Early changes in gene expression induced by tobacco smoke: Evidence for the importance of estrogen within lung tissue.
Lung cancer is the leading cause of cancer deaths in the United States, surpassing breast cancer as the primary cause of cancer-related mortality in women. The goal of the present study was to identify early molecular changes in the lung induced by exposure to tobacco smoke and thus identify potential targets for chemoprevention. Female A/J mice were exposed to either tobacco smoke or HEPA-filtered air via a whole-body exposure chamber (6 h/d, 5 d/wk for 3, 8, and 20 weeks). Gene expression profiles of lung tissue from control and smoke-exposed animals were established using a 15K cDNA microarray. Cytochrome P450 1b1, a phase I enzyme involved in both the metabolism of xenobiotics and the 4-hydroxylation of 17beta-estradiol (E(2)), was modulated to the greatest extent following smoke exposure. A panel of 10 genes were found to be differentially expressed in control and smoke-exposed lung tissues at 3, 8, and 20 weeks (P < 0.001). The interaction network of these differentially expressed genes revealed new pathways modulated by short-term smoke exposure, including estrogen metabolism. In addition, E(2) was detected within murine lung tissue by gas chromatography-coupled mass spectrometry and immunohistochemistry. Identification of the early molecular events that contribute to lung tumor formation is anticipated to lead to the development of promising targeted chemopreventive therapies. In conclusion, the presence of E(2) within lung tissue when combined with the modulation of cytochrome P450 1b1 and other estrogen metabolism genes by tobacco smoke provides novel insight into a possible role for estrogens in lung cancer.
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Sibele I
SI
Meireles
Gustavo H
GH
Esteves
Roberto
R
Hirata
Suraj
S
Peri
Karthik
K
Devarajan
Michael
M
Slifker
Stacy L
SL
Mosier
Jing
J
Peng
Manicka V
MV
Vadhanam
Harrell E
HE
Hurst
E Jordao
EJ
Neves
Luiz F
LF
Reis
C Gary
CG
Gairola
Ramesh C
RC
Gupta
Margie L
ML
Clapper
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001273:Atmosphere Exposure Chambers; D015415:Biomarkers; D056931:Cryptochromes / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D065633:Cytochrome P-450 CYP1B1; D004790:Enzyme Induction / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000096:biosynthesis; D004967:Estrogens / Q000378:metabolism*; D002393:Estrogens, Catechol; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D008861:Microsomes / Q000201:enzymology; D009376:Neoplasms, Hormone-Dependent / Q000209:etiology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D011897:Random Allocation; D012907:Smoking / Q000378:metabolism; D013997:Time Factors; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D015415:Biomarkers; C538964:Cry1 protein, mouse; D056931:Cryptochromes; D004967:Estrogens; D002393:Estrogens, Catechol; D012333:RNA, Messenger; D014028:Tobacco Smoke Pollution; D004958:Estradiol; C014036:4-hydroxyestradiol; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1