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2. Diet, body size, and breast cancer

A number of reviews on the associations between diet, obesity and risk of breast cancer have been published during recent years (Hunter and Willett 1996, Steinmetz and Potter 1996, Kohlmeier and Mendez 1997). Thus, the purpose of this section is not to offer an exhaustive review on the topic. Instead, the emphasis is on background to aid the reader in understanding the contents of Studies I-V presented in this dissertation.

2.1 Diet and carcinogenesis

Cancer is a cell disorder in which the structure and function of genetic information coded in the DNA have changed. Such a malignant transformation may increase the capacity of cells to grow rapidly in an uncontrolled manner, producing abnormal growth. Although more than a hundred cancer types have been identified, the basic causes of tumor development seem to be quite similar. The model of chemical carcinogenesis and the role of diet in this process are briefly presented below. The presentation is based mainly on the following publications: Sorsa (1985), Weinberg (1996), and the World Cancer Research Fund (1997).

Covalent binding of the chemical carcinogen with DNA appears to be the most important event in carcinogenesis. Several well-known carcinogens have been identified, such as cigarette smoke, and exposures in the diet and workplaces (Figure 1). These factors may cause direct DNA damage (e.g., tobacco), or it is possible that procarcinogens (e.g., N-nitroso compounds in the diet) are converted into carcinogens through normal metabolic pathways. The common feature of many chemical carcinogens is that they are strong electron-deficient molecules (electrophilic), which react easily with electron-rich molecules such as proteins and DNA. The electrophilic metabolite that binds to cellular DNA is termed an "ultimate carcinogen" (Simic and Bergtold 1991). The enzymatic biotransformation processes (phase I enzymes, including the cytochrome P450 system) tend to make foreign chemicals more water-soluble so that they can be excreted in urine, but at the same time enzymes may change a particular chemical to a reactive form that binds to DNA. Phase II detoxification enzymes, found especially in plant compounds, may prevent tumor development by detoxifying carcinogens in the diet.

Figure 1. Model of chemical carcinogenesis (adapted from Sorsa 1985, World Cancer Research Fund 1997).

Although there is no clear evidence of the multistep carcinogenic process in the mammary epithelial cells, many chemical carcinogens that are lipophilic substances (e.g., heterocyclic amines) can be stored in the adipose tissue of the breast (Morris and Seifter 1992, Ghoshal and Snyderwine 1993). It has also been suggested that hormones stimulate mitotic division of initiated cells at a promotional stage of breast carcinogenesis.

The three stages of carcinogenesis (initiation, promotion, and progression) have been demonstrated in animal models. In human cancer development, these stages are not necessarily sequential, and they may overlap. When the probability of cancer is assessed, the balance between factors that induce or prevent mutations is important.

Dietary factors may affect carcinogenesis in different ways. Natural carcinogens in the diet (e.g., aflatoxins in moldy nuts) and substances formed by metabolism (e.g., N-nitroso compounds in protein rich food) or cooking (e.g., heterocyclic amines and polycyclic aromatic hydrocarbons) may increase risk of cancer. Other substances mainly derived from plant compounds, such as phytochemicals and compounds found in the cabbage family (Steinmetz and Potter 1996), inhibit the development of cancer by increasing metabolic detoxification. Dietary fiber enhances the passage of materials and waste products through the intestine, thus in theory decreasing the risk of colon cancer. Some dietary factors, such as fat or energy intake, have been found to induce tumor promotion, whereas selenium and vitamin D may have protective effects. Evidence of the role of obesity in promotion of cancer has been obtained in studies on breast, endometrium, colon, and kidney cancer. The role of the diet is not clear in the DNA-repair system and progression.

2.2 Body size and energy

A modest positive association between height and risk of breast cancer was shown in a review of eight cohort studies (Hunter and Willett 1996). The largest of these studies, including 570,000 Norwegian women, found that height was significantly directly related to breast cancer incidence in all women and to mortality in women over 50 years of age (Tretli 1989). These results were not, however, adjusted for the known risk factors for breast cancer. In the Nurses' Health Study, postmenopausal women over 168 cm had a slightly higher risk of breast cancer (OR 1.3, 95% CI 1.0-1.7) than women under 160 cm (London et al. 1989). The review also included two cohort studies from the Netherlands, which found contradictory results. The first one from the 1970s showed a two-fold increase in the risk of postmenopausal breast cancer for each 15 cm difference in height (de Waard and Baanders-van Halewijn 1974), while the more recent study found no relationship between adult height and risk of postmenopausal breast cancer (den Tonkelaar et al. 1994). The multiethnic cohort study in Hawaii, not included in the review by Hunter and Willett (1996), found that risk of breast cancer increased linearly across the tertiles of height in postmenopausal women but not in premenopausal women (Galanis et al. 1998). In case-control studies, a positive association has been reported (Kalish 1984, Swanson et al. 1996) as well as results close to no association (Zhang et al. 1996).

One explanation for the relationship between height and risk of breast cancer is that height reflects the energy balance in youth (see de Waard and Trichopoulos 1988). Animal studies have strongly supported the hypothesis that energy restriction reduces the occurrence of mammary tumors, as reviewed by Welsh (1994). In a Norwegian cohort study, tallness seemed to be a risk factor for breast cancer only in women who lived their pubertal period during World War II, thus suggesting that a remarkable energy restriction in a critical growth period may decrease the lifetime risk of breast cancer (Vatten and Kvinnsland 1990). Another possible explanation is that the tallest girls mature and experience menarche earlier than do shorter girls. Early menarche has been related to increased risk of breast cancer by three biological pathways: regular menstrual cycles at earlier ages, high total lifetime estrogen levels, and earlier onset of hyperinsulinemia (Kelsey et al. 1993, Stoll 1998). However, no relationship between diet and age at menarche was found among girls in two cohort studies in Canada and the United States (Moisan et al. 1990, Maclure et al. 1991). On the other hand, diets rich in fat and low physical activity were associated with early menarche in a German cohort study (Merzenich et al. 1993). In all these three studies, height, weight, and obesity were inversely associated with early menarche.

Although most case-control studies have found no statistically significant association between obesity and risk of premenopausal breast cancer (see the World Cancer Research Fund 1997), an apparent inverse association (RR=0.69, p=0.0002) was summarized in a meta-analysis of 12 case-control studies when body mass index between the highest and lowest quintile was 10kg/m2 (Howe et al. 1990). Based on another meta-analysis, including 19 case-control studies, the estimated risk was 0.88 for premenopausal women (95% CI 0.76-1.02) for a BMI difference of 8kg/m2 (Ursin et al. 1995). Cohort studies, mostly carried out in the Scandinavian countries or in the United States, have found obesity to be associated with decreased risk of premenopausal breast cancer (Le Marchand et al. 1988, Tretli 1989, Vatten and Kvinnsland 1992, Törnberg and Carstensen 1994, Huang et al. 1997). No association, however, appeared in a recent cohort study in the United States (Yong et al. 1996).

Obesity has been positively associated with increased occurrence of postmenopausal breast cancer in case-control studies (see Howe et al. 1990, World Cancer Research Fund 1997). However, because the results of cohort studies have been contradictory, it has been concluded that obesity does not seem to be among the major risk factors for postmenopausal breast cancer (Swanson et al. 1988, London et al. 1989, Tretli 1989, Ballard-Barbash et al. 1990, Törnberg and Carstensen 1994, Yong et al. 1996, Kaaks et al. 1998). A cohort study in Hawaii indicated that the association between obesity and breast cancer was strongest for women aged 65 years or more (Galanis et al. 1998).

The inverse association between obesity and premenopausal breast cancer may be explained by anovulatory menstrual cycles more common in obese women. Infrequent ovulatory cycles have been related to low breast cancer incidence (see Pike 1990). For example, it has been found that women with a body mass index between 18 and 23 kg/m2 have the lowest anovulatory infertility (Rich-Edwards et al. 1994). In obese postmenopausal women, the level of endogenous estrogens remains high because of the conversion of androgens to estrogens in adipose tissue (Ballard-Barbash 1994). High body mass index at younger ages may also protect against breast cancer after menopause (Willett 1998).

It seems that body mass index cannot entirely explain the association between obesity and risk of breast cancer. Some other factors, such as adult weight gain and body fat distribution, were assumed to be more informative as regarding sex-steroid metabolism, glucose metabolism and insulin-like growth factors (Ballard-Barbash 1994, Stoll 1996). In the Nurses' Health Study, weight gain after the age of 18 increased the risk of breast cancer (Huang et al. 1997). The relative risk in this study was 1.99 (95% CI 1.43-2.76) for postmenopausal women who had gained more than 20 kg in weight but never used postmenopausal estrogen replacement therapy. A high waist-to-hip ratio has also been associated with increased risk of breast cancer in some studies (Ballard-Barbash et al. 1990, Folsom et al. 1990, Kaaks et al. 1998).

2.3 Fat

The leading dietary hypothesis about breast cancer until the mid-1980s was that high fat intake increases the risk of breast cancer. This hypothesis was based mainly on animal and ecological studies (Hunter et al. 1996).

Since the 1940s, animal studies have shown that high fat intake is associated with development of spontaneous breast tumors as well as those induced by chemicals (Tannenbaum 1942). In general, n-6 polyunsaturated fatty acids have been shown to be more potent in promoting mammary tumors than saturated fatty acids, whereas n-3 polyunsaturated fatty acids may even inhibit breast tumors (Wynder et al. 1994, Fay and Freedman 1997). However, if the required level for linoleic acid was achieved, only a small additional effect of polyunsaturated fatty acids on breast cancer appeared (Ip 1987).

Animal studies have been criticized because many of them have not considered energy intake in high-fat diets. Some recent studies, however, have shown that energy restriction may be more efficient in inhibiting mammary carcinogenesis than is fat restriction (Ip 1993). In a large experimental study including over 10,000 rats and mice, the daily dose of corn oil was fed at different levels of fat and energy intake, but no marked differences were found in mammary tumor incidence (Appleton and Landers 1986). Three meta-analyses of animal studies did not achieve any agreement whether or not the effect of fat intake is independent of total energy intake (Birt 1986, Albanes 1987, Freedman et al. 1990).

Ecological studies have shown a strong correlation between fat consumption and breast cancer incidence and mortality (r=0.7-0.9) (Armstrong and Doll 1975, Rose et al. 1986, Hursting et al. 1990), and the relationship has remained statistically significant after adjustment for the known risk factors (Prentice et al. 1988). An ecological study of 65 Chinese counties where the fat intake ranged from 6% to 25% found a weaker correlation between fat consumption and breast cancer mortality in postmenopausal women (r=0.4, p<0.10) (Marshall et al. 1992).

The results of case-control studies have been inconsistent. Some of them - but not all - have shown an increased risk of breast cancer with high fat intake (see the World Cancer Research Fund 1997). When studies were stratified by geographical location, the association between fat and breast cancer was stronger in Europe (OR 1.45, 95% CI 1.26-1.67) than in North America (OR 1.00, 95% CI 0.90-1.11) or other places (OR 1.01, 95% CI 0.85-1.20) (Boyd et al. 1993). The authors suggested that the difference in results between Europe and North America may be caused by larger variation in fat intake in Europe. A meta-analysis of 12 case-control studies indicated a statistically significant increase in risk of postmenopausal breast cancer when fat intake was high (OR 1.46 for a 100 g increase in daily fat intake, p<0.0001) (Howe et al. 1990). This meta-analysis did not include the large case-control study (2,024 breast cancer cases) conducted in the United States, which found no increase in the risk with high fat intake (Graham et al. 1982). On the other hand, a recent case-control study in Italy, including 2,569 breast cancer cases, reported an inverse association (p=0.01) (Franceschi et al. 1996). This association could be explained by unsaturated fatty acids, and possibly their high correlation with the consumption of raw vegetables.

Total fat intake was not associated with the risk of breast cancer in a pooled analysis of seven cohort studies including 4,980 cases from 337,819 recruited women (Hunter et al. 1996). The energy-adjusted relative risk for the highest quintile of fat intake was 1.05 (95% CI 0.94-1.16). It should be noted that all these cohorts were carried out in Western countries, where fat intake is rather high: four in the United States (Mills et al. 1989, Graham et al. 1992, Kushi et al. 1992, Willett et al. 1992), one each in Canada (Howe et al. 1991a), the Netherlands (van den Brandt et al. 1993), and Sweden (Holmberg et al. 1994). In the Nurses' Health Study (Willett et al. 1992), the relative risk for the highest versus lowest quintile of fat intake was 0.96 (95% CI 0.73-1.26) in premenopausal and 0.91 (95% CI 0.73-1.14) in postmenopausal women. It has been criticized that the follow-up times of the cohort studies (on average five years) have not been long enough to cover the latent period between exposure and the disease (Kushi et al. 1992). However, no differences between fat intake and risk of breast cancer were found after 4, 8, 12, and 14 years of follow-up in the Nurses' Health Study (Willett et al. 1987a, Willett et al. 1992, Willett 1998, Holmes et al. 1999).

As a consequence of the null findings in cohort studies, it has been suggested that, in the development of breast cancer, the type of fat may be more relevant than its total amount. In particular, high consumption of olive oil has been associated with decreased risk of breast cancer in the Mediterranean countries (Landa et al. 1994, Martin-Moreno et al. 1994, La Vecchia et al. 1995, Trichopoulou et al. 1995). This association may be explained by monounsaturated fatty acids rich in olive oil. A 4-year follow-up study in Sweden indicated an inverse association with monounsaturated (OR 0.45, 95% CI 0.22-0.95) but a positive association with polyunsaturated fatty acids (OR 1.69, 95% CI 1.02-2.78) (Wolk et al. 1998). That study comprised 674 breast cancer cases among 61,471 women between 40 and 76 years of age. As mentioned, n-3 polyunsaturated fatty acids have also been related to a lower risk of breast cancer in animal studies (see Wynder et al. 1994). The low rates of breast cancer in Alaskan Eskimos (Lanier et al. 1989) and in Norwegian fishermen's wives (Lund and Bønaa 1993) support the hypothesis that also a diet rich in fish may protect against human breast cancer. Epidemiological studies, in general, have not related n-3 polyunsaturated fatty acids or fish consumption to the risk of breast cancer (Willett 1997). Two case-control studies have analyzed the association between trans-fatty acids in adipose tissue and risk of postmenopausal breast cancer. The EURAMIC study showed an increased risk of postmenopausal breast cancer (OR 1.40, 95% CI 1.02-1.93) between the highest and lowest quartile of trans-fatty acids in adipose tissue (Kohlmeier et al. 1997). Another study in the United States found no association between trans-fatty acids in adipose tissue and risk of breast cancer (London et al. 1993).

Epidemiological studies have been inconsistent in their findings concerning specific high-fat foods and risk of breast cancer. Meat has been found to be a risk factor for breast cancer in some studies (Vatten et al. 1990a, Toniolo et al. 1994, Gaard et al. 1995) but not in all (Ambrosone et al. 1998). In a meta-analysis of cohort and case-control studies by Boyd (1993), a weakly increased risk of breast cancer was found for subjects who consumed a lot of meat, milk, and cheese. None or an indirect association has been found in studies not included in the meta-analysis (van't Veer et al. 1989a, Toniolo et al. 1994).

Although the metabolic effects of fat on the development of breast cancer have not been completely understood, various mechanisms have been proposed. One explanation for the relationship may be that the level of circulating estrogens has been shown to correlate positively with fat intake (Wynder et al. 1994). In a randomized trial, serum estradiol concentration decreased after 6 months on a low-fat diet in postmenopausal women whose baseline estradiol concentration was high (Rose et al. 1993). Further, it has been found that vegetarian women had lower serum estrogen than did non-vegetarians (Goldin et al. 1982, Prentice et al. 1990). Increased exposure to estrogen may enhance risk of breast cancer by stimulating the division of tumor cells (Lipworth 1995). Fat may also affect free-radical reactions, membrane alterations, immune responses, and activation of oncogene expression (see Hankin 1993, Wynder et al. 1994). Animal studies have shown that high fat intake has more effect on promotion than on initiation of carcinogenesis (World Cancer Research Fund 1997).

2.4 Dietary fiber

Fibers are complex carbohydrates which can be classified into two groups according to whether they are soluble or insoluble in water (Weisburger et al. 1993). Important dietary sources of water-soluble fibers are fruit, vegetables, and certain grains, such as oats, whereas the main source of water-insoluble fibers is cereal grains. A high amount of fiber in the diet inhibits the intestinal reabsorption of estrogen excreted in bile, and thus it may be a protective factor for breast cancer. An experimental study in premenopausal women indicated that the level of serum estrogen sulfate was 36% lower in a low-fat high-fiber diet than in the diet usually consumed in industrialized countries (Woods et al. 1989).

In two cohort studies conducted in the United States (Graham et al. 1992, Willett et al. 1992), high fiber intake was not associated with a decreased risk of breast cancer, whereas a cohort study in Canada showed an inverse association between fiber intake and breast cancer risk (RR=0.68, 95% CI 0.46-1.00, the highest vs. lowest quintile) (Rohan et al. 1993). In the same way, a recent case-control study in New York associated high fiber intake (the highest vs. lowest quartile) with a decreased risk of breast cancer in women aged 40 or over (OR 0.52, 95% CI 0.32-0.85) (Freudenheim et al. 1996). The association with fruit and vegetable fiber was more relevant (OR 0.48, 95% CI 0.30-0.78) than that with cereal fiber (OR 1.03, 95% CI 0.64-1.65). Case-control studies in southeast England failed to find any relationship for dietary fiber (Cade et al. 1998).

There is a general consensus that diet with high fruit and vegetable content is related to a lower than average occurrence of cancer, although the evidence is not consistent for hormone-related cancers (Block et al. 1992a, Steinmetz and Potter 1996). According to a review by Steinmetz and Potter (1996), 69% of the studies on breast cancer found an inverse association for at least one fruit or vegetable. A relatively low breast cancer mortality has also been found in vegetarians (Frentzel-Beyme et al. 1988), although the duration of membership in the Seventh-day Adventist church (mainly vegetarians) was not related to breast cancer incidence (Mills et al. 1989). Other dietary components besides fiber may also explain the observed inverse association, for example, fruit and vegetables include plenty of anticarcinogenic substances, such as antioxidants, flavonoids, folic acid, and isoflavones (Steinmetz and Potter 1996).

The relatively low incidence of breast cancer in Japanese women has attracted attention to phytoestrogens in soybean. Phytoestrogens have been shown to change estrogen metabolism in the gut, and thus to reduce the amount of free estradiol in blood. Because the structure of phytoestrogens resembles that of estrogens, they may also act as weak estrogens (on average 0.1% of normal estrogen activity) and compete with estradiol of target receptors. At the same time, phytoestrogens may increase the synthesis of serum sex hormone-binding globulin in the liver (Adlercreutz and Mazur 1997, World Cancer Research Fund 1997). In Finland, the most important sources of phytoestrogens are rye products rich in enterolactone. High consumption of rye bread has been suggested as explaining the difference between breast cancer incidence in Finland and the United States (Adlercreutz and Mazur 1997). Many animal studies have supported the hypothesis that phytoestrogens may prevent the development of breast cancer (Messina et al. 1994). Furthermore, one case-control study including 144 Australian breast cancer cases showed that women with high urinary excretion of enterolactone and equol had a 60% lower risk of breast cancer than did women with low excretion (Ingram et al. 1997).

2.5 Vitamin A

Vitamin A is a lipid-soluble vitamin the chemical name of which is retinol. It is obtained directly from animal sources and indirectly from fruit and vegetables as carotenoids with provitamin A activity (for example beta-carotene), and carotenoids can be partially converted to retinol in the intestine. However, in dietary studies the variable "retinol" usually means retinol only from animal sources. Vitamin A may regulate differentiation of epithelial cells (Steinmetz and Potter 1996), inhibit cell proliferation (Phillips et al. 1993), and enhance cell-to-cell communication (Wolf 1994) and immune responses (Krinsky 1991). Beta-carotene is also a potent antioxidant, which may protect against free radicals (Steinmetz and Potter 1996). All these biological functions have been related to cancer pathogenesis.

Findings concerning the association between vitamin A intake and risk of breast cancer are mainly based on epidemiological studies. A weak protective effect for high vitamin A intake was found in some (Hunter et al. 1993, Rohan et al. 1993) but not all cohort studies (Graham et al. 1992, Kushi et al. 1996). Vitamin A supplements were found beneficial only in women with diets low in vitamin A (Hunter et al. 1993). Although it has in general been assumed that high beta-carotene intake may be more protective than retinol intake in the development of breast cancer, the women in the Nurses' Health Study in the highest quintile of retinol intake had a 20% reduction in risk of breast cancer, whereas no significant reduction was found for beta-carotene (Hunter et al. 1993).

A multinational case-control study conducted in Northern Ireland, Germany, the Netherlands, Spain, and Switzerland found no association between beta-carotene in adipose tissue and postmenopausal breast cancer (van't Veer et al. 1996). In fact, the beta-carotene concentration of adipose tissue was lowest in women residing in southern Europe, although breast cancer incidence is also relatively low in these areas. Some studies have shown that carotenoids other than beta-carotene may act as active agents, for example lycopene or lutein/zeaxanthin (Freudenheim et al. 1996, Dorgan et al. 1998).

The association of vitamin A intake and its status is only indirect. Thus, measurements of vitamin A in food and in body fluids should not be equated. This concerns especially retinol, which has limited interpretability in populations whose food consumption is adequate, and therefore a large reserve of vitamin A is in the liver (Olson 1984). Blood carotenoid level, however, is quite sensitive to dietary intake because it is not closely regulated by homeostatic mechanisms.

2.6 Vitamin E

Vitamin E is a term for eight different kinds of lipid-soluble substances: four tocopherols and four tocotrienols with vitamin E (a-tocopherol) activity. Several biological pathways have been suggested for the anticarcinogenic effect of vitamin E; vitamin E may protect polyunsaturated fatty acids in cell membranes from oxygen radicals and terminate free-radical chain reactions (Ames 1983, Knekt 1991). Further, vitamin E may strengthen the anticarcinogenic capacity of selenium (Steinmetz and Potter 1996) and immune responses (see Dorgan and Schatzkin 1991). Vegetable oil, margarine, whole grains, and eggs are sources of vitamin E.

High vitamin E intake has decreased the risk of breast cancer in many animal studies as reviewed by Wang et al. (1989), Knekt (1991), and Kimmick et al. (1997). This decrease was particularly found in studies with experimental diets rich in polyunsaturated fatty acids (Ip 1982).

Some of the case-control studies - but not all - have indicated an inverse association between vitamin E intake and risk of breast cancer as reviewed by Kimmick et al. (1997). No association was found in a recent case-control study in southeast England (Cade et al. 1998) or in the three cohort studies published thus far (Graham et al. 1992, Hunter et al. 1993, Rohan et al. 1993). Furthermore, a multicenter case-control study found no association between alpha-tocopherol in adipose tissue and risk of postmenopausal breast cancer (van't Veer et al. 1996). Studies on vitamin E concentration in blood and risk of breast cancer have involved only a small number of cases, however, and thus have suffered from methodological limitations in detecting small risk differences (Kimmick et al. 1997).

2.7 Vitamin C

Vitamin C is the most abundant water-soluble vitamin in the body, and is derived from fruit, berries, and vegetables. Vitamin C may protect against breast cancer as an antioxidant as well as affect collagen synthesis and immune responses ( see World Cancer Research Fund 1997).

Epidemiological studies based on vitamin C intake or vitamin C concentration in blood have shown inconclusive results in terms of breast cancer risk. Three cohort studies carried out in the United States and Canada found a statistically non-significant reduction in the risk (Hunter et al. 1993, Rohan et al. 1993, Kushi et al. 1996). In addition, no association between vitamin C and risk of breast cancer was reported in a cohort study in the United States by Graham et al. (1982), whereas a significant inverse association (RR=0.53, 95% CI 0.33-0.86) was observed in their other study (Freudenheim et al. 1996). A meta-analysis of 12 case-control studies estimated a relative risk of 0.63 (for a 300 mg increase in daily vitamin C intake p<0.0001) for the highest quintile of vitamin C intake among postmenopausal women compared to the lowest quintile (Howe et al. 1990). This inverse association remained after adjustment for beta-carotene and dietary fiber (OR 0.73, p=0.03). Recent case-control studies, not included in the meta-analysis, have reported no association in Italy (Negri et al. 1996) or in the United Kingdom (Cade et al. 1998).

Consumption of vitamin C supplements was not related to decreased risk of breast cancer in a cohort study including 34,387 postmenopausal women in Iowa (Kushi et al. 1996).

2.8 Selenium

Selenium is an essential micronutrient. It acts in attachment with glutathione peroxidase enzymes which act in various tissues as antioxidants. Selenium may also participate in immune responses, in the control of thyroid hormone (thyroid deiodinases) metabolism, and in the detoxification of heavy metals (Fleet and Mayer 1997, Holben and Smith 1999). Several ecological and animal studies have associated low selenium status with high mortality and high incidence of cardiovascular diseases and cancer, especially breast and colon cancer (Schrauzer et al. 1977, Fishbein 1986, Clark et al. 1991).

The association between selenium and human breast cancer is still uncertain, mostly because of methodological limitations of the studies. For example, most of the studies carried out thus far have included fewer than 100 breast cancer cases (see Willett et al. 1991). Three recent studies, a cohort study including the 434 breast cancer cases of the Nurses' Health Study (Hunter et al. 1990) and another cohort study in the Netherlands (355 postmenopausal cases) (van den Brandt et al. 1994), and a case-control study carried out in five European countries (van't Veer et al. 1996) including 374 postmenopausal cases, found no association between toenail selenium and risk of breast cancer. One case-control study has measured selenium status from various sources such as plasma, erythrocytes, and toenail and from diet (van't Veer et al. 1990). The results for all the measured factors were non-significant.

Interaction between selenium and other antioxidants is controversial. Some studies have found that the protective effect of selenium was strongest when the level of other antioxidants such as beta-carotene was low (van den Brandt et al. 1994, van den Brandt et al. 1994). In contrast, other studies showed that the effect of selenium may be reinforced by a high level of beta-carotene (Kok et al. 1987, Knekt et al. 1990). In a multicenter study of five European countries, however, no interaction existed between toenail selenium and other antioxidants (van't Veer et al. 1996).

Because the soil content of selenium and its bioavailability to plants in Finland is one of the lowest in the world, and many studies had reported a high risk of cardiovascular diseases and cancer among subjects whose serum selenium concentration was under 50 µg/l (Salonen et al. 1982, Salonen et al. 1985), the Finnish Ministry of Agriculture and Forestry decided in 1984 to supplement all commercial fertilizers with selenium (Aro et al. 1998). The nationwide selenium supplementation, a program unique in the world, has raised the serum selenium of the Finns to one of the highest in Europe (80 µg/l) (Alfthan and Neve 1996).

2.9 Alcohol

High alcohol consumption has been associated with increased risk of breast cancer in many countries and diverse cultures since 1977 (Williams and Horm 1977, Willett and Stampfer 1997). However, the evidence is weak, and there may be a threshold below which alcohol has no noticeable effect.

A pooled analysis of six cohort studies: four in the United States and Canada, one in the Netherlands, and one in Sweden, showed that women whose alcohol consumption was more than 30 g per day (2-3 drinks) had an increased risk of breast cancer (RR=1.41, 95% CI 1.18-1.69) compared to that of non-drinkers (Smith-Warner et al. 1998). That pooled analysis included 4,335 breast cancer cases diagnosed among 322,647 premenopausal and postmenopausal women. A positive dose-response relationship was found when the analyses of 38 cohort and case-control studies were combined (Longnecker 1994). The relative risks were 1.11 (95% CI 1.07-1.16), 1.24 (95% CI 1.15-1.34) and 1.38 (95% CI 1.23-1.55) for women whose daily alcohol consumption was one drink, two drinks, and three drinks, respectively, compared to non-drinkers. The relative risk of death from breast cancer was 2.10 (95% CI 1.18-3.72) in women who consumed alcohol over 60 g per day (about 5 drinks) compared to non-drinkers in the study of the American Cancer Society, the biggest cohort study thus far, including 2,933 breast cancer deaths from the follow-up data of 581,321 women (Garfinkel et al. 1988). A lower threshold value (15 g alcohol per day) for the increased risk was found in postmenopausal women of the Iowa Women's Health Study (Gapstur et al. 1992) and in premenopausal and postmenopausal women of the Nurses' Health Study (5 g per day) (Willett et al. 1987b). Cohort studies with the longest follow-up times have revealed the strongest direct association between alcohol consumption and risk of breast cancer (Longnecker 1994).

Based on the meta-analysis of six case-control studies, women whose alcohol consumption was more than 40 g per day had an increased risk of breast cancer (OR 1.69, 95% CI 1.19-2.40) compared to that of non-drinkers (Howe et al. 1991b). The largest case-control studies, one in the United States (6,662 breast cancer cases) (Longnecker et al. 1995) and one in Italy (2,402 cases) (La Vecchia et al. 1989), observed that high alcohol consumption was related to an increased risk of both premenopausal and postmenopausal breast cancer, whereas another study in the United States (3,498 cases) found no such relationship (Chu et al. 1989). The accumulated evidence shows that the strongest associations (about 2.5-fold risk) were found in countries where alcohol is a regular component of the diet and the consumption per capita high. Studies from the Mediterranean countries and France are good examples (La Vecchia et al. 1989, Richardson et al. 1989, Toniolo et al. 1989, Ferraroni et al. 1991, Katsouyanni et al. 1994). Alcohol consumption explained 12% of the breast cancer incidence in a recent case-control study in Italy (Ferraroni et al. 1998). A much lower estimate (4%) was made in the United States, where alcohol consumption is low in general (Longnecker 1994).

No differences were found between various alcoholic beverages and the risk of breast cancer in a combined analysis of six case-control studies (Howe et al. 1991b). On the other hand, the alcoholic beverage consumed most within one country has tended to have the strongest association. Thus, it seems that amount of alcohol is more important than type of alcoholic beverage.

Some studies have provided information on past (Hiatt et al. 1988, La Vecchia et al. 1989, van't Veer et al. 1989b, Nasca et al. 1990, Freudenheim et al. 1995, Holmberg et al. 1995, Bowlin et al. 1997) or total lifetime alcohol consumption (Longnecker et al. 1995). These factors may be more important in the pathogenesis of breast cancer than is current alcohol consumption. The findings, however, have been inconsistent, and it is not known which is more relevant, alcohol consumption in early life or later on. Harvey et al. (1987) found that women who consumed alcohol before the age of 30 and then stopped and those who continued to drink alcohol had a similarly increased risk of breast cancer. A multicenter case-control study conducted in France, Switzerland, Northern Ireland, the Netherlands, and Spain indicated an increased breast cancer risk only for postmenopausal ex-drinkers (Royo-Bordonada et al. 1997). Both poor recall and current alcohol consumption may effect the reporting of alcohol consumption. For example, when ethanol grams per day and duration of consumption were simultaneously included in the multivariate model, duration was not important as a risk factor (Bowlin et al. 1997). Furthermore, the positive association between total lifetime alcohol consumption and risk of breast cancer disappeared after adjustment for current alcohol consumption (Swanson et al. 1997).

Ecological studies cannot be done to correlate alcohol consumption with breast cancer rates because per capita consumption usually reflects more men's than women's alcohol consumption (Longnecker 1994). For example, the proportion of women's of the total alcohol consumption in Finland is only 20-25% (Simpura et al. 1995, Männistö et al. 1997). In animal studies, alcohol has been found to increase the proliferation of mammary gland cells (Singletary et al. 1991). In a controlled trial in premenopausal women, 30 g alcohol per day increased total estrogen concentration and amount of bioavailable estrogens (Reichman et al. 1993). Alcohol may also act as a tumor promoter, induce free-radical production, inhibit the DNA repair system, and influence immune responses (Katsouyanni et al. 1994).

2.10 Summary of factors related to diet

Obesity may increase the risk of postmenopausal breast cancer, but nonexistent or even inverse associations have been demonstrated for premenopausal women. Because of the contradictory results between case-control and cohort studies, additional information about factors identifying obesity more accurately, for example in terms of body fat distribution and timing of weight gain, has been called for. Some findings have related high waist-to-hip ratio and weight gain to increased risk of breast cancer, but more studies are needed to reach a reasonable conclusion. Height has also been associated with increased risk of breast cancer, at least in postmenopausal women. The positive energy balance in youth and early menarche may explain this association.

The association between fat intake and risk of breast cancer is still uncertain. Ecological and animal studies have shown that high fat intake increases the risk of breast cancer, but it is possible that total energy intake acts as a confounder. Case-control studies have reported diverse results, whereas cohort studies have found no association. However, because of promising results between high consumption of olive oil and relatively low risk of breast cancer in Mediterranean countries, it has been suggested that the type of fat, e.g., monounsaturated fatty acids, n-3 polyunsaturated fatty acids, and trans-fatty acids, may be more important in the development of breast cancer than is total fat intake. A high amount of fiber in the diet may also be a protective factor against breast cancer, although the results from epidemiological studies have been contradictory. In this respect, Finland is an interesting country because not only fat intake but also fiber intake is high, and because of the important role of dairy products in the Finnish diet.

A diet rich in antioxidants, such as beta-carotene, vitamins E and C, and selenium, may decrease breast cancer incidence by protecting breast tissue from oxidative damage. The results of human studies, however, have been inconsistent. To clarify the situation, more studies are needed, in particular those with adjustment for the known risk factors for breast cancer. Dietary supplements and combined benefits of other antioxidants have also seldom been considered. Finland is one of the countries where the soil content of selenium is very low. Because many studies had showed increased risks of cardiovascular disease and cancer among subjects whose selenium intake was low, it was decided in 1984 to supplement all commercial fertilizers with selenium. More than a decade after the beginning of supplementation, it may be possible to assess whether selenium intake now has reached a level at which it is no longer related to risk of diseases.

It seems that women who consume more than 30 g alcohol per day have an increased risk of breast cancer. This association has been found to be stronger in countries where alcohol is part of the normal diet, whereas in countries where alcohol consumption is low, the role of alcohol is still unclear. Furthermore, the critical time periods of women's lifetimes when alcohol consumption has the most substantial effect on the development of breast cancer have not yet been determined. Measuring past alcohol consumption is methodologically challenging, and validated innovative methods are needed.

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