Research ArticleCancer

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

Science Translational Medicine  03 Aug 2016:
Vol. 8, Issue 350, pp. 350ra104
DOI: 10.1126/scitranslmed.aad6066

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The right drug for the right tumor

The expression of a tumor suppressor called C/EBPα is often lost in non–small cell lung cancer, as well as in other cancer types. Yong et al. discovered that lung tumors deficient in C/EBPα often overexpress a particular oncogenic protein, BMI1, and that higher expression of BMI1 correlates with worse prognosis in this group of patients. The authors characterized the role of these two proteins and their interaction in lung cancer development, then used cell lines and a genetic mouse model to test a therapeutic approach, showing that a pharmaceutical inhibitor of BMI1 is effective against non–small cell lung cancer with low C/EBPα and high BMI1.

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.

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