This exploratory grant proposal is focused on investigating the functional relevance of Fra-1 protooncogene in lung tumor initiation and progression promoted by cigarette smoke carcinogens in vivo. Fra-1 is a dimeric partner of AP-1 transcription factor and regulates gene expression implicated in both normal and pathologic processes. Emerging data obtained from cell culture based studies have unequivocally demonstrated a causative role for Fra-1 in various cancer cell progression and invasion. We have shown that Fra-1 is strongly activated in lung epithelial cells by cigarette smoke, a major determinant of lung cancer, as well as tumor promoting mitogenic and pro-inflammatory stimuli. We have demonstrated that overexpression of Fra-1 promotes lung epithelial cell motility and invasion in vitro, but it requires other activated protooncogene(s) to impart its oncogenic potential in vivo in immunocompromised mice. Our preliminary results suggests that a matrix mettalloproteinase (MMP) mediated EGFR-activated Ras-ERK pathway is crucial for cigarette smoke induced Fra-1 expression. This pathway is also critical for Fra-1 induced lung epithelial cell motility and invasion. Based on these preliminary observations, we hypothesize that Fra-1is a critical determinant of lung tumorogenesis and progression in vivo and this transcription factor may provide a good target for lung cancer therapy. To test this hypothesis, we will determine whether Fra-1 protoconogene is a critical mediator of oncogenic K-Ras-induced lung tumor initiation and development in vivo (Specific Aim 1). In complimentary studies, we will investigate whether a targeted disruption of Fra-1 in lung epithelium inhibits lung tumor initiation and progression promoted by cigarette smoke carcinogens in vivo (Specific Aim 2). Conventional deletion of Fra-1 results in embryonic lethality. Thus, we will examine for the first time the specific roles of Fra-1 in lung neoplasms using mice with a Fra-1 "floxed" allele to conditionally delete Fra- 1 in lung cell types. The proposed studies are not only novel in terms of elucidating the biology and functions of Fra-1 but will also provide critical insights into the mechanistic basis underlying toxicant-induced lung tumor development. As protooncogenic transcription factors control expression of genes that promote lung tumor initiation and growth, these results could enable us to target Fra-1, or steps that specifically regulate Fra-1, as novel therapeutic agent(s) against cigarette smoke-induced lung neoplasms in subsequent studies.

Public Health Relevance

Lung tumor initiation and progression involves molecular changes such as silencing of tumor suppressor genes and deregulation of proto-oncogene expression and/or activation that promote cell growth and transformation leading to tumor development. Thus, specifically targeting the effector proto-oncogenic transcription factors activated by toxicants that promote lung tumor initiation, growth and/or maintenance may provide new therapeutic opportunities to develop novel treatment strategies for the prevention and/or treatment of second hand tobacco smoke -induced lung neoplasms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES018998-03
Application #
8212283
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Nadadur, Srikanth
Project Start
2011-01-10
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$196,250
Indirect Cost
$71,250
Name
University of Illinois at Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Rajasekaran, Subbiah; Reddy, Narsa M; Zhang, Wei et al. (2013) Expression profiling of genes regulated by Fra-1/AP-1 transcription factor during bleomycin-induced pulmonary fibrosis. BMC Genomics 14:381
Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I et al. (2012) The transcription factor encyclopedia. Genome Biol 13:R24