PT - JOURNAL ARTICLE AU - Igor L. Bado AU - Hai Wang AU - Jingyuan Hu AU - Poonam Sarkar AU - Jun Liu AU - Zbigniew Gugala AU - Zhan Xu AU - Weijie Zhang AU - William Wu AU - Hin-Ching Lo AU - Lucian Li AU - Ik-Sun Kim AU - Swarnima Singh AU - Mahnaz Janghorban AU - Aaron Muscallera AU - Amit Goldstein AU - Purba Singh AU - Hyun Hwan Jeong AU - Ying-Wooi Wan AU - Huang Shixia AU - Rachel Schiff AU - Gaber M. Waleed AU - Zhangdong Liu AU - Matthew J. Ellis AU - Xiang H.-F. Zhang TI - Phenotypic plasticity of ER+ breast cancer in the bone microenvironment AID - 10.1101/2020.11.14.383000 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.11.14.383000 4099 - http://biorxiv.org/content/early/2020/11/15/2020.11.14.383000.short 4100 - http://biorxiv.org/content/early/2020/11/15/2020.11.14.383000.full AB - ER+ breast cancer exhibits a strong bone-tropism in metastasis. How the bone microenvironment impacts the ER signaling and endocrine therapies remains poorly understood. Here, we discover that the osteogenic niche transiently and reversibly reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. As BMMs progress, the ER reduction and endocrine resistance may partially recover in cancer cells away from the osteogenic niche, creating phenotypic heterogeneity in macrometases. Using multiple approaches including an evolving barcoding strategy, we demonstrated that this process is independent of clonal selection, and represents an EZH2-mediated epigenomic reprogramming. EZH2 drives ER+ BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. These data exemplify how epigenomic adaptation to the bone microenvironment drives phenotypic plasticity of metastatic seeds, fosters intra-metastatic heterogeneity, and alters therapeutic responses. Our study provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.Competing Interest StatementThe authors have declared no competing interest.