Linkage between retinoid and fatty acid receptors: implications for breast cancer prevention.

Certain dietary retinoids and polyunsaturated fatty acids (PUFAs) consistently inhibit progression of mammary carcinogenesis both in animal studies and cell culture, but clinically, their effect is inconsistent. New evidence of synergistic interaction between the nuclear receptors for the two groups of nutritional agents suggests that appropriate selective ligands from each group might be combined in breast cancer chemoprevention studies. Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear receptor that is activated by PUFAs, eicosanoids and antidiabetic agents such as troglitazone. Such activation can cause growth inhibition in human mammary cancer cells in culture and the effect is enhanced by ligands of retinoic acid receptor (RAR) and retinoid X receptor (RXR). In mouse mammary tissue in organ culture, an RXR-selective ligand has been shown to enhance the effect of troglitazone in suppressing carcinogen-induced pre-neoplastic changes. A PPAR/RXR heterodimer is involved in tumour growth inhibition and has been shown to bind directly to nuclear oestrogen response elements (ERE) independently of oestrogen receptor (ER) activity. A combination of an RXR-selective retinoid with either troglitazone or else a long-chain n-3 PUFA, is proposed for a short-term study in postmenopausal women after primary surgery for intraductal breast cancer. The resulting activation of PPAR/RXR expression may increase response to retinoid administration, especially in the presence of obesity and insulin resistance, because of the ability of PPAR gamma ligands to reduce insulin-like growth factor I (IGF-I) concentrations. Serial core biopsies of breast tissue over a short term are proposed to identify changes in phenotype, which may influence progression to invasiveness. In addition to cytomorphological criteria, expression of ER alpha and beta, RAR alpha and beta, and IGF-I receptor in the nucleus should be examined.

Upper abdominal obesity, insulin resistance and breast cancer risk.

PURPOSE: A majority of prospective studies show breast cancer risk to be higher in obese postmenopausal women with upper abdominal adiposity than in those with overall adiposity. The evidence is more limited and inconsistent in the case of premenopausal women. The review examines evidence that aberrant insulin signalling may be involved in the promotion of mammary carcinogenesis. The aetiology and concomitants of abdominal visceral obesity are examined. MECHANISMS: Clinical and experimental evidence suggests that the higher breast cancer risk associated with greater abdominal visceral obesity may be related to aberrant insulin signalling through the insulin receptor substrate 1 pathway, leading to insulin resistance, hyperinsulinaemia and increased concentrations of endogenous oestrogen and androgen. The putative role of aberrant insulin signalling in the promotion of mammary carcinogenesis may help to explain clinical relationships between breast cancer risk and age at menarche, pregnancies and onset of obesity. CONCLUSION: Overall adiposity in women adversely affects breast cancer risk mainly by greater exposure of mammary epithelial tissue to endogenous oestrogen. Upper abdominal adiposity appears to involve an additional effect related to the presence of insulin resistance. Aetiological factors in the development of hyperinsulinaemic insulin resistance are still uncertain but may involve aberrant susceptibility genes in adipocyte insulin receptors or in the insulin receptor substrate 1 pathway. Epigenetic factors are also likely to contribute, including high free fatty acid levels and obesity. Dietary fatty acids, particularly polyunsaturated fatty acids, are known to regulate adipocyte differentiation through the nuclear peroxisome proliferator-activated receptor gamma, and may also have a role in insulin resistance. These aetiological factors are likely to be relevant to the high risk of postmenopausal breast cancer in industrialised Western populations.

Oestrogen/insulin-like growth factor-I receptor interaction in early breast cancer: clinical implications.

UNLABELLED: The expression of oestrogen receptor (ER) and that of the insulin-like growth factor-I receptor (IGF-IR) are positively correlated in breast cancer specimens. Their function is strongly linked in enhancing proliferative activity in normal and malignant human mammary epithelial cells in culture. This review examines the likely role of such a mechanism in the increased breast cancer risk reported in postmenopausal women with abdominal obesity. Precancerous breast lesions show an increased proportion of ER-positive cells with high proliferative activity, and recent studies suggest that genetic mutations or epigenetic variants in the ER alpha gene may increase the ER's sensitivity to oestrogen stimulation. Abdominal obesity in women is associated with higher concentrations both of free oestradiol and free IGF-I. Activation of their respective receptors may induce synergistic stimulation of mammary carcinogenesis. However, there is clinical evidence that progression in precancerous breast lesions may be delayed or reversed. Involution occurs spontaneously in a proportion of duct carcinoma in situ (DCIS) (intraductal) lesions as women approach the menopause, and antioestrogen therapy has been shown to reduce recurrence and progression of DCIS lesions. CONCLUSIONS: Intervention trials in breast cancer prevention would greatly benefit from surrogate response markers which could predict long-term benefit. Changes in ER and IGF-IR expression apart from those in standardised cytomorphological criteria, might predict the likelihood of DCIS involution in cancer prevention trials. Future studies could involve examination of serial core biopsies from normal breast tissue during trials of antioestrogens, retinoids or weight-reduction interventions. Correlation of changes in these markers with changes in circulating IGF-I and oestradiol concentrations may help to clarify the roles of the markers.

Biological mechanisms in breast cancer invasiveness: relevance to preventive interventions.

Migration studies suggest that the high incidence of postmenopausal breast cancer in Western women is related mainly to epigenetic factors. Progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) also appears to involve environmental rather than genetic factors, and a role has been postulated for metabolic-endocrine changes related to the Western lifestyle. Protein kinase C (PKC) is important in cell signal transduction, and laboratory studies show that PKC stimulates the activities of urokinase plasminogen activator, matrix metalloproteinases and cell adhesion molecules, all of which are known to increase invasiveness in human mammary cancer cell lines. In rodents, the activity of PKC in tissue cells is enhanced by insulin, and PKC isoenzymes have been shown to stimulate the development of hyperinsulinaemic insulin resistance in rodents. Clinically, hyperinsulinaemia and the concomitant increase in circulating levels of free oestradiol and bioactive insulin-like growth factor 1 (IGF1) are each confirmed markers of high risk for breast cancer in women. Lesions of DCIS show evidence of regression with mammary involution, but it is postulated that this may be opposed by the concomitants of hyperinsulinaemic insulin resistance. The prevalence of the latter is increasing in Western populations, and a combination of high IGF1 and low IGF-binding protein 3 concentrations has been associated with the presence of DCIS lesions in premenopausal women. Measures that enhance insulin sensitivity in such women may reduce the risk of progression in DCIS lesions, and a clinical trial is proposed to test the hypothesis.

Adiposity as a risk determinant for postmenopausal breast cancer.

BACKGROUND: Cross-cultural studies have long suggested that the high incidence of breast cancer in developed Western countries may be linked to the high prevalence of obesity and to high total energy intake. Recent studies show that hyperinsulinemia, increased concentration of insulin-like growth factor 1 and greater abdominal fat accumulation are markers of high risk for breast cancer. Increased serum concentrations of free estradiol and free testosterone are similar risk markers and are frequent concomitants of hyperinsulinemia. MECHANISMS: The mechanism by which such metabolic-endocrine abnormality may promote mammary carcinogenesis is uncertain, but its effect is likely to predominate in the years approaching the menopause when obesity is common among Western women. In obese subjects, enlargement of adipose deposits is known to produce an excess of free fatty acids and tumor necrosis factor alpha, both of which may be involved in the pathogenesis of insulin resistance. In middle-aged women, the concomitants of hyperinsulinemia may activate invasive and proliferative activity in preneoplastic mammary lesions such as in situ duct carcinoma of the comedo type. This will enhance the risk of progression to invasive breast cancer, which is likely to manifest clinically mainly after the menopause. CONCLUSION: Weight reduction combined with a program of regular physical exercise has been shown to reduce both estrogen and insulin concentrations in obese women and such a regimen might be tested in clinical trials for an effect on breast cancer risk in obese women. Intervention is best begun around the age of 45 y, this being the age when in situ duct carcinoma would normally begin to show evidence of spontaneous involution in women without clinical evidence of invasive breast cancer. International Journal of Obesity (2000) 24, 527-533

Dietary supplements of dehydroepiandrosterone in relation to breast cancer risk.

OBJECTIVE: Dietary supplements of the adrernocertical hormone dehydroepiandrosterone (DHEA) are widely taken in the hope of staving off the aging process. Potential dangers have not been fully researched, particularly evidence of a correlation between increased serum concentrations of DHEA and higher breast cancer risk in postmenopausal women. DESIGN: The review examines reports of clinical, epidemiological experimental studies for evidence that DHEA may be a factor in promoting the growth of mammary cancer. Biological mechanisms which might be involved are identified. RESULTS: DHEA is reported to inhibit the growth of human mammary cancer cells in vitro and also the growth of chemically-induced mammary cancer in rats. However, growth inhibition occurs only in the presence of high oestrogen concentrations, and growth stimulation occurs in both models in the presence of a low-level oestrogen milieu. Epidemiological studies report a positive correlation between higher serum concentrations of DHEA and increased breast cancer risk in the case of postmenopausal but not premenopausal women. Postulated mechanisms include a direct effect on mammary cells by androgenic metabolites of DHEA or an indirect effect by an increase in bioavailable oestrogen levels. The increased serum concentration of free insulin-like growth factor 1 which follows prolonged DHEA intake may also have a role by stimulating oestrogen receptor activity in breast tissue. CONCLUSION: Late promotion of breast cancer in postmenopausal women may be stimulated by prolonged intake of DHEA, and the risk may be increased by the endocrine abnormality associated with pre-existing abdominal obesity. Caution is advised in the use of dietary supplements of DHEA particularly by obese postmenopausal women.

Premalignant breast lesions: role for biological markers in predicting progression to cancer.

Biological markers associated with in situ carcinoma and atypical intraductal hyperplasia in the breast are examined to help in identifying a subgroup of premalignant lesions whose natural history may be influenced by epigenetic factors. The biomarkers may be used as indices in clinical trials aiming to assess the effect of weight reduction, dietary intervention or hormone replacement therapy on the risk of progression to invasive breast cancer. In the current state of knowledge, the expression of oestrogen receptors, p53, bcl-2 and HER-2 neu oncogenes and the Ki-67 index of proliferative activity, are the most useful biomarkers for this purpose. In situ carcinoma of the breast manifests a variety of morphological phenotypes with specific biological characteristics. There is evidence that only a proportion of premalignant lesions are committed to progression to invasive cancer while other lesions undergo spontaneous regression at the time of the menopause. Cross-cultural studies suggest that it is the late-stage epigenetic promoting factors which are responsible for the high incidence of postmenopausal breast cancer in Western women. Obesity in middle life and the Western diet favour the development of hyperinsulinaemic insulin resistance, and the metabolic-endocrine effects of its concomitants may promote mammary carcinogenesis around the time of the menopause and increase the incidence of invasive cancer after the menopause. Because biomarker changes in premalignant lesions are nearer in time to these promoting influences, they could provide intermediate endpoints for testing the hypothesis.

Western nutrition and the insulin resistance syndrome: a link to breast cancer.

OBJECTIVE: The incidence of breast cancer in the Western world runs parallel to that of the major components of the insulin resistance syndrome--hyperinsulinaemia, dyslipidaemia, hypertension and atherosclerosis. Evidence is reviewed that the growth of breast cancer is favoured by specific dietary fatty acids, visceral fat accumulation and inadequate physical exercise, all of which are thought to interact in favouring the development of the insulin resistance syndrome. DESIGN: Clinical, epidemiological and experimental studies linking breast cancer risk with evidence of insulin resistance and its concomitants, were searched for in the MEDLINE database since 1985. RESULTS: Clinical and epidemiological evidence suggests that both breast cancer and the metabolic disorders comprising the insulin resistance syndrome are polygenic and multifactorial in origin. Experimental evidence suggests that hyperinsulinaemia and its concomitants can increase the promotion of mammary carcinogenesis and the mechanism is likely to involve increased bioactivity of insulin-like growth factor 1 (IGF-1). Case-control and cohort studies have shown that higher serum levels of IGF-1 are associated with increased breast cancer risk. Pharmacological agents which lower IGF-1 concentrations are under clinical trial for breast cancer prevention. CONCLUSIONS: Nutritional and lifestyle modifications that improve insulin sensitivity may not only decrease a tendency to atherosclerosis but also reduce breast cancer risk in women. In addition to a reduced fat intake, the dietary regimen might involve a reduced n-6/n-3 ratio of polyunsaturated fatty acids and should be associated with avoidance of obesity and regular physical exercise. Interventions to decrease breast cancer risk in first-degree relatives of breast cancer patients need to begin at an early age.

Perimenopausal weight gain and progression of breast cancer precursors.

This review examines evidence that weight gain in the years leading up to the menopause can contribute to a woman's risk of postmenopausal breast cancer and may involve perimenopausal stimulation of growth in cancer precursor lesions. We used the Medline database since 1980 to examine studies that assessed the association between increased risk of postmenopausal breast cancer and perimenopausal weight gain or abdominal fat accumulation. This review examines possible mechanisms by which the endocrine-metabolic concomitants of hyperinsulinemia may act as late-stage promoters of mammary carcinogenesis. It was found that, in obese postmenopausal women with breast cancer, excess weight is likely to have been gained before menopause. In Western women, evidence of abdominal obesity associated with hyperinsulinemia increases progressively after the age of 40. Weight gain in the years leading up to the menopause mainly involves abdominal obesity which is associated with insulin resistance, increased free estrogen levels, and imbalance in sex steroids levels. These endocrine-metabolic changes are likely to inhibit the tendency for cancer precursor lesions to regress at the menopause and may lead to late-stage promotion of mammary carcinogenesis.

Alcohol intake and late-stage promotion of breast cancer.

Breast cancer risk in women rises with increasing alcohol intake and is widely assumed to be mediated by increased oestrogen concentrations. However, observations that mechanisms and risk are likely to differ between pre- and postmenopausal women suggest that the postmenopausal disease in particular, may involve a promoting role for concomitants of hyperinsulinaemia which is commonly associated with alcoholic cirrhosis of the liver. The MEDLINE database and ongoing studies were examined for clinical, epidemiological and laboratory data on; (a) alcohol-related increase in the incidence of breast cancer in relation to menopausal status, oestrogen concentrations and the oestrogen receptor (ER) status of the tumour; (b) activation of insulin-like growth factor 1 receptor (IGF1R) in mammary tissue by alcohol-related hyperinsulinaemia; (c) interaction between ER and IGF1R in breast cancer cell systems. Epidemiological association between alcohol intake and increased breast cancer risk is more clearly seen in postmenopausal than premenopausal women, and a significant risk is associated with intake of more than two drinks (over 30 g) daily over a period of years. Alcohol-related hyperinsulinaemia is reported to increase with increasing degrees of cirrhosis and damage to liver function. Laboratory evidence suggests that hyperinsulinaemia can stimulate expression of IGF1R in mammary tissue, and this protein is likely to have a crucial role in mitogenesis and transformation to an oestrogen-independent malignant phenotype. It is postulated that in women with a history of long-term intake of moderate quantities of alcohol, the concomitants of hyperinsulinaemia may help to stimulate progression in precancerous breast lesions in the years leading up to the menopause and may increase the risk of breast cancer manifesting after the menopause.

Association between breast and colorectal cancers.

BACKGROUND: The risk of breast and colorectal cancers in immigrants from non-industrialised countries is sharply increased when they adopt a Western lifestyle. In addition, epidemiological studies on Western populations show an association between the two tumours, both in the same individual and also in close relatives. Most studies agree that high energy intake, obesity and inadequate physical exercise are associated with an increased risk of both tumours. METHODS: Risk markers for each cancer are examined in order to identify causative nutritional factors or metabolic-endocrine dysfunction. The role of steroid hormones and other possible carcinogenic mechanisms is discussed, concentrating on evidence of a role for insulin and insulin-like growth factors (IGFs) in the promotion of carcinogenesis in both organs. RESULTS: Individuals with a genetic susceptibility to insulin resistance show triggering of hyperinsulinaemia following excessive weight gain or long-term diet high in saturated fat. Case-control studies show an association between hyperinsulinaemia and evidence of breast or colorectal carcinoma. Multiple laboratory studies show that increased activity of IGFs can stimulate the growth of human breast and colorectal cancer cells. CONCLUSION: It is postulated that either insulin resistance and its concomitants promote the development of breast and colorectal cancers, or that they share common risk factors. Sex steroid metabolism and organ specificity may explain age and sex differences between the tumours in relation to the role of obesity. Recent research suggests that a diet high in n-3 polyunsaturated fatty acids may reduce the risk of developing insulin resistance. This observation may be applied to test the hypothesis that an effect on hyperinsulinaemia may modify the risk of developing breast or colorectal cancer.

Teenage obesity in relation to breast cancer risk.

While most studies show a higher body mass in Western women to be positively associated with an increased breast cancer risk in postmenopausal women, they show a negative association in the case of premenopausal women. A review of case-control and cohort studies suggest that such protection applies mainly to obesity in teenage girls, whereas obesity appearing after the teenage years is more likely to be associated with a higher risk of postmenopausal breast cancer. The mechanisms are uncertain. There is evidence that obesity and the components of the Western diet can independently provoke hyperinsulinaemic insulin resistance at puberty, and in adolescent girls this has been related to evidence of abnormal ovarian steroidogenesis and anovulation. This may decrease promotion of mammary carcinogenesis. If however, obesity continues after the teenage years, the higher concentration of insulin-like growth factor 1 (IGF1) associated with hyperinsulinaemia can interact with oestrogen receptors in mammary epithelium to lead to increased proliferative activity. This review postulates that the observed protective effect of early obesity against premenopausal breast cancer is likely to be replaced by an increased risk of postmenopausal breast cancer if obesity continues after the teenage years. The manifestation of breast cancer is merely postponed to an older age. Recent prospective and case-control studies suggest that increased bioavailability of IGF1 is a marker of increased breast cancer risk in premenopausal women. Nutritional intake in early life may programme later activity in the growth hormone-IGF1 axis and influence the progression of transformed cells in mammary tissue. The question remains whether deliberate weight loss can reverse the effects of weight gain.

Western diet, early puberty, and breast cancer risk.

The typical high fat, low fibre diet of the industrialised West, particularly when associated with inadequate exercise, is likely to advance the onset of puberty. This will manifest in girls as an earlier menarche, earlier onset of breast development, and an earlier growth spurt. Both earlier menarche and adult tallness are markers of increased risk to breast cancer. Earlier menarche in the West is usually associated with earlier onset of hyperinsulinaemia, and multiple case-control studies report that hyperinsulinaemia too is a marker of increased breast cancer risk. Although the Western diet is linked both to earlier menarche and also to earlier hyperinsulinaemia, the mechanism involved is not necessarily the same. While menarche is likely to be triggered by a threshold level of fatness, manifestation of insulin resistance is genetically-determined and strongly influenced by the fatty acid profile of the diet. The putative mechanisms by which they influence mammary carcinogenesis also differ. Early menarche is reported to be associated with a raised oestradiol level persisting into early adult life. On the other hand, hyperinsulinaemia is commonly associated with abnormal aromatase activity in the ovaries. In addition, the concomitant increase in bioactive levels of insulin-like growth factor-I may synergise with oestrogen in stimulating proliferative activity in mammary epithelium. Dietary modification and exercise regimens are proposed in families at high risk to breast cancer. The measures have been shown to reduce insulin levels in both children and adults, and serial monitoring of insulin and sex steroid levels could be used to detect a metabolic-endocrine effect.

Essential fatty acids, insulin resistance, and breast cancer risk.

This review compares the prevalence of hyperinsulinemic insulin resistance in Caucasian-American women with that in Japanese-American and Pima Indian minority groups in the United States. It also examines the differences in breast cancer risk between these ethnic groups and suggests that risk may be modulated by ethnic genetic susceptibility to the effect of the Western diet in precipitating insulin resistance. It is widely agreed that the Western diet with its high saturated fatty acid content and high n-6/n-3 ratio of polyunsaturated fatty acids (PUFAs) favors the manifestation of hyperinsulinemia in individuals who are genetically predisposed. A number of case-control studies have shown hyperinsulinemia to be a marker of increased breast cancer risk, particularly in obese postmenopausal women. Mechanisms that have been postulated include an increased sex steroid level associated with a decreased serum level of sex hormone-binding globulin and an increased bioactive level of insulin-like growth factor I, which may synergize with estrogen in promoting mammary carcinogenesis. Dietary supplements rich in n-3 PUFAs have been shown to inhibit the growth of human breast cancer implants in nude mice, and members of the n-3 PUFA series can inhibit the growth of human breast cancer cell lines in vitro. On the basis of this experimental evidence, some have proposed dietary supplements rich in n-3 PUFAs for breast cancer protection. However, increased consumption of PUFAs requires increased intake of antioxidants. Vitamin E may be the most suitable agent, especially because of its added advantage that in animal models it is reported to reduce the incidence of carcinogen-induced mammary tumors. Preliminary trials of the combination may best be planned as adjuvant treatment after primary surgery for breast cancer, and the insulin hypothesis could be tested in the trials by monitoring fasting insulin and sex steroid levels.

Breast cancer and the western diet: role of fatty acids and antioxidant vitamins.

Epidemiological reports are inconsistent on the association between breast cancer risk and the dietary intake of either individual fatty acids or of antioxidant vitamins. It is postulated here that the inconsistencies are in part due to interactions between the two classes of nutrients at the level of the cell membrane, affecting their potential role in mammary carcinogenesis. In this review, the effects of specific dietary fatty acids and antioxidant vitamins on experimental mammary cancer systems are compared with reported epidemiological associations of the same agents with breast cancer risk in humans. An increased ratio of n-3 to n-6 polyunsaturated fatty acids (PUFAs) in the diet inhibits the growth of the rat mammary cancer model. There is also evidence that members of the n-3 PUFA series can inhibit the growth of human breast cancer cells both in vitro and in explants. Clinical trials of supplementary n-3 PUFAs in conjunction with a reduced fat intake have been proposed for breast cancer prevention. It is postulated that further dietary supplementation with vitamin E and a retinoid is likely to increase the effectiveness of such a diet. A study of this type allows better control of specific dietary components than prospective trials of dietary fat reduction which are presently under evaluation. In particular, it is suggested that studies focusing on a single nutrient often fail to recognise interactions with other nutrients.

Impaired ovulation and breast cancer risk.

Conflicting results have been reported on the association between breast cancer risk and symptoms of luteal insufficiency, such as irregular or prolonged menstrual cycles and difficulty in becoming pregnant. Studies on the association between breast cancer risk and hormonal markers of impaired ovulation have also yielded conflicting results. Inadequate allowance for body mass and fat distribution may lead to inconsistent results when assessing the association between luteal insufficiency in premenopausal women and breast cancer risk. Ovulatory function is impaired by obesity, especially if it is predominantly abdominal in distribution. The Western diet and lifestyle favour early manifestation of hyperinsulinaemic insulin resistance in genetically-predisposed women. It is commonly associated with obesity which is predominantly abdominal in distribution. In a subset of premenopausal women, the concomitants of hyperinsulinaemia may impair maturation of ovarian follicles by a direct effect of insulin or insulin-like growth factors on ovarian tissue. Even when women are ovulating regularly, obesity may be associated with luteal insufficiency as shown by decreased levels of progestins or other changes in the sex steroid profile. Insulin resistance is likely to be involved and might explain the weak reduction in breast cancer risk associated with overweight in premenopausal Western women, in contrast with the increased risk widely reported in obese post menopausal women.

Macronutrient supplements may reduce breast cancer risk: how, when and which?

OBJECTIVE: To examine evidence that specific fibre-associated macronutrients are associated with a decreased breast cancer risk. To review possible mechanisms, the age group when dietary intervention might be most effective and the choice of a suitable dietary supplement. DESIGN: This review distinguishes specific hormone-metabolic effects of dietary composition from those of body mass and fat distribution, in relation to the age at which they exert major effects on breast cancer risk. RESULTS: Both obesity and a high-fat/low-fibre diet in Western women may be associated with increased estrogen levels which are widely assumed to increase the risk of developing breast cancer. Both obesity and the Western diet are likely to stimulate insulin resistance, leading to increased levels of bioavailable estrogen. The concomitants of hyperinsulinemia may synergize with estrogen in stimulating progression of pre-neoplastic lesions in the breasts of late pre-menopausal women. Increased intake of fibre-associated macronutrients may reduce insulin resistance in addition to reducing the circulating levels of estrogen. CONCLUSIONS: The effect of dietary intervention on breast cancer risk in Western women may be tested in pre-menopausal women over the age of 40 y, with evidence of atypical hyperplasia in a breast biopsy. The most suitable fibre-associated macronutrient is still problematical but soy protein constituents have been shown to inhibit the growth of rat mammary cancer models and also of human breast cancer cell line in the laboratory.

Eating to beat breast cancer: potential role for soy supplements.

BACKGROUND: The study reviews the anticancer properties of natural isoflavones which occur in especially high concentration in soybeans. It considers the suitability of soybean products for clinical trials aiming to reduce the progression of breast cancer. METHODS: Evidence is reviewed that plant isoflavones such as genistein show cytostatic activity against human mammary cancer cell lines in vitro and can also suppress carcinogen-induced mammary cancer in young and mature rats. RESULTS: Plant isoflavones are converted in the bowel to compounds with potential antioestrogenic and antioxidative properties. These compounds show cytostatic activity for both oestrogen receptor-positive and negative human mammary cancer cell lines, and also inhibit growth and progress of the rat mammary cancer model. The high content of soybean products in the diet of Asian women has been postulated as one reason for their relatively low breast cancer incidence. CONCLUSION: Preclinical studies suggest that soybean products be given priority for clinical trials in breast cancer protection. A pilot study could test soy protein supplements as long-term adjuvant dietary treatment after primary surgery for early breast cancer, looking for a decrease in the risk of recurrence or of second primary tumours.