Abstract Estrogen receptor (ER+) positive invasive lobular carcinoma comprises 15% of all breast cancer and is the second most common hormone-sensitive breast cancer (BC). Uniquely, ILC lacks e-cadherin expression resulting in relatively discohesive and multi-focal tumors within the breast, making it difficult to detect with conventional imaging. ILC is also highly metastatic to bone and compared to triple-negative breast cancer or luminal B ER+ BC, ILC has a low proliferative rate 15% and slower growing phenotype. Previously we have observed in mammary intraductal nipple injection (MIND) in vivo models that high GR (versus low GR) expression in ILC is associated with markedly reduced ILC cell proliferation without reducing metastatic colonization ability. Here we show the anti-tumor growth effect of GR+ on ILC cells in the primary engrafted mammary glands and the pro-metastatic effect. We observed decreased tumor cell proliferation and tumor burden 90 days post-mammary gland injection of GR+ expressing ILC cells compared to GR null or GR low cells in the MDA-IV-134, and BCK4 cell lines. Remarkably the slowed tumor growth had equivalent metastatic burden to GR-negative ILC with much larger primary tumors. This suggests that reduced proliferation in the mammary gland tumor does not affect metastatic efficiency in distant organs. We hypothesize that tumor intrinsic GR may increase bone metastatic colonization through activation of “bone mineralization gene expression signaling pathways” and “IL-6 signaling pathways” associated with GR activation in parallel in vitro experiments. Furthermore, ongoing studies including advanced light sheet microscopy and fluorescent-activated cell sorting allow us to quantify ILC cells in the bone as early as 90 days post MG nipple injection. In addition, we are performing bulk RNA sequencing from MG tumors to identify specific in vivo GR+ activated gene expression pathways that promote GR+ ILC bone metastasis. Future studies will also include GR modulation to uncover GR-regulated genes that favor more efficient ILC bone metastases. Citation Format: B. A. Porter-Hansen, A. Briceno, H. Borges, A. Devilbiss, K. Dean, L. Bennett, S. D. Conzen. Uncovering mechanisms of ILC glucocorticoid receptor activity in cell cycle regulation and bone metastasis using in vivo models and human samples abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-08-22.
Porter-Hansen et al. (2026) studied this question.