Abstract B52: Loss of anterior gradient protein in high-grade prostate cancer is associated with loss of tumor cell adhesion and epithelial cell polarity

Abstract

Abstract Prostate cancer has the highest rate of incidence among all cancers in men in the United States and the second leading cause of death behind lung cancer. The human homologue of the frog (Xenopus) anterior gradient protein (AGR-2) has gained considerable attention in recent years for its putative role in neoplastic growth, metastasis and poor survival of patients with breast and prostate cancers. AGR-2 is reported to be androgen dependent and expressed only during the early stages of prostate cancer progression, whereas significant decline in AGR-2 levels in higher grades tumors coincided with metastatic disease. Human primary prostate cancer tissues and regional metastasis were immunostained for AGR-2 expression. Results indicated that AGR-2 was localized in the glandular epithelium of the prostate gland. No significant difference in AGR-2 staining was observed between normal, BPH and well-differentiated prostate cancers, except in normal prostate, where AGR-2 was mostly concentrated in the nuclei. Similar results were observed in a spontaneously developing transgenic adenocarcinoma of mouse prostate (TRAMP) model. AGR-2 expressions was reduced significantly in moderately and poorly-differentiated tumors in both human and TRAMP mice. Higher AGR-2 levels were found in the metastatic tissue albeit lower expressions in the highest grades prostate tumors within the same individual, suggesting further requirement of AGR-2 for growth at the metastatic sites. Targeted silencing of AGR-2 in a bone metastatic prostate cancer cell line, PC3, resulted in significantly reduced cellular adhesion to various extracellular matrix proteins and a failure to form acinar structures following 3-dimensional growth on matrigel. We also determined that AGR-2 silencing led to down-regulation of crucial integrins in PC3 cells, which possibly explains mechanism by which AGR-2 maintains polarized morphology of epithelial cells through promotion of cell adhesion. Based on our findings, we hypothesize that loss of AGR-2 in prostate cancer cells allows detachment from the basement membrane of the primary site and initiates metastasis. AGR-2 as well as integrin levels are restored during passage through circulation and at the metastatic site(s), helping them re-attach to the new microenvironment. Citation Format: Diptiman Chanda, Anandi Sawant, Jonathan Adam Hensel, Tatyana Isayeva, Stephanie D. Reilly, Gene P. Siegal, Claire Smith, Selvarangan Ponnazhagan. Loss of anterior gradient protein in high-grade prostate cancer is associated with loss of tumor cell adhesion and epithelial cell polarity [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B52.