Is there a relation between dietary linoleic acid and cancer of the breast, colon, or prostate? 1,2

that animals fed high-fat diets develop some types of tumors more rapidly than those fed low-fat diets (1). Animal studies published > 30 y ago focused on total fat and energy, whereas in the past 25 y polyunsaturated fats have been the focus—specifically vegetable oils, which often contain linoleic acid as the main essential fatty acid (2). Several different dietary fats and oils have been compared with respect to carcinogen-induced tumorigenesis in animals, and the results clearly show that polyunsaturated fats caused a significant increase in primary breast and colon tumors whereas saturated fats had little effect (3). Fish oils also contain substantial amounts of polyunsaturated fatty acids, but n23 fatty acids found in fish oils have biological properties that are quite different from those of n26 fatty acids found in linoleic acid. The influence of dietary fatty acids on breast, colon, and prostate tumorigenesis in animals was reviewed recently (4–6). In general, studies in rodents showed that high amounts of dietary fat led to an increased incidence of experimental breast, colon, and prostate tumors compared with animals fed moderate or low amounts of dietary fat. Moreover, linoleic acid enhanced, whereas n23 fatty acids decreased, primary tumorigenesis. Linoleic acid also appears to be pivotal in the spontaneous metastasis of experimental tumors (7). In addition, linoleic acid increased the proliferation of human breast tumor cells in culture (8). Despite these findings in experimental animal models, the role of dietary fat, particularly of linoleic acid in human tumorigenesis, remains controversial. Thus, investigation of the role of linoleic acid in cancer of the breast, colon, and prostate has become an important issue to address, as was done in a meta-analysis of human cancer at select sites, the results of which are published in this issue in a study by Zock and Katan (9). The study by Zock and Katan focuses on a meta-analysis of the results of published epidemiologic studies to assess the relation of polyunsaturated fat or linoleic acid and select sites of tumorigenesis. Although the authors found no increased relative risk from breast, colorectal, or prostate cancer on the basis of case-control or prospective cohort studies, several critical issues remain such that a definitive conclusion about public health policy concerning linoleic acid is at best tenuous. Epidemiologic studies have provided us with much of the information available about diet and cancer risk in humans. Some of the data were originally based on geographic studies in which migrants from areas with a low incidence of cancer acquired the same high incidence of the population in the area to which they migrated. Concerns remain about the validity and interpretation of the resulting data, as outlined in the article by Zock and Katan. In contrast, case-control and cohort studies control for some, but certainly not most, of the known important risk factors. For example, known risk factors for breast cancer include the following: 1) genetic predisposition, 2) age, 3) length of reproductive life, 4) parity, 5) obesity, 6) exogenous estrogen concentrations, 7) fibrocystic changes with atypical epithelial hyperplasia, and 8) carcinoma of the contralateral breast or endometrium (10). Thus, it becomes important in all analyses to try and control for these known risk factors and to seriously consider in the analyses only those studies that addressed known risk factors, particularly in case-control studies. Another problem not addressed in some of the epidemiologic studies was the range and amount of energy consumed from fat. Generally, the range was 30–45% of total energy. A basic flaw in many studies is that patients and control subjects had similar high fat intakes. If consumption is above some yet unidentified threshold level, such as 25% of energy from fat, then it seems reasonable that no effect would be observed. Not only is it important to study subjects who have a wide range of fat intakes (as a percentage of energy), but it is also important to have enough subjects with high fat intakes and enough with low fat intakes to obtain meaningful results. This is less of a problem in ecologic studies but remains a concern in most case-control and cohort studies. An associated problem is that cancer patients may alter their eating habits as a result of the cancer. Much of the data reported for linoleic acid are based on consumption of vegetable oils and polyunsaturated fats, of which linoleic acid is the main component. Thus, conclusions are based on an extrapolation of linoleic acid concentrations when polyunsaturated fatty acid has been reported. This may be an oversimplification of a complex problem in which all polyunsaturated fats have been aggregated into one group. The use of biomarkers, as indicated in the article by Zock and Katan as well as in other publications, partially helps to overcome the inherent problems associated with data based on food-