Abstract 428: Targeting secreted heat shock protein-90alpha (hsp90α) to prevent breast cancer progression

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Targeting secreted heat shock protein-90alpha (Hsp90α) to prevent breast cancer progression Z. Zhao, C. Cheng, R. Kim, M. Chen, D. T. Woodley and W. Li* Department of Dermatology and the USC-Norris Comprehensive Cancer Center, the University of Southern California Keck School of Medicine, Los Angeles, California, 90033, USA Until recently, heat shock protein 90 (Hsp90) has been mostly known as an abundant, intracellular and ATP-driven chaperone with more than 100 target proteins that often play critical roles in various branches of the signaling networks for control of cell metabolism, survival, growth and differentiation. Since Hsp90 has been found either over-expressed or over-activated in cancer cells than in normal cells, this intracellular protein has become a target for anti-cancer drugs with a hope to simultaneously shut down multiple constitutively activated oncogene products in cancer cells. Despite of the high expectations, the toxicity of geldanamycin (GM)-derived inhibitors in humans has been a long-standing hurdle. Newer generations of GM inhibitors are still being tested currently in at least eight clinical trials. However, studies of past few years have demonstrated a surprising need for cancer cells to secrete Hsp90α for tissue invasion and metastasis. The mechanism of the extracellar Hsp90α action has since been actively investigated. We present here new evidence that the metastatic breast cancer cells, MDA-MB-231, constitutively secrete Hsp90α due to their constitutive expression of the hypoxia-inducible factor-1alpha (HIF1α). Down-regulation of either HIF1α or HIF1β or replacing them with their nuclear tanslocation-defective mutants completely blocked Hsp90α secretion. The main function of the secreted Hsp90α was to promote breast cancer cell motility via binding to the cell surface lipoprotein receptor LRP1 (LDL Receptor-Related Protein-1). Unlike its intracellular chaperone function that requires the N-terminal ATPase and the C-terminal dimerization domains, this extracellular Hsp90α promotes cell motility via a 27-amino acid peptide located at the boundary between the linker region (LR) and the middle domain (M) of Hsp90α. These studies led to the notion that a novel “secreted Hsp90α-LRP1 Receptor” autocrine signaling plays a role in breast cancer progression. Indeed, selective inhibition of the extracellular action of Hsp90 or down-regulation of LRP-1 receptor blocked breast cancer invasion in an in vitro matrigel assay and tumor formation in nude mice. Most intriguingly, since secretion of Hsp90α was only found to occur under pathological conditions such as cancer and is not part of normal cells’ life, anti-cancer drugs targeting the 27-amino acid peptide of the extracellular Hsp90α should be more effective and less toxic in humans. We propose here that the extracellular, not intracellular, Hsp90α is an effective and safer target for anti-cancer therapies. 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 428.