Elevated expression of polymorphonuclear leukocyte elastase in breast cancer tissue is associated with tamoxifen failure in patients with advanced disease

Abstract

Besides a variety of other proteases, polymorphonuclear leukocyte elastase (PMN-E) is also suggested to play a role in the processes of tumour cell invasion and metastasis. Yet, there is only limited data available on the relation between the tumour level of PMN-E and prognosis in patients with primary breast cancer, and no published information exists on its relation with the efficacy of response to systemic therapy in patients with advanced breast cancer. In the present study, we have measured with enzyme-linked immunosorbent assay the levels of total PMN-E in cytosolic extracts of 463 primary breast tumours, and have correlated their levels with the rate and duration of response on first-line tamoxifen therapy (387 patients) or chemotherapy (76 patients) in patients with locally advanced and/or distant metastatic breast cancer. Furthermore, the probabilities of progression-free survival and postrelapse survival were studied in relation to the tumour levels of PMN-E. Our results show that in logistic regression analysis for response to tamoxifen treatment in patients with advanced disease, high PMN-E tumour levels were associated with a poor rate of response compared with those with low PMN-E levels (odds ratio: OR, 0.40; 95% CI, 0.22 -0.73; P ¼ 0.003). After correction for the contribution of the traditional predictive factors in multivariate analysis, the tumour PMN-E status was an independent predictor of response (P ¼ 0.01). Furthermore, a high tumour PMN-E level was related with a poor progression-free survival (Po0.001) and postrelapse survival (P ¼ 0.002) in a time-dependent analysis. In contrast, the tumour level of PMN-E was not significantly related with the efficacy of response to first-line chemotherapy in patients with advanced breast cancer. Our present results suggest that PMN-E is an independent predictive marker for the efficacy of tamoxifen treatment in patients with advanced breast cancer.

Impact of cyclins E, neutrophil elastase and proteinase 3 expression levels on clinical outcome in primary breast cancer patients

“…No association with outcome was found for PR3 neither, which might be partially explained by its very low production by tumor cells. As another study by Foekens et al 9 reported the association between high NE levels and tamoxifen failure in advanced breast cancer patients, we investigated the predictive value of NE in our subgroup of ER-positive tamoxifen-only treated patients, but did not find any association with clinical outcome. However, direct comparisons could not be made due to differences in assays and patient cohorts.…”

“…The histological grade, as well as the ER status was significantly associated with clinical outcome in univariate analysis. All these variables were further compared in a multivariate model with backward stepwise selection based on hypotheses tests using likelihood ratios, starting only with the variables that had a As several studies reported CCNE and NE as markers predicting endocrine therapy failure, 5,9 we conducted a subgroup analysis in the 110 ER-positive tumors from patients treated with adjuvant tamoxifen only. The results regarding NE, PR3, CCNE1 and CCNE2 were visualized as Kaplan-Meier curves in Figure 2.…”

“…7 Recently, it has been shown that high levels of neutrophil elastase (NE) protein in breast cancer tissue extracts were associated with poor clinical outcome and with endocrine treatment failure in patients with advanced breast cancer disease. 8,9 This prognostic value was supposedly linked with the essential role of NE in the degradation of the extracellular matrix and the metastasis process. 10,11 But since NE may be aberrantly produced by breast cancer cells themselves and because NE has been implicated in the intracellular cleavage of CCNE in its LMW forms, its prognostic value may be linked to its property to cleave CCNE.…”

Cyclin-E is a strong predictor of endocrine therapy failure in human breast cancer

“…Firstly, a model including all established clinicopathological factors, irrespective of statistical significance in univariate analysis as has been recommended by Altman and Lyman (1998) for exploratory studies into new prognostic factors, was fitted with backward stepwise selection of significant factors based on their likelihood ratio. In a second block, the contributions of cyclin-E (as a continuous, log-transformed variable), treatment (radiotherapy, endocrine therapy or chemotherapy) and their interactions (by inclusion of product variables as described (Altman and Lyman, 1998;Harbeck et al, 2002;Foekens et al, 2003)) were investigated with the same selection procedure. Survival curves were generated using the method of Kaplan and Meier (1958).…”

The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing

“…Of the 3 general classes of human elastase that have been characterized [polymorphonuclear neutrophil elastase or leukocyte elastase, metalloelastase (or MMP12), and pancreatic elastase], the neutrophil elastase is highly expressed in human breast cancers and has been implicated in the processes of tumorigenesis (32). Importantly, the level and enzymatic activity of neutrophil elastase are an independent prognostic marker for breast cancer survival and clinical outcome as well as for metastasis progression of various cancers (33)(34)(35)(36). In this report, we demonstrate that the dietary phytochemical I3C is a noncompetitive inhibitor of human elastase enzymatic activity that directly accounts for the disrupted cyclin E processing in human breast cancer cells, and therefore we have identified the first functional cellular target protein for I3C that mediates the indole-induced G 1 cell-cycle arrest of human cancer cells.…”