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The transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) is a tissue-specific differentiation factor and it plays a major role in the terminal differentiation of many tissues. C/EBPα is highly expressed in type II pneumocytes as well as cells of the bronchial epithelium and it regulates the expression of several genes during lung development. Abnormal proliferation and lack of differentiation of type II pneumocytes are also seen in C/EBPα conditional knockout mice with lung cancers developing in some of these adult mice. Our group demonstrated that C/EBPα is down-regulated in over 60% of lung cancer cell lines and in over half of non-small cell lung cancers (NSCLCs). Induction of this gene’s expression in lung cancer cell lines led to growth arrest, apoptosis, and cellular differentiation. Therefore, C/EBPα is a novel tumor suppressor gene in lung cancer with a potential to be targeted for therapy. The main mechanism of inactivation of C/EBPα in lung cancer has been shown to involve epigenetic changes of the upstream promoter of this gene. To attempt to specifically target the pathways abrogated in tumors with down-regulation of C/EBPα, we sought to by-pass the effects of this transcription factor by inducing other members of the C/EBP family. We previously reported that in a model of down-regulation of C/EBPα in myeloid cells, another C/EBP member - C/EBPβ - was able to induce normal granulocytic differentiation in emergency states. To explore the role of C/EBPβ in the lung, we created an inducible lung cancer cell line (H358, bronchoalveolar carcinoma with endogenous down-regulation of C/EBPα) expressing C/EBPβ under the control of β-estradiol. We observed that nuclear induction of C/EBPβ led to both proliferation arrest as well as morphologic changes consistent with cellular differentiation. These changes were similar to the ones seen by the induction of C/EBPα. Next, we tested for compounds that could induce C/EBPβ in different NSCLC cell lines and observed that the synthetic triterpenoids, CDDO-Im and CDDO-Me were able to induce C/EBPβ expression and also led to analogous morphologic changes as well as increase in surfactant proteins (hallmark of a more differentiated state). Ongoing studies are trying to better identify the similarities and disparaties between the roles of C/EBPα and C/EBPβ in NSCLC. These studies might provide a novel treatment strategy for lung cancer.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA