The bone microenvironment increases phenotypic plasticity of ER+ breast cancer cells

Igor L. Bado, Weijie Zhang, Jingyuan Hu, Zhan Xu, Hai Wang, Poonam Sarkar, Lucian Li, Ying Wooi Wan, Jun Liu, William Wu, Hin Ching Lo, Ik Sun Kim, Swarnima Singh, Mahnaz Janghorban, Aaron M. Muscarella, Amit Goldstein, Purba Singh, Hyun Hwan Jeong, Chaozhong Liu, Rachel SchiffShixia Huang, Matthew J. Ellis, M. Waleed Gaber, Zbigniew Gugala, Zhandong Liu, Xiang H.F. Zhang

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1100-1117.e9
JournalDevelopmental cell
Issue number8
StatePublished - Apr 19 2021


  • FGFR/EZH2 axis
  • barcoding
  • bone metastasis
  • bone tropism
  • chromatin alteration
  • clonal evolution
  • endocrine resistance
  • epigenomic reprogramming
  • osteogenic cells
  • stemness

ASJC Scopus subject areas

  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • Developmental Biology
  • Cell Biology


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