Latest @ CSI

Targeted BMI1 Inhibition Impairs Tumor Growth in Lung Adenocarcinomas with Low CEBPα Expression (Science Translational Medicine, Aug 2016)

Kol Jia Yong1,*, Daniela S. Basseres2,3,4,5,*, Robert S. Welner3,4,5,6, Wen Cai Zhang3,4,7, Henry Yang1, Benedict Yan8, Meritxell Alberich-Jorda3,4,5,9, Junyan Zhang3,4,5, Lorena Lobo de Figueiredo-Pontes3,4,5,10, Chiara Battelli3,4,†, Christopher J. Hetherington3,4,5, Min Ye3,4,5, Hong Zhang3,4,5, Giorgia Maroni11, Karen O’Brien3,4,5,‡, Maria Cristina Magli11, Alain C. Borczuk12, Lyuba Varticovski13, Olivier Kocher3,4, Pu Zhang3,4,5, Young-Choon Moon14, Nadiya Sydorenko14, Liangxian Cao14, Thomas W. Davis14, Bhavin M. Thakkar1, Ross A. Soo1,15, Atsushi Iwama16, Bing Lim3,4,7,§, Balazs Halmos17, Donna Neuberg18, Daniel G. Tenen1,4,5,¶ and Elena Levantini3,4,5,11,¶

1Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
2Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo 05508, Brazil.
3Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
4Harvard Medical School, Boston, MA 02215, USA.
5Harvard Stem Cell Institute, Boston, MA 02215, USA.
6Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
7Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
8Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore 119074, Singapore.
9Institute of Molecular Genetics of the ASCR, Prague 14200, Czech Republic.
10Hematology Division, Department of Internal Medicine, Ribeirao Preto Medical School, University of São Paulo, São Paulo 14020, Brazil.
11Institute of Biomedical Technologies, National Research Council (CNR), Pisa 56124, Italy.
12Department of Pathology, Weill Cornell University Medical Center, New York, NY 10065, USA.
13Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20817, USA.
14PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
15Department of Haematology-Oncology, University of Western Australia, Crawley, Western Australia 6009, Australia.
16Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
17Division of Hematology/Oncology, Montefiore Hospital, Bronx, NY 10461, USA.
18Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

¶Corresponding author. Email: elevanti@bidmc.harvard.edu (E.L.); csidgt@nus.edu.sg (D.G.T.)
* These authors contributed equally to this work.
† Present address: New England Cancer Specialists, Scarborough, ME 04074, USA.
‡ Present address: Novartis Institutes for BioMedical Research Inc., Cambridge, MA 02176, USA.
§ Present address: Merck Research Laboratories, Translational Medicine Research Centre, Singapore 138665, Singapore.

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.