Polycomb Group Protein Bmi1 Is Required for Growth of RAF Driven Non-Small-Cell Lung Cancer

Matthias Becker,Katharina Luetkenhaus,Christian Korn,Robert Voswinckel,Arnold R Sienerth,Ulf R Rapp,Fatih Ceteci,Mauricio Rojas

doi:10.1371/journal.pone.0004230

Abstract

BackgroundWe have previously described a RAF oncogene driven transgenic mouse model for non small cell lung cancer (NSCLC). Here we examine whether tumor initiation and growth requires the stem cell self-renewal factor Bmi1.Principal FindingsIn order to evaluate Bmi1 function in NSCLC two founder lines that differ in incidence and latency of tumor formation were compared. Ablation of Bmi1 expression in both lines had a dramatically decreased tumor growth. As the line with shorter latency matched the life span of Bmi1 knock out mice, these mice were chosen for further study. The absence of Bmi1 did not decrease the number of tumor initiation in these mice as only the size and not the number of tumors decreased. Reduction in tumor growth resulted from an increase in cell death and decrease in cell cycle progression that corresponded with up-regulation of the p16INK4a and p19ARF.SignificanceThe data identifies Bmi1 as an important factor for expansion but not initiation of RAF driven NSCLC.

Highlights

Lung cancer is the leading cause of cancer death in the western world
Development of non small cell lung cancer (NSCLC) in BXB23 and BXB11 mice Lung adenoma formation was compared between BXB23 and
We show that BXB11 has a four fold higher incidence and shorter latency of adenomas allowing examination of advanced disease in the absence of Bmi1

Summary

Introduction

Lung cancer is the leading cause of cancer death in the western world. Based on histology two different types of lung cancer, non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are defined. 1) Induction of oncogene expression and deletion of tumor suppressor genes via adenovirus directed expression of Cre-recombinase [2,3,4,5]. This approach mimics occurrence of somatic mutations in adult tissues. 2) Constitutive oncogene expression in target cells through the use of cell type specific promoters [6,7]. The latter models may be more appropriate for gestationally acquired mutations. We have previously described a RAF oncogene driven transgenic mouse model for non small cell lung cancer (NSCLC). We examine whether tumor initiation and growth requires the stem cell self-renewal factor Bmi

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