@article{a2b0cf9782a64fd59771f0ed476f5b8f,
title = "The bone microenvironment increases phenotypic plasticity of ER+ breast cancer cells",
abstract = "Estrogen receptor-positive (ER+) breast cancer exhibits a strong bone tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine therapy 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 macrometastases. 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 BME promotes 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.",
keywords = "FGFR/EZH2 axis, barcoding, bone metastasis, bone tropism, chromatin alteration, clonal evolution, endocrine resistance, epigenomic reprogramming, osteogenic cells, stemness",
author = "Bado, {Igor L.} and Weijie Zhang and Jingyuan Hu and Zhan Xu and Hai Wang and Poonam Sarkar and Lucian Li and Wan, {Ying Wooi} and Jun Liu and William Wu and Lo, {Hin Ching} and Kim, {Ik Sun} and Swarnima Singh and Mahnaz Janghorban and Muscarella, {Aaron M.} and Amit Goldstein and Purba Singh and Jeong, {Hyun Hwan} and Chaozhong Liu and Rachel Schiff and Shixia Huang and Ellis, {Matthew J.} and Gaber, {M. Waleed} and Zbigniew Gugala and Zhandong Liu and Zhang, {Xiang H.F.}",
note = "Funding Information: We thank the Breast Center Pathology Core, the Antibody-Based Proteomics Core (CPRIT Core Facility award [RP170005] and P30 Cancer Center Support Grant [ NCI-CA125123 ]), the Small Animal Imaging Facility (SAIF) at Texas Children Hospital , and the Genomic and RNA Profiling core (GARP) for their technical support. We also thank Epizyme (Cambridge, MA) for providing the EZH2 inhibitor EPZ-011989. We express our gratitude to Drs. Rosen Jeffrey, Michael Lewis, and Xi Chen for advice and technical support. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672) and the NIH ( CA125123 and RR024574 ) and the assistance of Joel M. Sederstrom. X.H.-F.Z. is supported by US Department of Defense DAMD W81XWH-16-1-0073 (Era of Hope Scholarship), NCI CA183878 , NCI CA251950 , NCI CA221946 , DAMD W81XWH-20-1-0375 , Breast Cancer Research Foundation , and McNair Medical Institute . Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = apr,
day = "19",
doi = "10.1016/j.devcel.2021.03.008",
language = "English (US)",
volume = "56",
pages = "1100--1117.e9",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "8",
}