Abstract LB-136: The role of ER chaperone GRP94 in endometrial cancer progression

Abstract

Abstract Endometrial cancer is the most prevalent gynecologic cancer in the United States and accounts for nearly 50,000 incident cases annually. One of the most common mutations detected in the more prevalent Type 1 endometrial cancer is the loss of the tumor suppressor gene, Pten (phosphatase and tensin homolog). Pten mutations are involved in a wide variety of human cancers, including >60% of endometrial cancer. The glucose-regulated protein 94 (GRP94), also known as glycoprotein 96 (gp96), is a major chaperone protein in the ER. The client proteins of GPR94 include important regulators of cell growth and cell adhesion such as IGF-1, Toll-like receptors and integrins. GRP94 is known to play major roles in immune modulation. GRP94 also possesses anti-apoptotic properties. GRP94 elevation has been reported in a variety of human cancers and has been implicated in cancer development. Previously, GRP94 knockout in multiple myeloma reduced cell proliferation and survival, through inhibiting Wnt-LRP-survivin pathway. GRP94 knockout in macrophages reduced inflammatory colon tumorigenesis. On the other hand, GRP94 knockout in hepatocytes resulted in liver progenitor cell proliferation and acceleration of liver cancer, associating with repopulation of GRP94-positive hepatocytes. Therefore, the role of GRP94 in cancer appears to be context-dependent due to its multifaceted functions. Currently, little is known about GRP94 expression and function in endometrial cancer. We examined GRP94 expression in human endometrial cancer tissues and robust GRP94 expression was observed. In human endometrial cancer cell line, GRP94 knockdown by siRNA led to decreased proliferation and cell migration. To examine the requirement of GRP94 in the initiation and development of endometrial cancer, we utilized the Progesterone Receptor-Cre to specifically delete genes in the mouse endometrium. Before studying GRP94 in endometrial cancer, we first determined the effect of GRP94 depletion in normal uteri. Surprisingly, GRP94 single knockout uteri showed squamous cell metaplasia, confirmed by expression of K14 and p63, and reduction in size. Next, we created the biallelic mutant mice with concurrent deletion of Pten and Grp94 in the endometrium. We monitored the progress of endometrial cancer development, with mice bearing Pten knockout alone serving as the positive controls. As expected, Pten single knockout mice develop endometrial cancer by 4 week and initiate invasion into myometrium by 8 week. Analysis of the mice uteri indicated that GRP94 deficiency delayed the onset of endometrial cancer, associating with altered cell adhesion properties and pro-oncogenic signaling pathways. This study expands our understanding of GRP94 function in the progression of solid tumors and provides the first evidence that GRP94 could be a target for combating endometrial cancer. Citation Format: Jieli Shen, Yvonne G. Lin, Louis Dubeau, Amy S. Lee. The role of ER chaperone GRP94 in endometrial cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-136. doi:10.1158/1538-7445.AM2015-LB-136