Smoke Exposure Alters Gene Expression and Estrogen Metabolism in the Lungs of Mice

Results may begin to explain gender differences in lung cancer incidence

June 1, 2010

PHILADELPHIA (June 1, 2010) – Lung cancer rates are increasing substantially in women, particularly in non-smoking women, with no known reason for the increase. Now researchers at Fox Chase Cancer Center may have uncovered a critical piece in the puzzle.

Working in a mouse model of smoking-induced lung cancer, Margie Clapper, PhD, Co-leader of the Cancer Prevention and Control Program at Fox Chase Cancer Center, and colleagues found that smoke triggers rapid changes in gene expression in the lungs of female mice, including increasing expression of a network of genes involved in estrogen metabolism.

Based on these data, published in the June 2010 issue of Cancer Prevention Research, the team hypothesizes that estrogen metabolism may contribute to lung cancer in non-smoking women as well.

Following smoke exposure for 3, 8, or 20 weeks, Sibele Meireles, PhD, an assistant member in the Clapper Lab, found that 10 genes were differentially expressed in the lungs of smoke-exposed female mice as compared with control animals. The gene most affected by smoke was cytochrome P450 1b1 (Cyp1b1), which is responsible for breaking down toxins and is a key enzyme for estrogen metabolism. Additionally, when the team looked at networks of genes, they saw that genes involved in estrogen metabolism were altered within the lungs of animals exposed to smoke as compared to controls.

“We found a link between hormones and lung cancer through Cyp1b1 when we weren’t looking for it -very exciting,” says Clapper. “Previous work has suggested that estrogen may play a role in lung cancer, but no one has shown that smoke can actually accelerate the metabolism of estrogen within the lungs;  the suggestion from our data.”

The investigators hypothesize that estrogen plays a role in the formation and progression of lung cancers, similar to the role it plays in some breast cancers. The idea is consistent with previous studies indicating that women with lung cancer who take hormone replacement therapy have a poorer prognosis than women who do not, regardless of their smoking history. Additionally the observation that estrogen can be detected within the lungs and that its metabolism is upregulated in the lungs of smoke-exposed female mice may provide new insight into why lung cancer is rising so quickly in women, including non-smoking women world wide, according to Clapper.

The investigators decided to look at gene expression changes after short-term smoke exposure in hopes of finding ways to intervene in or reverse the process. “If we can identify the earliest events that happen within the lungs when you begin to smoke, we might be able to use therapeutics to block them as well as lung cancer,” says Clapper, who runs a chemoprevention laboratory at Fox Chase.

First author on the study is Sibele I. Meireles of Fox Chase. Co-authors include Suraj Peri, Karthik Devarajan, Michael Slifker, Stacy L. Mosier, and Jing Peng of Fox Chase, Gustavo H. Esteves of University of Paraíba State, Brazil, Roberto Hirata, Jr., and Jordao Neves of the University of São Paulo, Brazil, Manicka V. Vadhanam, Harrell E. Hurst, and Ramesh C. Gupta of the University of Louisville, Kentucky, Luiz F. Reis of the Hospital Sírio Libanês, Brazil, and C. Gary Gairola of the University of Kentucky in Lexington.

For more information on the current trends in lung cancer in women, please see a review by Clapper and colleagues in the December 2009 issue of Seminars in Oncology.


The Hospital of Fox Chase Cancer Center and its affiliates (collectively “Fox Chase Cancer Center”), a member of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.
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