title: Ki-67 is required for maintenance of cancer stem cells but not cell proliferation.
abstract: Ki-67 expression is correlated with cell proliferation and is a prognostic marker for various cancers; however, its function is unknown. Here we demonstrate that genetic disruption of Ki-67 in human epithelial breast and colon cancer cells depletes the cancer stem cell niche. Ki-67 null cells had a proliferative disadvantage compared to wildtype controls in colony formation assays and displayed increased sensitivity to various chemotherapies. Ki-67 null cancer cells showed decreased and delayed tumor formation in xenograft assays, which was associated with a reduction in cancer stem cell markers. Immunohistochemical analyses of human breast cancers revealed that Ki-67 expression is maintained at equivalent or greater levels in metastatic sites of disease compared to matched primary tumors, suggesting that maintenance of Ki-67 expression is associated with metastatic/clonogenic potential. These results elucidate Ki-67's role in maintaining the cancer stem cell niche, which has potential diagnostic and therapeutic implications for human malignancies.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Present address: Oncology iMED, AstraZeneca, Waltham, MA, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Cidado
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Hong Yuen
authors.initials: HY
authors.lastname: Wong
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: D Marc
authors.initials: DM
authors.lastname: Rosen
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Cimino-Mathews
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Garay
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Abigail G
authors.initials: AG
authors.lastname: Fessler
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Zeshaan A
authors.initials: ZA
authors.lastname: Rasheed
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hicks
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Rory L
authors.initials: RL
authors.lastname: Cochran
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Croessmann
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Zabransky
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Present address: Roche Sequencing, San Jose, CA, USA.
authors.forename: Morassa
authors.initials: M
authors.lastname: Mohseni
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Beaver
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chu
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Cravero
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Christenson
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Arielle
authors.initials: A
authors.lastname: Medford
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Mattox
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.affiliation: Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.|Departments of Physiology and Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Chawla
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Hurley
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: Lauring
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|The Whiting School of Engineering, Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D019394:Ki-67 Antigen
keywords: Ki-67; cancer stem cells; clonogenicity; proliferation; tumorigenicity
references.citation: J Cell Physiol. 2000 Mar;182(3):311-22
references.pmid: 10653597
references.citation: Clin Cancer Res. 2013 Aug 15;19(16):4521-31
references.pmid: 23812670
references.citation: J Biol Chem. 2001 Jul 6;276(27):25386-91
references.pmid: 11342549
references.citation: J Pathol. 2002 Feb;196(2):135-44
references.pmid: 11793364
references.citation: FEBS Lett. 2002 Feb 20;513(1):58-66
references.pmid: 11911881
references.citation: Nat Biotechnol. 2002 Jul;20(7):735-8
references.pmid: 12089561
references.citation: Int J Cancer. 2003 Jul 10;105(5):710-6
references.pmid: 12740923
references.citation: J Cell Physiol. 1987 Dec;133(3):579-84
references.pmid: 3121642
references.citation: J Cell Sci. 1989 Apr;92 ( Pt 4):531-40
references.pmid: 2689459
references.citation: Cytometry. 1991;12(1):50-63
references.pmid: 1999123
references.citation: Br J Haematol. 1993 Dec;85(4):835-6
references.pmid: 7918058
references.citation: N Engl J Med. 2004 Dec 30;351(27):2817-26
references.pmid: 15591335
references.citation: J Clin Oncol. 2005 Oct 1;23(28):7212-20
references.pmid: 16192605
references.citation: Life Sci. 2006 Jan 11;78(7):724-9
references.pmid: 16111722
references.citation: Nat Protoc. 2007;2(11):2865-74
references.pmid: 18007621
references.citation: Ann Surg Oncol. 2008 Oct;15(10):2927-33
references.pmid: 18663533
references.citation: Nature. 2008 Dec 4;456(7222):593-8
references.pmid: 19052619
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2835-40
references.pmid: 19196980
references.citation: Cancer Biol Ther. 2007 Jul;6(7):1025-30
references.pmid: 17611398
references.citation: J Immunol Methods. 2009 Aug 15;347(1-2):70-8
references.pmid: 19567251
references.citation: Arch Surg. 2012 Jan;147(1):18-24
references.pmid: 22250106
references.citation: Hum Pathol. 2012 Jul;43(7):1003-11
references.pmid: 22154362
references.citation: J Cell Physiol. 2013 Feb;228(2):408-15
references.pmid: 22740326
references.citation: J Biol Chem. 2000 Sep 15;275(37):28888-92
references.pmid: 10878014