Lung cancer is the leading cause of cancer-related death in the United States. Cigarette smoke (CS) is a well- known risk for lung cancer. Inflammation has clearly emerged as a key process contributing to the development of lung and other cancers. However, the gene targets and pathways modulated by inflammation that impact cancer development have not been clearly elucidated. This application builds on emerging studies from the literature and by our group that implicate an important role for MUC1 in linking inflammation and carcinogenesis. The central hypothesis of this application is that airway inflammation resulting from CS induces MUC1 expression, which triggers lung cancer development through potentiation of the EGFR- mediated Akt and extracellular signal-regulated kinases (ERK) pathways. This hypothesis will be tested in the three Specific Aims: 1. To determine if the pro-inflammatory cytokine TNF? mediates CS-induced MUC1 expression in bronchial epithelial cells and if MUC1 potentiates cell transformation;2. To determine if MUC1 facilitates CS-induced bronchial epithelial cell transformation through potentiation of the EGFR-mediated Akt and ERK pathways;3. To investigate the role of MUC1 in CS-induced lung carcinogenesis with CS-derived carcinogen benzo(a)pyrene (BaP)- and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced A/J lung cancer models and in a xenografted human lung tumor model in nude mice. Successful completion of this study will likely reveal a new molecular mechanism of CS-induced lung carcinogenesis that involves Muc1 and will provide new insights into how inflammation influences cell transformation and tumor development and could identify novel targets for prevention and intervention therapy for lung cancer.

Public Health Relevance

The proposed research will likely unravel a new molecular mechanism of tobacco smoke-induced lung carcinogenesis. The outcome from this study may lead to new strategies for lung cancer prevention and therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017328-03
Application #
8240086
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Reinlib, Leslie J
Project Start
2010-08-09
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$427,112
Indirect Cost
$205,729
Name
Lovelace Biomedical & Environmental Research
Department
Type
DUNS #
045911138
City
Albuquerque
State
NM
Country
United States
Zip Code
87108
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