Abstract 3329: Investigations into the tumor specific regulation of HER2 by Grp94 in breast cancer

Abstract

Abstract Background: Grp94 is the Endoplasmic Reticulum (ER) paralog of the Hsp90 family of chaperones. Overexpression of Grp94 in tumors correlates with advanced stage and poor survival in various cancers and is closely linked to cancer growth and metastasis. Until recently, the major focus of cancer related studies on Grp94 was on the involvement of this protein in the secretion of IGF-II and the regulation of Toll-Like Receptors (TLRs) and integrins. Objective/Hypothesis: Our group combined compound library screening with computational tools to develop potent and selective inhibitors of Grp94 and of Hsp90, the cytosolic HSP90 paralog. We hypothesize that these small molecules are important pharmacologic tools to investigate, in a tumor-by-tumor manner, Grp94 and Hsp90 associated oncogenic mechanisms. Approach/Results: Using the Hsp90 paralog specific inhibitors we produce preliminary evidence for an unanticipated role for Grp94 in maintaining the architecture of high density HER2 formations at the plasma membrane, particularly in cancer cells where HER2 is required to channel an amplified signaling through the receptor. Our data indicate that under conditions in which stress is imposed on the cell by proteome alterations (i.e. HER2 overexpression), the chaperoning function of Grp94 is vital for proper HER2 functioning. In these cells Grp94 translocates to the plasma membrane where it functions to maintain an active conformation of HER2 and to stabilize downstream signaling through the receptor. Our data show that inhibition of Grp94 in these cells is sufficient to destabilize membrane HER2, inhibit its signaling properties and target HER2 towards a degradative pathway. These effects are associated with cancer cell viability loss and induction of apoptosis. Significance: These findings reveal a novel mechanism of HER2-regulation at the plasma membrane, where Grp94 is implicated in HER2 regulation at this location in the specific case of HER2 positive tumors. They also provide a strong rationale for the use of these inhibitors in the investigation of Grp94 associated oncogenic mechanisms. Further, this study proposes the development of Grp94-based cancer therapeutics for HER2 overexpressing breast cancer. Citation Format: Pengrong Yan, Hardik Patel, Chenghua Yang, Tony Taldone, Gabriela Chiosis. Investigations into the tumor specific regulation of HER2 by Grp94 in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3329. doi:10.1158/1538-7445.AM2014-3329