The Spearman rank order correlation was calculated for each measured parameter to determine the strength of association between (1) the parameters and the patient risk scores and (2) pairs of measured parameters. By using the overall medians as the cutoff points, uPA and PAI-1 levels were grouped as high versus low on the basis of whether the value was above or below the overall median. For the initial subset of 56 patients, ² analysis was applied to compare the number of patients with uPA, PAI-1, or both increased versus subjects without these characteristics and stratified by cancer positive versus cancer negative, similar in fashion to analyses previously performed on these markers in breast cancer tissue.¹⁸

For the subset of cancer-positive patients, ² analysis was applied to compare the numbers of patients with increased (above the median) versus not increased uPA, PAI-1, and uPAR, stratified by T, N, M, or stage. Multiple logistic regression analysis was applied to the data to determine which factors (uPA, PAI-1, uPAR, age, race, and menopause status) contributed significantly to the maximum likelihood model of cancer prediction and cancer progression. For tumor size, categories of 0 or 1 were collapsed to 0, whereas categories of 2 or 3 were collapsed to 1, to satisfy the underlying conditions for logistic regression analysis. Similarly, stages 0 and 1 were assigned 0, and stages 2, 3, and 4 were assigned 1. The statistical software SigmaStat for Windows version 2.03S (SPSS, Inc., Chicago, IL) was used for all analyses, and the significance level was set at P < .05.

	RESULTS

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NAF Expression of PAI-1, but Not uPA or uPAR, Is Associated With the Presence of Breast Cancer
NAF was successfully collected in 88 of 90 attempts. Expression of uPA, PAI-1, and uPAR were measured by enzyme-linked immunosorbent assay in 56 NAF samples from subjects with and without breast cancer, and univariate analysis was performed to assess the association of each of the markers with the presence of breast cancer. PAI-1 was expressed at a significantly higher level (P = .009) in the NAF of subjects with than those without breast cancer. No significant differences were noted in uPA or uPAR expression from subjects with versus without breast cancer (Table 1).

NAF Expression of uPAR, but Not uPA or PAI-1, Is Associated With Advanced Breast Cancer
We analyzed NAF samples for uPA, PAI-1, and uPAR expression from 50 women with DCIS or invasive breast cancer. We then compared the expression of these markers with known correlates of advanced breast cancer, including disease stage, tumor size, nodal status, and distant disease spread. Among subjects with invasive breast cancer, uPAR expression increased with larger tumor size and higher disease stage. Expression of uPAR was significantly associated (P = .047; Fig. 1) with advanced breast cancer stage. None of the markers was associated with the other parameters of advanced disease (Table 2).

View larger version (22K): [in this window] [in a new window]   FIG. 1. Nipple aspirate fluid (NAF) urokinase-type plasminogen activator receptor (uPAR) increases with increasing disease stage. A box and whisker plot is shown of uPAR expression in NAF. The uPAR expression increases from small, node-negative (stages 0 and 1) breast cancer to more advanced (stages 2–4) breast cancer. Outlier values of uPAR (not shown) for stages 0 and 1 were 2.45 and 5.14 ng/mg; for stage 2, they were 3.21 and 3.76 ng/mg.

Multiple Logistic Regression
Multiple logistic regression analysis was performed to identify markers that independently predicted the presence of breast cancer or advanced disease. Increasing age (P = .003), uPA (P = .031), and uPAR (P = .044) were identified as significant predictors of cancer presence. T, N, and M data identified no variable that differentiated patients with regard to advanced disease. Expression of uPAR categorized by stage was an independent predictor (P = .026) of advanced disease. None of the other independent variables (age, race, menopause status, uPA, or PAI-1) was significantly associated with stage.

	DISCUSSION

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There is no generally accepted marker to predict who has or will develop breast cancer. uPA, PAI-1, and uPAR have been studied in tissue and blood to determine the usefulness of their expression in both breast cancer diagnosis and prognosis. Whereas studies in breast cancer prognosis have focused on tumor tissue, those in diagnosis have investigated circulating levels of uPA, PAI-1, and uPAR.^20,21 Plasma levels of uPAR²² were found to be significantly higher in women with breast cancer than in controls. Higher levels of uPAR in the blood of women with breast cancer than in healthy women suggest that soluble uPAR is released from the tumor into the bloodstream. The uPA/PAI-1 complex was detectable in the plasma of 95% of women with breast cancer but in only 20% of normal women.²³ Unfortunately, blood levels of uPA, PAI-1, and uPAR have not been consistently associated with the detection of breast cancer²¹ or with advanced disease.²⁴

We found that NAF, a breast specific fluid which unlike blood is not diluted by contributions from other organs in the body, expressed uPA, PAI-1, and uPAR. We also found that PAI-1 (in univariate analysis) and uPA and uPAR (in multivariate analysis) were associated with the presence of breast cancer. We attribute the fact that PAI-1 expression was not associated with breast cancer in multivariate analysis to the influence of confounders, which limited its independent predictive ability.

There is overwhelming evidence that tissue levels of uPA, PAI-1, and uPAR provide prognostic information for women with breast cancer. Breast cancer patients with a high level of uPA in their primary tumors have a shorter disease-free interval than patients with low uPA.⁸ The prognostic information provided by uPA is independent of tumor size, grade, axillary node status, and steroid receptor status.²⁵ High tumor cytosol levels of uPAR are associated with poor prognosis.²⁶ Women with DCIS whose tumors had high expression of uPAR had a 40% recurrence rate, whereas those with normal expression of uPAR had a 0% recurrence rate.²⁷ Despite high uPAR levels being associated with poor prognosis, uPAR levels are higher in smaller, earlier-stage tumors versus larger and later-stage tumors.²⁸

Unlike the findings in tumors, we found that uPAR expression in NAF was associated with increasing disease stage for women with invasive breast cancer, stages 1 to 4. It is interesting to note that uPAR expression decreased between DCIS, stage 0, and early invasive breast cancer, stage 1. Thus, the lowest uPAR levels in NAF are in T1, stage 1 tumors, whereas in tumor tissue, uPAR levels are highest in these tumors.²⁸ We also observed this with tumor size, which decreased between DCIS and T1 (<2 cm) invasive breast cancers. The uPAR expression was similar between DCIS and stage 2 tumors and was higher in stage 3 and 4 tumors than in DCIS. The reasons for this are unclear, although it is possible that the secretion of uPAR from tumor cells into NAF increases with tumor progression. Another way to look at uPAR expression and advanced disease is illustrated in Fig. 1, in which small node-negative (stage 0–1) breast cancers have the lowest uPAR expression, which increases with larger, more advanced-stage tumors.

Because subjects who enrolled could not be receiving adjuvant therapy for their disease, most subjects in our study had smaller tumors without distant disease spread. Thus, there were no T4 lesions in our data set. In addition, there were only three subjects with T3 tumors and two subjects with distant metastases. The limited number of subjects with T3/4 or M1 tumors may have limited the power of our analyses to detect differences based on tumor size or distant disease spread.

Multiple prospective studies document that knowing the tumor levels of both uPA and PAI-1 provides more prognostic information than either marker alone, including information on the risk of disease recurrence^18a,19 and response to chemotherapy.¹³ In these studies, subjects were categorized as low risk when both uPA and PAI-1 were below a cut point versus high risk if either or both markers were above the designated cut point. In our studies, we evaluated the data on uPA and PAI-1, considering the association with cancer when both factors were high versus when either or both were low. We determined that there was no significant relationship between increases in both uPA and PAI-1 expression and the incidence of cancer in these patients. Similarly, when categorizing subjects as high risk if uPA, PAI-1, or both were increased versus low risk when both were low, we did not identify a significant relationship with the incidence of cancer.

Our logistic regression studies confirm and expand the findings in our univariate analyses. Age, NAF uPA, and NAF uPAR expression were independent predictors that a woman had breast cancer. NAF uPAR expression categorized by disease stage was an independent predictor of breast cancer progression. These preliminary observations with univariate and multivariate analyses suggest that NAF evaluation of uPA, uPAR, and, perhaps, PAI-1 (significant only in univariate analysis) may provide useful breast cancer diagnostic and prognostic information, but this will need confirmation in a larger patient population.

	ACKNOWLEDGMENTS

 
The acknowledgments are available online at www.annalssurgicaloncology.org.

Supported by National Institutes of Health grant CA-87391.

	FOOTNOTES

 
Nipple aspirate fluid urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor are associated with cancer detection, and urokinase-type plasminogen activator receptor is associated with advanced disease in the breast.

Received for publication March 6, 2003. Accepted for publication June 23, 2003.

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