Abstract
Abstract Deregulated protease activity promotes diverse aspects of tumorigenesis, including tumor growth, invasion, inflammation, and angiogenesis. Elafin is an endogenous inhibitor of the serine protease, Neutrophil Elastase (NE). Imbalance between NE and its inhibitors is implicated in the pathogenesis of many chronic inflammatory diseases. We hypothesize that elafin is deregulated during breast cancer progression, resulting in increased NE activity, accelerated tumor progression, and overall poor patient outcome. To test this hypothesis, we examined elafin expression by immunohistochemistry (IHC) in normal breast tissue from reduction mammoplasty, pre-malignant Ductal Carcinoma In Situ (DCIS), and invasive breast carcinoma (n>1000, using Tissue Microarray [TMA]). We observed that elafin is intracellularly (predominate nuclear localization) expressed in normal breast tissue. In the majority (>80%) of DCIS cases, intracellular elafin is expressed in a manner consistent with normal breast tissue. However, in cases of invasive breast cancer, intracellular elafin is largely downregulated (>80% of cases) suggesting elafin loss may have a role in progression to invasive carcinoma. Interestingly, examination of elafin expression in invasive breast cancer also revealed a subset (10-20%) of tumors with robust cytoplasmic overexpression of elafin, correlating with poor outcome. Similar results were seen in TMAs of high-grade ovarian carcinoma (n>200). Examination of publically available microarray data (TCGA) demonstrates that elafin measured at the mRNA level is correlates with poor outcome in ovarian cancer, consistent with our IHC results, and good outcome in breast cancer, incompatible with our IHC results. To further investigate the expression of elafin in breast cancer we examined by IHC a patient cohort (>200 patients) for whom full sections (not TMA) were available. Using these patient samples we found a unique subset of breast cancer patients that demonstrate high-level secretion of elafin into the tumor stroma, significantly correlating with increased survival especially in ER negative patients. Collectively, these data suggest that the prognostic role of extracellular elafin is related to the well-characterized ability of elafin to modulate inflammation and immunity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2466. doi:1538-7445.AM2012-2466
Published Version
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