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Angiopoietin-2 promotes ER+ breast cancer cell survival in bone marrow niche

Authors
 Hyun Ho Han  ;  Baek Gil Kim  ;  Joo Hyun Lee  ;  Suki Kang  ;  Ji Eun Kim  ;  Nam Hoon Cho 
Citation
 Endocrine-Related Cancer, Vol.23(8) : 609-623, 2016 
Journal Title
 Endocrine-Related Cancer 
ISSN
 1351-0088 
Issue Date
2016
MeSH
Angiopoietin-1/metabolism ; Angiopoietin-2/genetics ; Angiopoietin-2/metabolism* ; Antineoplastic Agents, Hormonal/therapeutic use ; Bone Marrow/metabolism* ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism* ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Survival ; Cells, Cultured ; Coculture Techniques ; Estrogen Antagonists/therapeutic use ; Estrogens/deficiency ; Estrogens/metabolism* ; Female ; Human Umbilical Vein Endothelial Cells ; Humans ; Integrin beta1/metabolism* ; Kaplan-Meier Estimate ; Mesenchymal Stromal Cells ; Receptor, TIE-2/metabolism* ; Receptors, Estrogen/metabolism
Keywords
bone ; breast ; cell signaling ; endocrine therapy resistance ; metastasis
Abstract
In estrogen receptor-positive (ER+) breast cancer, it is recognized that metastases may develop after a long period of dormancy. Bone marrow (BM) vascular niche is where the dormant tumor cells are most likely to reside. So far, it is not fully understood why the dormant tumor cells become proliferative and eventually generate tumor. We hypothesized that therapeutic or menopause-related estrogen depletion may be the switch behind dormant ER+ tumor cell awakening in BM. We utilized an existing experimental model of BM endothelial niche that can simulate ER+ tumor cell dormancy to test our hypothesis. In results, estrogen depletion paradoxically promoted ER+ tumor cell proliferation in the BM endothelial niche, and their molecular phenotype shifted from dormant to awaken. Following estrogen depletion, the BM niche cells produced angiopoietin-2 (ANGPT2), which destabilized niche endothelium by interfering ANGPT1/Tie2 signaling, and promoted ER+ tumor cell survival under estrogen deficiency via cell surface integrin &1. Knockdown of ANGPT2 completely negated ER+ tumor cell awakening in the niche. Furthermore, ANGPT2 expression in ER+ tumor human samples was associated with increased risk of distant metastasis only in those who underwent adjuvant estrogen depletion therapy, not in those who did not undergo adjuvant therapy. In conclusion, we demonstrate that ANGPT2 signaling activated after estrogen depletion paradoxically triggers ER+ tumor cell awakening from dormancy in their BM niche, partly indirectly via endothelial Tie2 receptor and partly directly via tumor cell surface integrin &1.
Files in This Item:
T201603613.pdf Download
DOI
10.1530/ERC-16-0086
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
강숙희(Kang, Suki) ORCID logo https://orcid.org/0000-0002-9957-3479
김백길(Kim, Baek Gil) ORCID logo https://orcid.org/0000-0001-6270-1433
조남훈(Cho, Nam Hoon) ORCID logo https://orcid.org/0000-0002-0045-6441
한현호(Han, Hyun Ho) ORCID logo https://orcid.org/0000-0002-6268-0860
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/152027
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