Phenotypic plasticity of ER+ breast cancer in the bone microenvironment
Summary 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 reduces ER expression and activities specifically in bone micromet...
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Published in | bioRxiv |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Paper |
Language | English |
Published |
Cold Spring Harbor
Cold Spring Harbor Laboratory Press
27.11.2020
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Subjects | |
Online Access | Get full text |
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Summary: | Summary 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 reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. This is mediated by gap junctions and paracrine FGF/PDGF signaling, which together generate a stable “memory”: cancer cells extracted from bone remain resistant to endocrine therapies for several generations. Using single cell-derived populations (SCPs), 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. Our data demonstrates how epigenomic adaptation to the bone microenvironment drives phenotypic plasticity of metastatic seeds and alters their therapeutic responses together with clonal selection, and provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵7 Lead Contact |
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DOI: | 10.1101/2020.11.14.383000 |