Abstract 3212: Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche

Abstract

Abstract Distant metastases are the major cause of death from breast cancer. In estrogen receptor positive (ER+) breast cancer (BC) in particular, metastatic relapse can occur years after initial treatment, suggesting that disseminated tumor cells have a prolonged dormant phase before becoming proliferative. A major site of early disease dissemination and metastatic relapse of ER+ BC is the bone, although the critical signals that allow circulating breast cancer cells (BCCs) to identify bone marrow (BM) vasculature, enter the tissue, and tether to the BM microenvironment (BMM) are little understood. Investigating these interactions of BCCs with the BMM, however, could enable us to target the key biologic determinants allowing safe harbor for metastases within bone. To address the features of breast tumors associated with late recurrence, but not confounded by variations in systemic treatment, we compiled breast tumor gene expression data from 4,767 patients and established a discovery cohort consisting of 743 lymph node-negative patients who did not receive systemic neoadjuvant or adjuvant therapy. Using this data set, we found that expression of E-selectin ligands and CXCR4 were significantly elevated in ER+ tumors that had late recurrences. Based on these observations, we used intravital fluorescence microscopy to study the precise functions of E-selectin ligands and CXCR4 (SDF-1 receptor) in tumor metastasis in in vivo xenograft models and found that these play distinct roles in ER+ BCC migration in the BMM. Using highly specific E-selectin (GMI-1271) and CXCR4 (AMD3100) inhibitors, we determined that E-selectin interactions were critical for BCC entry into bone, while CXCR4/SDF-1 interactions anchored BCCs to the BMM. CXCR4 inhibition led to significant mobilization of BC micrometastases from the BMM into the peripheral circulation. Moreover, we found that dormant and proliferating BCCs occupy distinct regions of the BMM, with dormant BCCs predominantly found in SDF-1 and E-selectin rich regions and thus highly susceptible to AMD3100 mobilization. These findings shed light on how dormant and proliferating BCCs interact with the BMM and suggest new interventions to break the foothold of dormant BC micrometastases in bone. Citation Format: Trevor T. Price, Clara H. Lee, Qing Cheng, H. Kim Lyerly, William E. Fogler, John L. Magnani, Dorothy A. Sipkins. Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche. [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 3212. doi:10.1158/1538-7445.AM2015-3212