Public Release: 

Genetic Makeup May Explain Why Some Women Smokers Develop Breast Cancer While Others Don't, UB Study in JAMA Reports

University at Buffalo

BUFFALO, N.Y. -- The answer to the question of whether smoking increases a women's risk of developing breast cancer may lie in her genes, researchers at the University at Buffalo and the National Cancer Institute have found.

Results of their study, the first to consider genetic variability as a factor in a person's breast-cancer susceptibility to the carcinogens in cigarette smoke, will be published in the Nov. 13 issue of the Journal of the American Medical Association.

The results showed that postmenopausal women born with the slow-acting gene for N-acetyltransferase (NAT2), an enzyme known to detoxify carcinogenic compounds in cigarette smoke, and who smoked more than a pack of cigarettes a day 20 years before diagnosis, had seven times the risk of developing breast cancer than women born with the fast-acting gene.

The risk was highest for women who began smoking before the age of 18.

The two genotypes are referred to as slow or fast acetylators. No relationship was found between genotypes and risk of breast cancer among premenopausal women who smoked.

Christine Ambrosone, Ph.D., who conducted the research while a post-doctoral fellow in the UB Department of Social and Preventive Medicine, said the findings provide new insight into why previous epidemiologic studies may have failed to show a consistent association between cigarette smoking and breast cancer, when the association is clear in many other organs.

"These findings on breast cancer require substantial replication, but the potential implications may be important," said Ambrosone, now a research epidemiologist at the National Center for Toxicological Research in Arkansas.

"If further investigations in other study populations reveal similar associations between NAT2 genotype, cigarette smoking and breast-cancer risk, it would be an important insight into the etiology of this disease," she added. "It is one more cancer site in which cigarette smoking has been implicated."

Earlier studies showed that smokers with the slow-acetylation genotype for NAT2 had higher levels of tobacco's carcinogenic compounds in their bloodstream, and were at higher risk of developing bladder cancer, a disease known to be associated with cigarette smoking. Components of cigarette smoke also have been shown to cause breast cancer in rodents.

To investigate the possibility that slow-versus-fast acetylation could affect the incidence of breast cancer among smokers, the researchers used data from an earlier case-control study of the disease. Extensive data were gathered on medical and reproductive history and blood samples were collected for DNA analysis. Researchers were able to obtain genetic data from the blood samples of 398 postmenopausal women (185 cases and 213 controls), and 233 premenopausal women (119 cases and 213 controls). All participants were Caucasian.

A food-consumption record for the two years prior to the interview and a lifetime smoking history also were obtained.

Analysis showed a strong association between smoking and breast cancer in postmenopausal women with the slow-acetylation genotype. The risk was highest for women who began smoking before the age of 18. Intensity of smoking -- the number of cigarettes smoked per day at two, 10 and 20 years prior to the interview -- appeared to be more significant than duration of smoking. Among slow acetylators, there was a four-fold increase in risk for women who smoked more than a pack a day in both the distant and recent past.

Among rapid acetylators, there were no significant associations between breast-cancer risk and total years smoked, packs per average year or pack-years smoked. Neither genotype nor smoking history was associated independently with cancer risk.

Ambrosone said that the differences in cancer risk for pre- and postmenopausal women could be caused by a number of factors, among them:

  • Pre- and postmenopausal breast cancer may be different diseases, with different etiologic factors
  • Younger women may have smoked for a shorter period of time
  • Not enough time may have elapsed among premenopausal smokers to allow the entire carcinogenic process to develop
  • Other enzymes may mediate the NAT2 effect
Additional researchers contributing to the study were Jo L. Freudenheim, Ph.D.; Saxon Graham, Ph.D.; John E. Vena, Ph.D.; John R. Brasure; Arthur M. Michalek, Ph.D.; Rosemary Laughlin, Ph.D.; James R. Marshall, Ph.D., and Takuma Nemoto, M.D., all from the UB Department of Social and Preventive Medicine.

Also, K. Gillenwater, Anita Harrington and Peter G. Shields, M.D., from the

Laboratory of Human Carcinogenesis, National Cancer Institute.

Portions of this study were presented at the American Association for Cancer Research meeting in Toronto in March.

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