"This study shows that a link between smoking and breast cancer exists, and may have important implications for certain populations," said Peter G. Shields, M.D., one of the authors of the study from NCI's Laboratory of Human Carcinogenesis. "For most scientists, smoking has not been among the list of breast cancer risk factors."
"This study shows that genetic susceptibility to carcinogens in cigarette smoke is a risk factor for breast cancer and may help to resolve the inconsistencies in previous studies," he continued. "It also implies that an important number of the world's women are susceptible to breast cancer if they are exposed to tobacco smoke."
The investigators hypothesized that smokers with a decreased ability to detoxify mutagens in cigarette smoke might represent a subset of smokers at increased risk for breast cancer because mutagens from cigarette smoke come into direct contact with breast epithelial cells and can cause mutations.
To test their hypothesis, the researchers looked at the enzyme, N-acetyltransferase (NAT2), which is known to play a role in detoxifying aromatic amines, one class of mutagens found in tobacco smoke. Previous work showed that distinct mutations in the gene for NAT2 play a role in the enzyme's effectiveness. People with an normal enzyme are called rapid acetylators, whereas people with genetic mutations who produce a weakened form of the enzyme are slow acetylators.
In this study, researchers analyzed mutations in the NAT2 gene using DNA from blood samples of 304 Caucasian women with primary breast cancer and 327 community controls who were enrolled in a case control study completed in 1991 by the State University of New York at Buffalo.
Fifty-seven percent of pre-menopausal and 55 percent of post-menopausal women were classified as slow acetylators. Neither slow acetylators nor heavy smokers by themselves had an increased risk of breast cancer before or after menopause. But post-menopausal women who were both slow acetylators and heavy smokers had an increased incidence of breast cancer. The number of cigarettes smoked daily and smoking at young age rather than number of years smoked, appeared to confer the most risk in this latter group.
For example, post-menopausal women who were slow acetylators and who smoked more than a pack a day for 20 years, had 3.9 times greater risk than the non-smoking slow acetylators. Similarly, one part of the analysis showed that post-menopausal women who began smoking at or before age 16, had three times the breast cancer risk of women who began smoking at a later age. Neither smoking intensity nor duration was associated with increased risk in post-menopausal rapid acetylators.
Christine B. Ambrosone, Ph.D., the principal investigator, who is now at the National Center for Toxicological Research in Jefferson, Ark., commented: "If further investigations in other study populations reveal similar associations between the NAT2 genotype, cigarette smoking and breast cancer risk, it would be an important insight into the etiology of the disease. It is one more cancer site in which smoking has been implicated."
The authors speculate that the differences between pre- and post-menopausal women could be explained by the fact that pre-menopausal women have had fewer years of exposure to tobacco or not enough elapsed time for the entire carcinogenic process to develop. However, since pre- and post-menopausal breast cancer are different types of cancers, NAT2 mutations may not be a risk factor at all for pre-menopausal breast cancer.
The results may explain in part the worldwide geographic variability in breast cancer incidence. Slow acetylators comprise about 65-90 percent of people of Middle Eastern descent, 55 percent of Caucasians, 35 percent of U.S. African-Americans, and 10-20 percent of Asians.
Previous studies have shown that NAT2 slow acetylators who smoke also may be more susceptible to bladder cancer. Even though smokers and NAT2 slow acetylators independently have been shown to have an increased bladder cancer risk, studies comparing smoking NAT2 slow acetylators with smoking NAT2 fast acetylators have had inconsistent results.
"Clearly these results need to be corroborated by other investigators," said Shields. "But it may be that some portion of breast cancer cases may be due to ineffective mechanisms of inactivating mutagens. At the very least, our data provide another good reason not to smoke, particularly at an early age."
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1The title of the study is "Cigarette Smoking, N-Acetyltransferase Genetic Polymorphisms, and Breast Cancer Risk." The authors are Christine B. Ambrosone, Jo L. Freudenheim, Saxon Graham, James R. Marshall, John E. Vena, John R. Brasure, Arthur M. Michalek, Rosemary Laughlin, Takuma Nemoto, Kari A. Gillenwater, Anita M. Harrington, and Peter G. Shields.