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Jill M. Seigfried, Ph.D.

University Of Pittsburgh-Led Team Finds Biological Reason For Women’s Increased Risk Of Smoking-Related Lung Cancer

PITTSBURGH, January 4, 2000 — A gene for a protein that fuels lung cancer growth is more active in women than in men, according to a report by a University of Pittsburgh-led research team, which also discovered that nicotine found in cigarettes induces gene activity.

Their report, published in the Jan. 5 issue of the Journal of the National Cancer Institute, offers the first biological explanation for the greatly increased risk women face versus men in developing lung cancer. If substantiated in future studies, this research could provide a valuable marker for predicting which women are most likely to develop the disease or dangerous pre-cancerous changes.

The research team found in women an increase in the expression of the gene for gastrin-releasing peptide receptor (GRPR), which is found on the surface of cells lining the lung. When stimulated by its hormone, gastrin-releasing peptide, GRPR triggers cell proliferation typically seen in lung cancer. The Pittsburgh-based research team also discovered that nicotine found in cigarettes stimulates expression of the GRPR gene in lung cells.

"Our research strongly suggests that women are likely to develop lung cancer after much less smoking exposure than men and much earlier in life, regardless of their smoking history," said Sharon Shriver, Ph.D., principal investigator on the study who is now an instructor of biology at the University Park campus of Pennsylvania State University. "The take-home message, especially for teenage girls, is that they should stop smoking or, better yet, never start."

"Prior reports have suggested various molecular markers associated with an increased risk in women smokers; however, ours is the first study to provide a mechanism for cancer promotion in this population," said Jill Siegfried, Ph.D., senior author on the paper, professor of pharmacology at the University of Pittsburgh and co-director of the University of Pittsburgh Cancer Institute’s Lung Cancer Center. "This study also validates previous population studies suggesting that women are at substantially increased risk of smoking-related lung cancer."

The scientists looked at normal lung tissue samples from 38 women and 40 men, including 58 patients with lung cancer. They found that 55 percent of the non-smoking women and 75 percent of women with less than 25 pack-years of smoking expressed GRPR mRNA (a precursor of the GRPR protein). (A pack-year is one package of 20 cigarettes smoked each day for one year). By contrast, none of the male nonsmokers and only 20 percent of men with a 25 pack-year or less smoking history expressed GRPR mRNA.

The difference between the sexes is related to the location of the GRPR gene on the X chromosome, according to the investigators. Women have two X chromosomes, whereas men have one copy. Normally in a woman, genes are inactivated on one of the X chromosomes. However, both copies of the GRPR gene are active in women.

"Women may be at increased risk because they have two copies of the GRPR gene that are inducible by nicotine, whereas men only have one nicotine-inducible copy. Another possibility is that one GRPR gene in women is chronically active, even before exposure to nicotine. In fact, both mechanisms could be at work," remarked Dr. Shriver.

Because they did not measure exposure to passive smoke, the scientists could not distinguish the role that such exposure might play in activating the GRPR gene in women. Future large-scale studies are addressing this question and others to determine whether GRPR gene expression can provide a reliable marker of lung cancer risk. Already, the scientists have found that GRPR expression in circulating blood cells mirrors that seen in lung cells, thus possibly providing a minimally invasive way to measure lung cancer risk.

This research was supported by grants from the National Cancer Institute, the American Lung Association and the University of Pittsburgh Cancer Institute.

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