Smoking, NAT2 Polymorph isms, and Breast Cancer Risks
ABSTRACT & COMMENTARY
Synopsis: Smoking is an important risk factor for breast cancer among postmenopausal women who are slow acetylators but not for those who are fast acetylators. This heterogeneity likely explains why epidemiological studies have yielded inconsistent results.
Source: Ambrosone CB, et al. JAMA 1996;276:1494-1501.
No study has considered genetic variability as the explanation for why some individuals are susceptible to cigarette smoke carcinogens. Aromatic amines found in tobacco smoke are mutagenic and carcinogenic, and they are concentrated in nipple secretions and breast tissue. These aromatic amines are detoxified by enzymes, including N-acetyltransferase 2 (NAT2). The activity of NAT2 varies within the population. Slow acetylators are at increased risk for urinary bladder cancer, particularly with occupational exposure to aromatic amines. In a recent study, Ambrosone et al hypothesized that genetic differences called polymorphisms in NAT2 result in decreased capacity to detoxify carcinogenic aromatic amines in cigarette smoke and thus would increase susceptibility to breast cancer in this subpopulation. The study population consisted of 617 premenopausal and 933 postmenopausal white women from New York State in whom NAT2 status was determined by polymerase chain reaction followed by restriction length polymorphism analysis. Hormone replacement therapy was not associated with breast cancer risk in this study. Slightly fewer than half of the women were rapid acetylators. Among postmenopausal women, cigarette smoking and NAT2 genotype interacted with breast cancer risk. Neither acetylator status nor smoking status alone was independently associated with breast cancer risk, but women who were slow acetylators and who had smoked more than a pack a day for 20 years had a risk of breast cancer seven times greater than for women who were fast acetylators. Smoking intensity conferred more risk than duration. Slow acetylators who began smoking at or before the age of 16 years were at highest breast cancer risk.
COMMENT BY SARAH L. BERGA, MD
I was surprised and delighted by the brilliance of this study. It shows us that the risk for breast cancer can be conferred through a number of different mechanisms. In this case, Ambrosone et al have revealed that even known carcinogens do not behave as such in women who are "fast acetylators" and can get rid of the offending agents. The same might be true for any number of other agents causally linked to breast cancer. For instance, much attention has been focused upon hormone and reproductive exposures. But there is more to hormones than the actual circulating concentrations to which one is exposed across a life span. Hormone action also must be considered. Apparently, there is known population variation in postreceptor events and metabolic clearance rates for all hormones. In epidemiological studies, populations are treated as if they are composed of homogenous units; it is difficult to account for molecular and genetic heterogeneity unless one knows to look for it. Without an appreciation of pertinent heterogeneity, studies yield inconsistent results and foster therapeutic confusion. This study is a beautiful example of how heterogeneity can be taken into account and contribute to our understanding about the impact of a given agent. One can only hope that we will discover more about similar subtleties in hormone action so that practitioners can give wise counsel. For instance, decisions regarding whether to give hormones to a woman who has survived breast cancer tend to rely on whether the cancer had estrogen receptors. But the mere presence of receptors will not tell whether the cancer will respond to estrogen exposure by growing and metastasizing. Perhaps some women should forego the benefits of hormones, but until we understand more about postreceptor events and the cellular pathophysiology of breast cancer, we will be mired in therapeutic confusion. The authors of this study point out that in women who are fast acetylators, smoking may actually provide some protection against breast cancer by reducing estrogen exposure. Thus, the final effect of any potentially carcinogenic agent has as much to do with the host as with the agent itself.
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