Since the early 1990s soyfoods have been widely investigated for their potential role in cancer prevention.1 Much of this research has been conducted because soyfoods are uniquely-rich sources of isoflavones. Most of the cancer research involving soy has focused on breast and prostate cancer because these cancers are known to be hormonally regulated and countries that consume soyfoods have low incidence rates of both cancers.2 Previous issues of this newsletter have addressed these two cancers and the reader is referred to the references for additional information on breast3-7 and prostate8-10 cancer.
The etiology of a number of cancers is thought to include a hormonal component and isoflavones potentially inhibit carcinogenesis through both hormonal and non-hormonal mechanisms.11 In fact, initial interest in the chemopreventive effects of isoflavones was based on the ability of genistein to inhibit the activity of an enzyme overexpressed in cancer cells.12 Therefore, soy may impact the development of several cancers, not just breast and prostate cancer. This article provides a brief overview based primarily on the clinical and epidemiologic research of the current understanding of soy intake and risk of cancers of the endometrium, colon and rectum, lung, bladder, skin and thyroid.
Endometrial Cancer (EC)
Endometrial cancer (cancer of the corpus uteri) represents the most common gynecological malignancy in the industrialized world and is the seventh most common cancer among females (although incidence and mortality rates vary markedly among geographical regions and countries).2 The highest rates of this cancer are in the United States and Europe and the lowest are in Asia and Africa.13
Several observations support the important role that estrogen plays in the etiology of EC14 although the extent to which this is true may be influenced by estrogen receptor (ER) polymorphisms.15 “Ever users” of unopposed estrogen therapy are about two to three times more likely to develop EC as “never users”16-18 and women with EC have increased ovarian volume and higher estradiol levels.19 For this reason, soyfoods could be theorized to increase or decrease EC risk because they contain isoflavones.
Two recently published meta-analyses of the epidemiologic data have evaluated the relationship between soy intake and EC risk. One such analysis involving 10 studies (eight case-control, two prospective) found soy intake was inversely associated with EC risk with an overall risk estimate (RE) of 0.81 (95% confidence interval [CI]: 0.72, 0.91).20 Subgroup analyses revealed statistically significant protective effects for both Asian (RE = 0.79, 95% CI: 0.66, 0.95) and non-Asian (RE = 0.83, 95% CI: 0.71, 0.96) populations.
The second analysis also found soy (isoflavone) intake was protective against EC (odds ratio [OR] = 0.81, 95% CI: 0.74, 0.89) but sub-analysis indicated reduced risks were limited to the 10 case-control studies (OR 0.81: 95% CI: 0.73, 0.90). Nevertheless, there were only three cohort studies in the analysis and the reduction in risk was close to significant.21 Dietary isoflavones were associated with protection against EC in both Asian and non-Asian countries.
Clinical studies indicate that unlike estrogen, isoflavones do not adversely affect the endometrium. This conclusion is based on a review by the European Food Safety Authority of 25 clinical studies that measured endometrial thickness and nine that measured histopathological changes in the endometrium.22 Interestingly, a recently published meta-analysis found that when all clinical studies (N=23; 2,167 participants) were included in the analysis, there was no effect of isoflavones on endometrial thickness, whereas there was a significant (P=0.04) decrease in thickness when considering only the seven North American trials which involved 726 women.23 On the other hand, there was a small increase in thickness among women involved in the three Asian trials, but none of these studies actually intervened with isoflavones derived from soybeans.
Finally, Bitto et al.24 found in a six-month trial involving 56 premenopausal women with non-atypical endometrial hyperplasia that the isoflavone genistein (54 mg/day) significantly improved symptoms in comparison to a placebo and had a similar effect as norethisterone acetate (a progestin used to treat hyperplasia). These results suggest genistein was functioning as an anti-estrogen possibly by upregulating ERβ expression. The daily amount of genistein taken by the women in this study is provided by ~4 servings of soyfoods.
Colorectal Cancer (CRC)
Colorectal cancer is the third most prevalent cancer worldwide and one of the most common solid carcinomas in Western countries.25 CRC incidence rates are higher in developed nations than in developing countries.26
A meta-analysis of 17 epidemiologic studies, which consisted of 13 case-control and four prospective cohort studies, showed that soy isoflavone consumption was associated with a reduction in CRC risk (relative risk [RR] = 0.78, 95% CI: 0.72, 0.85). However, subgroup analysis indicated a protective effect was observed only in Asian populations (RR = 0.79; 95% CI: 0.72-0.87), and in case-control studies (RR = 0.76; 95% CI: 0.68-0.84).27 The lack of effect in non-Asian studies is not surprising because, as pointed out more than a decade ago, typical Western isoflavone intake is likely too low to exert physiological effects.28
A 2016 meta-analysis concurs with the aforementioned meta-analysis in finding a non-significant decreased risk of CRC associated with isoflavones among prospective studies (RR = 0.94, 95% CI: 0.83, 1.07) whereas the association was significant among case-control studies for total isoflavone intake (RR = 0.86; 95% CI: 0.77, 0.96).29
Theoretically, isoflavones could reduce CRC risk because they preferentially bind to ERβ in comparison to ER;30 targeting ERβ has been suggested as being a novel clinical approach for management of colorectal adenomatous polyps and prevention of colorectal carcinoma in patients at risk for this disease.31 However, a 12-month trial comparing the effects of 58 g/day soy protein containing either 3 or 83 mg isoflavones found the isoflavone-rich protein did not reduce colorectal epithelial cell proliferation or the average height of proliferating cells in the cecum, sigmoid colon, and rectum and actually increased cell proliferation measures in the sigmoid colon.32
Lung Cancer (LC)
Smoking contributes to 80% and 90% of lung cancer (LC) deaths in women and men, respectively. Men who smoke are 23 times more, and women who smoke are 13 times more likely to develop LC than never smokers.33 Nevertheless, there still appears to be a role for lifestyle in the etiology of LC.
A meta-analysis of 11 epidemiologic studies found an inverse association between soy protein intake and risk of LC that was of borderline statistical significance (OR = 0.98, 95% CI: 0.96, 1.00). Sub-analysis indicated the inverse association was statistically significant in nonsmokers (OR = 0.96; 95% CI: 0.93, 0.99) and stronger than in smokers (P for difference <0.05).34 The findings did not differ according to gender, study design or types of soyfoods consumed. Soy protein was used as a common measure of soy intake in this analysis.
Similar results were reported for a meta-analysis of eight prospective and seven case-control studies wherein isoflavones were associated with a significantly decreased risk of LC in both prospective and case-control studies; however, sub-analysis indicated isoflavones were associated with a decreased risk of LC among never smokers (5 datasets from 4 studies, RR = 0.64, 95% CI: 0.51, 0.79) but not among former/current smokers (4 datasets from 3 studies, RR = 1.03, 95% CI: 0.86, 1.24).29
No clinical studies relevant to LC were identified, but in animal models of LC the administration of isoflavones significantly decreases tumor incidence and increases the life span of the tumor-bearing animals,35 particularly in female mice.36 Emerging evidence suggests that estrogen signaling promotes LC progression and ER antagonists such as tamoxifen may counteract the detrimental effect of hormone therapy on LC.37 Therefore, although very speculative, the proposed protective effects of soy against LC could result from isoflavones exerting an anti-estrogenic effect. On the other hand, it is recognized that the molecular profile of tumors from smokers differs from non-smokers with the latter being more likely to have mutations of the epidermal growth factor receptor,38 an oncogene which may be suppressed by the isoflavone genistein.39 Finally, a mouse study reported that soy isoflavones given pre- and post-radiation protect the lungs against the adverse effects of radiation treatment for LC.40
Bladder Cancer (BC)
Bladder cancer is one of the most common malignancies affecting the urinary system. It is the third commonest male and tenth commonest female cancer in the United States.41 In comparison, the incidence of bladder cancer in Asia is relatively low.42-43 Nevertheless, two Chinese prospective studies raised the possibility that soy could increase risk of BC.
The Shanghai Cohort Study reported that, compared to men consuming soy less than once a week, the RR (95% CI) for those who consumed soy 1-<3 times per week, 3-<7 times a week and daily were 2.05 (0.80, 5.29), 2.45 (0.89, 6.76) and 4.61 (1.57, 13.51), respectively (p for trend = 0.004) after controlling for a number of potential confounders. The study involved 18,244 men aged 45-64 years who were followed for as long as 16 years.44Similar results were reported in the Singapore Chinese Health Study. Relative to the lowest quartile of energy-adjusted total soy intake (<36.9 g/1000 Kcal), the highest quartile of total soy intake (≥92.5 g/1000 Kcal) was associated with a 2.3-fold increase in bladder cancer risk (95% CI: 1.1, 5.1) after adjustment for potential confounders.45 However, in contrast, a meta-analysis that included these two studies, two additional prospective studies and one case-control study, found no relationship between BC risk and isoflavone intake, although the increased risk was close to significant.29
In contrast to the epidemiologic data, Zhou et al.46, 47 reported that soybean isoflavones and soy phytochemical concentrates inhibit the growth of murine and human bladder cell lines in vitro and in vivo in a dose-dependent manner, and Wang et al.48 showed that genistein enhanced the efficacy of a commonly used drug to treat bladder cancer in mice.
Finally, a phase two randomized, placebo-controlled trial by Messing et al.39found that genistein administration for 14 to 21 days before surgery decreased phosphorylation of epidermal growth factor receptor in bladder tumors, suggesting that this isoflavone could inhibit one aspect of the carcinogenesis pathway. However, because a pharmacological dose (300 mg/day) of genistein was used, the findings from this trial may not be applicable to the consumption of soyfoods.
Skin Cancer (melanoma)
Only very limited preclinical research involving isoflavones and melanoma has been conducted, but there is a theoretical basis for speculating that these soybean constituents reduce risk of skin cancer.
Melanoma incidence is higher in males than in females and females have a significant survival advantage over men. ERβ is the predominant ER in melanoma and its expression decreases in melanoma progression which supports its role as a tumor suppressor.49 For this reason, ERβ is now considered an effective molecular target for melanoma treatment, and ERβ agonists are proposed as effective in helping to prevent and/or treat melanoma.49 As noted previously, isoflavones preferentially bind to and activate ERβ in comparison to ER.30
A study with mice implanted with melanoma cells showed that genistein (15 mg/kg body weight) decreased tumor volume and weight by approximately 30% and reduced the quantity of melanin (and the degree of erythema) in direct proportion to the number of days of treatment. Furthermore, no metastasis to the liver was recorded in the treated group whereas significant metastasis occurred in the control mice.50While these findings are impressive, their relevance to humans consuming soyfoods is very unclear given the large dose of genistein employed and the fact that it was administered by intraperitoneal injection.
A second mouse study, which may be more relevant, compared the effects of isolated soy protein (ISP) and selenium-enriched ISP with a casein-containing diet on pulmonary metastasis of murine melanoma cells. Mice were fed their respective diets for two weeks before and two weeks after injection of the cancer cells. In comparison to mice fed casein, the number of mice with ≥50 tumors was significantly decreased in animals fed soy protein, and the exposure to selenium further enhanced tumor suppression.51
The suggestion has been made that soy intake may increase thyroid cancer risk, perhaps by increasing serum levels of thyroid stimulating hormone (TSH).52-54 However, the clinical evidence shows conclusively that neither soy nor isoflavones increase TSH levels in people with normal-functioning thyroids.55, 56 Furthermore, although Kimura et al.57 found that the addition of soy to iodine-deficient diets increased malignant goiter in Wistar rats, Son et al.58, 59 found no effect of isoflavones on thyroid carcinogenesis in male58 and female59 rats. Furthermore, Seike et al.60 found that dietary genistein inhibited chemically-induced thyroid cancer.
Epidemiologic data reported by Takezaki et al.61 found that soy intake was unrelated to thyroid cancer risk among Japanese women in Nagoya. Furthermore, a U.S. case-control study by Horn-Ross et al.62 found that isoflavone intake was inversely related to risk of thyroid cancer. Also, although thyroid cancer incidence rates are higher among Southeast Asians living in the United States in comparison to other ethnic groups, low soy/isoflavone intake was identified as contributing to these higher rates.63
Summary and Conclusions
Definitively establishing diet—cancer relationships is extremely difficult. Understanding of these relationships is based primarily on cohort studies. Intermediary markers for cancer are less well established then they are for other chronic diseases such as heart disease (blood pressure, LDL-cholesterol) and osteoporosis (bone mineral density). Consequently, clinical studies focused on intermediary markers for cancer are generally less revealing than they are for other chronic diseases. Although animal studies are widely used in cancer research, they often fall short of being able to predict human responses.64, 65
Of the cancers addressed above, the epidemiologic data are most supportive of a protective effect of soy against EC and CRC although this support is based primarily on case-control rather than cohort studies. For a variety of reasons, case-control studies carry less weight within the epidemiologic community than cohort studies. Although there is a theoretical basis for soy reducing risk of these cancers, clinical data are lacking. In contrast, the rather limited epidemiologic data suggest that soy could increase risk of BC; however, the animal studies show just the opposite.
Epidemiologic evidence suggesting that soy decreases risk of LC among non-smokers is particularly intriguing because expression of the oncogene that is increased in tumors from non-smokers may be suppressed by genistein. The skin cancer data are much too limited to meaningfully speculate about a role for soy, whereas the thyroid cancer data provide considerable assurance that soy does not increase risk of this cancer.
Finally, it is important to emphasize that most of the epidemiologic data relevant to understanding the impact of soy intake on cancer risk comes from studies involving Asian populations. These studies are valuable because, unlike the situation in non-Asian countries, soy consumption is less likely to identify individuals that differ markedly from their non-soy-consuming counterparts so confounding is less of an issue. On the other hand, there are always concerns about extrapolating the results from one ethnic group to another. Since in general soy intake is low among non-Asian populations, meaningful insight into the soy—cancer relationship is most likely to come from Western cohort studies such as the Adventist Health Study-2 and the he Oxford component of the European Prospective Investigation into Cancer and Nutrition (EPIC), which include significant numbers of high-soy-consumers.
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