MISSION

Presented at the Annual Meeting of the American Association for Cancer Research, April 2006.
Zhou W, Heist RS, Liu G, Neuberg DS, Asomaning K, Su L, Wain JC, Lynch TJ, Giovannucci E,
Christiani DC. Polymorphisms of vitamin D receptor and survival in early-stage non-small cell lung
cancer patients. Cancer Epidemiol Biomarkers Prev 2006;15:2239-45.
Zhou W, Heist RS, Liu G, Park S, Neuberg DS, Asomaning K, Wain JC, Lynch TJ, Christiani DC.
Smoking cessation before diagnosis and survival in early stage non-small cell lung cancer patients. Lung
Cancer 2006;53:375-80.
Zhou W, Liu G, Park S, Wang Z, Wain JC, Lynch TJ, Su L, Christiani DC. Gene-smoking interaction
associations for the ERCC1 polymorphisms in the risk of lung cancer. Cancer Epidemiol Biomarkers Prev
2005;14:491-496.
Zhou W, Park S, Liu G, Miller DP, Wang LI, Pothier L, Wain JC, Lynch TJ, Giovannucci E, Christiani
DC. Dietary iron, zinc, and calcium and the risk of lung cancer. Epidemiology 2005;16:772-779.
Zhou W, Suk R, Liu G, Park S, Neuberg DS, Wain JC, Lynch TJ, Giovannucci E, Christiani DC. Vitamin
D is associated with improved survival in early-stage non-small cell lung cancer patients. Cancer
Epidemiol Biomarkers Prev 2005;14:2303-2309.
THE ROLE OF THE TRANSCRIPTION FACTOR C/EBP ALPHA IN NORMAL LUNG DEVELOPMENT AND IN MURINE
MODELS OF LUNG CANCER AND TOBACCO-DAMAGED AIRWAY EPITHELIUM
Elena Levantini, PhD; Harvard University; YCSA 2006
Lung cancer is the principal cause of worldwide cancer mortality. Advances in lung cancer therapy
require a greater understanding of its molecular pathogenesis. Previously, Dr. Levantini showed that the
transcription factor CCAAT/enhancer binding protein alpha (C/EBPa) is downregulated in NSCLC
patients. Furthermore, using a mouse model where excision of C/EBPa is under the control of the
Surfactant Protein C (SPC) promoter (C/EBPa SPC-deleted) mice, Dr. Levantini showed that this
transcription factor regulates alveolar type II cell differentiation. Subsequently she investigated the effects
of C/EBPa downregulation in predisposing the mouse lung epithelium to tumorigenesis and
demonstrated that the C/EBPa SPC-deleted mouse lung epithelium displays increased numbers of
proliferating cells and decreased numbers of apoptotic cells. The PI also identified potential target genes
that may elucidate the mechanisms by which C/EBPa acts. For example, the cell survival gene Gli-1, a
transcription factor downstream of sonic hedgehog signaling, is upregulated and its contribution in
promoting the malignant phenotype promises to be important biologically and therapeutically. Therefore,
Dr Levantini and collaborators hypothesized that loss of C/EBPa in the adult lung epithelium is a
transforming event. Consistently, their data indicate that C/EBPa is detected at the level of
bronchoalveolar stem cells, a pulmonary population that has been recently linked to adenocarcinoma
initiation. Moreover, Dr Levantini has data from two different lung conditional models [SPC and Clara
Cell (CC10)-driven excision] that supports her hypothesis that C/EBPa is a lung tumor suppressor, in that
they develop adenocarcinoma. Furthermore, their data indicate that Gli-1, a transcriptional effector of the
sonic hedgehog pathway, is highly active only in C/EBPa-deleted pulmonary cells that, according to her
hypothesis, represent the cells of origin of the lung adenocarcinomas found in her murine models. Gli-1
expression peaks in the lung stem cells, it is reduced in progenitor cells, but it is still active in the
adenocarcinoma. Overall, Dr Levantini’s data show that loss of C/EBPa might increase the susceptibility
to lung cancer development and supports the hypothesis that C/EBPa acts as a tumor suppressor for lung
cancer in vivo.
FAMRI Supported Publications
Basseres D, Levantini E, Ji H, Monti S, Elf S, Dayaram T, Fenyus M, Kocher O, Golub T, Wong KK,
Halmos B, Tenen DG. Respiratory failure due to differentiation arrest and expansion of alveolar cells
following lung-specific loss of the transcription factor C/EBP-alpha in mice. Mol Cell Biol
2006;26:1109- 1123.
Koschmieder S, D’Alo F, Radomska H, Schoneich C, Chang JS, Konopleva M, Kobayashi S, Levantini E,
Suh N, DiRuscio A, Voso MT, Watt JC, Santhanam R, Sargin B, Kantarijan H, Andreeff M, Sporn MB,
Perrotti D, Berdel WE, Muller-Tidow C, Serve H, Tenen DG. CDDO induces granulocytic
differentiation of myeloid leukemic blasts through translational upregulation of p42 CCAAT enhancer
binding protein alpha. Blood 2007; 110(10):3695-705.
Koschmieder S, Halmos B, Levantini E, Tenen DG. Dysregulation of the C/EBPa differentiation pathway
in human cancer. Journal Clinical Oncology 2009;27(4):619-28.
Kubo S, Levantini E., Kobayashi S, Kocher O, Halmos B, Tenen DG, Takahashi M. In vitro three-
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