Abstract
IntroductionElafin is an elastase-specific inhibitor with increased transcription in normal mammary epithelial cells compared to mammary carcinoma cells. In this report, we test the hypothesis that inhibition of elastase, through induction of elafin, leads to inhibition of human breast cancer cell viability and, therefore, predicts survival in breast cancer patients.MethodsPanels of normal and immortalized breast epithelial cells, along with breast carcinoma cells, were used to examine the impact of adenoviral-mediated elafin expression or shRNA-mediated inhibition of elastase on the growth of cells and xenografts in nude mice. To determine the prognostic significance of decreased elafin in patients with invasive breast cancer, previously published gene array datasets were interrogated.ResultsElafin expression had no effect on non-tumorigenic cells but resulted in marked inhibition of cell growth in breast cancer cell lines. Control-treated xenografts generated a tumor burden that necessitated sacrifice within one month of initial treatment, whereas xenograft-bearing mice treated with Ad-Elafin were alive at eight months with marked reduction in tumor growth. Elastase inhibition mimicked these results, showing decreased tumor cell growth in vitro and in vivo. Low expression of elafin gene correlated with significantly reduced time to relapse, and when combined with high expression of elastase gene was associated with decreased survival in breast cancer patients.ConclusionOur data suggest that elafin plays a direct role in the suppression of tumors through inhibition of elastase and thus serves as a prognostic indicator for breast cancer patients.
Highlights
Elafin is an elastase-specific inhibitor with increased transcription in normal mammary epithelial cells compared to mammary carcinoma cells
Elafin was found in tumor cell nests, and DNA fragmentation was noted in these cell layers, suggesting that elafin was involved in induction of apoptosis [13]
Two cell clones were selected that had been treated with Short hairpin RNA (shRNA) specific to elastase (231-Elastase1 and 231-Elastase2), or with nonspecific shRNA constructs as controls (231-Control1 and 231-Control2)
Summary
Elafin is an elastase-specific inhibitor with increased transcription in normal mammary epithelial cells compared to mammary carcinoma cells. Increased levels of elastase have been shown to be strongly associated with recurrence and death in breast cancer patients [3]. A study of 313 breast cancer patients with a median of 18.5 years of follow-up showed that elastase in tumor extracts was an independent prognostic factor associated with increased risk of recurrence [4]. These studies suggest that elastase could have a role in tumor progression. Elafin was found in the cytoplasm just beneath the cell membrane, and elastase was present adjacent to these elafin-positive cells [11,12], suggesting that elafin is involved in suppressing the progression of tumors, possibly through inhibition of elastase
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