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Smoking, breast cancer and tobacco metabolizing genes

Institution: Childrens Hospital, Los Angeles
Investigator(s): Jan Van Tornout, M.D., M.S.
Award Cycle: 1999 (Cycle 8) Grant #: 8RT-0111 Award: $120,000
Subject Area: Epidemiology
Award Type: Research Project Awards

Initial Award Abstract
Does smoking increase the risk for breast cancer? This simple question has yet to be conclusively answered. One of the reasons why this is such a controversial issue, is that the effect of smoking on the breast tissue is influenced by a woman's own 'household' genes. This helps explain why a particular person will smoke and develop lung cancer for instance, whereas another person who smokes as much, may never develop cancer. To date, a definitive answer regarding the relationship between smoking and female breast cancer has not been universally accepted.

The major goal of this study is to help resolve the existing controversies regarding the association between smoking and breast cancer risk in women. We think that smoking does play a role in he development of breast cancer but mainly in women who have certain genetic variants that facilitate the metabolism of tobacco smoke, and render them more susceptible to the cancer-inducing effects of tobacco smoke. Therefore, we want to compare the frequencies of he tobacco-metabolizing genes among women with breast cancer who smoke, to the frequencies of the same genes in women with breast cancer who are non-smokers.

If we are correct in our hypothesis, we would expect to find a higher number of those variants of the tobacco metabolizing genes among the women with breast cancer who smoked compared to the frequencies of these genes among women with breast cancer who are not smokers. If this were to be the case, it would suggest that smoking is a risk factor for developing breast cancer in this population. If so, then this would be an extremely important public health issue since breast cancer among these women would then become more preventable by implementing smoking cessation strategies.

Last but not least, this exploratory study is very cost-effective, since it builds on a funded study by the State of California Breast Cancer Research Program to investigate the effect of oral contraceptive use on the risk of breast cancer in young women.

Final Report
The effect of smoking on the pathogenesis of female breast cancer remains controversial with various studies showing conflicting results regarding the risk for developing breast cancer among pre- and postmenopausal women-smokers. This may be partially due to the fact that thus far, the question whether smoking affects the risk of developing breast cancer has been investigated using traditional ca-co interview studies that correlate exposure to smoking with the risk of developing breast cancer.. With small relative risks (RR), as for female breast cancer in relationship to smoking, it may be impossible to rule out confounding by family history, reproductive history, life style (diet, exercise), or other factors.. Thus a definite causal relationship between breast cancer and smoking has not been universally accepted, and additional studies of the same design are unlikely to clarify this situation.

Genetic polymorphisms in the phase I & II genes coding for metabolizing enzymes (MBE) responsible for the activation and detoxification of tobacco-derived procarcinogens, can modify the risk for developing a tobacco-induced cancer. This may explain the interindividual variation in susceptibility to the effects of tobacco and preliminary studies have suggested that women-smokers carrying the 'at-risk' phase I and/or II genotypes may be at a higher risk of breast cancer than women with the wildtype allele(s).

In this pilot study under the Shannon Award, we have genotyped the polymorphic smoking metabolizing genes in 192 women with breast cancer. We are correlating the genotypes with the smoking information as it progressively becomes available. The genotypes that have been completed include the metabolic phase I enzyme CypIAI (a substrate inducible enzyme involved in the metabolism of PAH), the metabolic phase II enzyme GST-Pi, and the NAT2 system of enzymes. The latter are all specifically involved in the metabolism of smoking related carcinogens.

In addition to the originally proposed work under the award, we genotyped for the polymorphic CYP3A5 gene, one of the most abundant genes in the liver that is also involved in smoking metabolism as well as in the metabolism of estrogens. Furthermore we genotyped for the IGF-1 (a polymorphic growth factor) for it has been associated with breat cancer etiology in other studies and we wanted to see whether there could be an association with smoking status and IGF-1 polymorphism. Lastly, we genotyped the polymorphic DNA repair gene XRCC3 involved in repair of alkylator-type DNA damage as the one induced by smoking. The results of the 192 cases that were genotyped are attached in the appended file.

The hypothesis under which we are conducting this work is that smoking plays a role in the ethiopathogenesis of breast cancer that occurs in the subgroup of women who are genetically predisposed to be more susceptible to the effects of tobacco; i.e., women who are homozygous for the'at-risk' genotypes involved in the metabolism of tobacco related (pro)carcinogens. In essence this work will allow us to determine whether there is an interaction between smoking, the "at-risk" phase I & II polymorphic genotypes and breast cancer risk. If our hypothesis proves correct, we should find an excess in prevalence of these'at-risk' polymorphic tobacco-metabolizing genotypes in smokers compared to non-smokers with breast cancer.