Abstract 3057: The serine protease inhibitor, elafin, exhibits novel tumor suppressor functions in the context of breast cancer

Abstract

Abstract Serine proteases and their inhibitors have an established role in cancer progression, invasion, and metastasis. Elafin is an endogenously expressed inhibitor of human neutrophil elastase. In mammary epithelial cells elafin is highly expressed; however in breast cancer it is transcripitionally downregulated. We hypothesize that the loss of elafin is critical to the development of the malignant phenotype in breast cancer. In human mammary epithelial cells (HMECs) and breast cancer cell lines, the regulation and activity of elafin is dependent on the critical tumor suppressor retinoblastoma (Rb). Elafin is dramatically upregulated in quiescent HMECs following growth factor deprivation. This upregulation is characterized by an Rb dependent increase in elafin stability and cytoplasmic accumulation. Knockdown of elafin by shRNA in HMECs causes them to be refractory to growth factor deprivation induced quiescence; suggesting that elafin upregulation is a key regulator of cellular quiescence. Overexpression of elafin by adenovirus in both HMECs and breast cancer cell lines lacking Rb causes caspase-3 dependent, apoptotic cell death. Additionally, adenoviral elafin causes Rb-dependent cell cycle arrest in tumor cells with functional Rb. The Rb pathway is lost or inactivated in the majority of cancers. The design of a therapeutic strategy capable of specifically targeting tumor cells with Rb inactivation may prove to have significant utility in the treatment of cancer. The data summarized here demonstrates that overexpression of elafin is cytostatic in Rb-positive breast cancer cells and cytotoxic in Rb-negative breast cancer cells expressing caspase 3; suggesting that elafin could be engineered into a therapeutic modality in the treatment of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3057.