title: Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression.
abstract: Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPα (CCAAT/enhancer binding protein α) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPα suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPα expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPα expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBPα deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPα-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPα is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPα loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPα and high BMI1.
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
authors.forename: Kol Jia
authors.initials: KJ
authors.lastname: Yong
authors.affiliation: Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo 05508, Brazil. Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Basseres
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA. Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Welner
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Wen Cai
authors.initials: WC
authors.lastname: Zhang
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore 119074, Singapore.
authors.forename: Benedict
authors.initials: B
authors.lastname: Yan
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA. Institute of Molecular Genetics of the ASCR, Prague 14200, Czech Republic.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Alberich-Jorda
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Junyan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA. Hematology Division, Department of Internal Medicine, Ribeirao Preto Medical School, University of São Paulo, São Paulo 14020, Brazil.
authors.forename: Lorena Lobo
authors.initials: LL
authors.lastname: de Figueiredo-Pontes
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Battelli
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hetherington
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Biomedical Technologies, National Research Council (CNR), Pisa 56124, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Maroni
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: O'Brien
authors.affiliation: Institute of Biomedical Technologies, National Research Council (CNR), Pisa 56124, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Magli
authors.affiliation: Department of Pathology, Weill Cornell University Medical Center, New York, NY 10065, USA.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Borczuk
authors.affiliation: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20817, USA.
authors.forename: Lyuba
authors.initials: L
authors.lastname: Varticovski
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kocher
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA.
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Young-Choon
authors.initials: YC
authors.lastname: Moon
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Nadiya
authors.initials: N
authors.lastname: Sydorenko
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Liangxian
authors.initials: L
authors.lastname: Cao
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Davis
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
authors.forename: Bhavin M
authors.initials: BM
authors.lastname: Thakkar
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore. Department of Haematology-Oncology, University of Western Australia, Crawley, Western Australia 6009, Australia.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Soo
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
authors.affiliation: Division of Hematology/Oncology, Montefiore Hospital, Bronx, NY 10461, USA.
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA. elevanti@bidmc.harvard.edu csidgt@nus.edu.sg.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA. Institute of Biomedical Technologies, National Research Council (CNR), Pisa 56124, Italy. elevanti@bidmc.harvard.edu csidgt@nus.edu.sg.
authors.forename: Elena
authors.initials: E
authors.lastname: Levantini
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C069077:BMI1 protein, human; C489421:Bmi1 protein, mouse; D022763:CCAAT-Enhancer-Binding Protein-alpha; D011518:Proto-Oncogene Proteins; D063150:Polycomb Repressive Complex 1