title: Angiopoietin-2, an angiogenic regulator, promotes initial growth and survival of breast cancer metastases to the lung through the integrin-linked kinase (ILK)-AKT-B cell lymphoma 2 (Bcl-2) pathway.
abstract: The early onsets of breast cancer metastasis involve cell retention, survival, and resistant to apoptosis and subsequent growth at target vascular beds and tissues in distant organs. We previously reported that angiopoietin-2 (Ang2), an angiogenic regulator stimulates MCF-7 breast tumor metastasis from their orthotopic sites to distant organs through the α(5)β(1) integrin/integrin-linked kinase (ILK)/Akt pathway. Here, by using an experimental tumor metastasis model and in vitro studies, we further dissect the underlying mechanism by which Ang2 promotes the initial growth and survival of MCF-7 breast cancer metastasis in the lung of animals. We show that Ang2 increases cell survival and suppresses cell apoptosis through ILK-induced phosphorylation of Akt1, Akt2, and up-regulation of Bcl-2 in breast cancer cells. Inhibition of ILK, Akt1, and Akt2, and their effector Bcl-2 diminishes Ang2-stimulated breast cancer cell survival and Ang2-attenuated apoptosis in vitro, and initial survival and growth of breast cancer metastasis in the lung of animals. Additionally, siRNA knockdown of endogenous Ang2 in three human metastatic breast cancer cell lines also inhibits phosphorylation of Akt, expression of Bcl-2, and tumor cell survival, migration, and increases cell apoptosis. Since increased expression of Ang2 correlates with elevated potential of human breast cancer metastasis in clinic, our data underscore the importance that up-regulated Ang2 not only stimulates breast cancer growth and metastasis at late stages of the process, but is also critical at the initiating stages of metastases onset, thereby suggesting Ang2 as a promising therapeutic target for treating patients with metastatic breast cancer.
authors.affiliation: Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Otorhinolaryngology, Head and Neck Surgery, Keio University, School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
authors.forename: Yorihisa
authors.initials: Y
authors.lastname: Imanishi
authors.affiliation: Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213. Electronic address: hub@upmc.edu.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors.forename: Gutian
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Anhui Laboratory of Cellular Dynamics and Chemical Biology, Hefei National Laboratory for Physical Sciences at Nanoscale, Hefei 230027, China, and; Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310.
authors.forename: Xuebiao
authors.initials: X
authors.lastname: Yao
authors.affiliation: Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213. Electronic address: chengs@upmc.edu.
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D042702:Angiopoietin-2 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D000099200:Scaffold Protein ILK
chemical_list: D042702:Angiopoietin-2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D000099200:Scaffold Protein ILK; C494918:AKT1 protein, human; C494921:AKT2 protein, human