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

 Hyun Ho Han  ;  Baek Gil Kim  ;  Joo Hyun Lee  ;  Suki Kang  ;  Ji Eun Kim  ;  Nam Hoon Cho 
 ENDOCRINE-RELATED CANCER, Vol.23(8) : 609-623, 2016 
Journal Title
Issue Date
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
bone ; breast ; cell signaling ; endocrine therapy resistance ; metastasis
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.
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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
Kang, Suki(강숙희) ORCID logo https://orcid.org/0000-0002-9957-3479
Kim, Baek Gil(김백길) ORCID logo https://orcid.org/0000-0001-6270-1433
Cho, Nam Hoon(조남훈) ORCID logo https://orcid.org/0000-0002-0045-6441
Han, Hyun Ho(한현호) ORCID logo https://orcid.org/0000-0002-6268-0860
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