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Sci Transl Med. 2016 Aug 3;8(350):350ra104. doi: 10.1126/scitranslmed.aad6066.

Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression.

Author information

1
Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
2
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.
3
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.
4
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.
5
Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore 119074, Singapore.
6
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.
7
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA. Harvard Stem Cell Institute, Boston, MA 02215, USA.
8
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.
9
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02215, USA.
10
Institute of Biomedical Technologies, National Research Council (CNR), Pisa 56124, Italy.
11
Department of Pathology, Weill Cornell University Medical Center, New York, NY 10065, USA.
12
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20817, USA.
13
PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
14
Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore. Department of Haematology-Oncology, University of Western Australia, Crawley, Western Australia 6009, Australia.
15
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
16
Division of Hematology/Oncology, Montefiore Hospital, Bronx, NY 10461, USA.
17
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
18
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.
19
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.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02404480.

PMID:
27488898
DOI:
10.1126/scitranslmed.aad6066
[Indexed for MEDLINE]

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