title: Angiopoietin-2 promotes ER+ breast cancer cell survival in bone marrow niche.
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.
authors.affiliation: Brain Korea 21 Plus Project for Medical ScienceYonsei University College of Medicine, Seoul, South Korea Department of PathologyYonsei University College of Medicine, Seoul, South Korea.
authors.forename: Hyun Ho
authors.initials: HH
authors.lastname: Han
authors.affiliation: Department of PathologyYonsei University College of Medicine, Seoul, South Korea.
authors.forename: Baek Gil
authors.initials: BG
authors.lastname: Kim
authors.affiliation: Brain Korea 21 Plus Project for Medical ScienceYonsei University College of Medicine, Seoul, South Korea.
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of PathologyYonsei University College of Medicine, Seoul, South Korea.
authors.forename: Suki
authors.initials: S
authors.lastname: Kang
authors.affiliation: Brain Korea 21 Plus Project for Medical ScienceYonsei University College of Medicine, Seoul, South Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Brain Korea 21 Plus Project for Medical ScienceYonsei University College of Medicine, Seoul, South Korea Department of PathologyYonsei University College of Medicine, Seoul, South Korea Severance Biomedical Science Institute (SBSI)Yonsei University College of Medicine, Seoul, South Korea Global 5-5-10 System BiologyYonsei University, Seoul, South Korea cho1988@yuhs.ac.
authors.forename: Nam Hoon
authors.initials: NH
authors.lastname: Cho
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001853:Bone Marrow / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D004965:Estrogen Antagonists / Q000627:therapeutic use; D004967:Estrogens / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D059630:Mesenchymal Stem Cells; D042787:Receptor, TIE-2 / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: C467630:ANGPT1 protein, human; C586513:ANGPT2 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D004967:Estrogens; D019012:Integrin beta1; D011960:Receptors, Estrogen; D042787:Receptor, TIE-2
keywords: bone; breast; cell signaling; endocrine therapy resistance; metastasis