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Dairy Product Consumption and the Risk of Breast Cancer

Human Nutrition and Health Research, Dairy Australia, Melbourne, AUSTRALIA

Address reprint requests to: Dr Peter Parodi, 9 Hanbury St., Chermside, 4032, Queensland, AUSTRALIA. E-mail: peterparodi{at}uq.net.au

	ABSTRACT

TOP ABSTRACT INTRODUCTION DAIRY PRODUCT CONSUMPTION AND... FAT, FAT TYPE AND... INSULIN-LIKE GROWTH FACTOR AND... SEX HORMONES AND BREAST... GROWTH HORMONE COMPONENTS OF MILK WITH... CONCLUSION REFERENCES

 
It has been suggested in some reports that dairy product consumption may increase the risk of breast cancer. This review gives a brief overview of the etiology of breast cancer and in particular the roles of fat, bovine growth hormone, insulin-like growth factor-1 and estrogens. Evidence from animal studies and epidemiology does not support a role for fat in the etiology of breast cancer. The daily intake of insulin-like growth factor-1 and biologically active estrogens from dairy products is minute in comparison to the daily endogenous secretion of these factors in women, whereas bovine growth hormone is biologically inactive in humans. On the other hand, milk contains rumenic acid, vaccenic acid, branched chain fatty acids, butyric acid, cysteine-rich whey proteins, calcium and vitamin D; components, which have the potential to help prevent breast cancer. Evidence from more than 40 case-control studies and 12 cohort studies does not support an association between dairy product consumption and the risk of breast cancer.

Key words: breast cancer, dietary fat, insulin-like growth factor-1, estrogens, growth hormone, rumenic acid, calcium

Key teaching points:

• The etiology of breast cancer is still largely undetermined. A women’s reproductive history provides the most consistent evidence for risk, but the relative risk for most risk factors is close to the null value of 1.

• More than 40 case-control and 12 cohort studies do not suggest that dairy product consumption is associated with the risk of breast cancer.

• It has been suggested by some researchers that dairy products may increase the risk of breast cancer due to their content of fat, insulin-like growth factor-1, estrogens or growth hormone. However, the available evidence does not support this association.

• Animal studies and epidemiology do not suggest a role for fat in the etiology of breast cancer. Bovine growth hormone is biologically inactive in humans. Daily intake of insulin-like growth factor-1 and biologically active estrogens is insignificant compared to daily endogenous secretion in women.

• Milk contains rumenic, vaccenic, butyric and branched chain fatty acids, whey protein, calcium and vitamin D, which have the potential to protect against breast cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION DAIRY PRODUCT CONSUMPTION AND... FAT, FAT TYPE AND... INSULIN-LIKE GROWTH FACTOR AND... SEX HORMONES AND BREAST... GROWTH HORMONE COMPONENTS OF MILK WITH... CONCLUSION REFERENCES

 
Breast cancer is the most common - and most feared - malignancy in women living in developed countries, and is second only to lung cancer as a cause of cancer death. There is large international variation in breast cancer rates. In developed countries the age-standardized incidence rates are around 100/100,000 women with mortality rates about 25/100,000. These rates are up to 5-fold higher than those reported from Asian regions, which have the lowest incidence of breast cancer [1]. Breast cancer is rarely found before the age of 25 years. Thereafter, the incidence increases with age until menopause when the rate of increase is less pronounced. About three-quarters of diagnosed cases are in postmenopausal women [2–7].

Despite extensive research to find the cause of breast cancer the etiology is largely undetermined. It is estimated that around 75% of women who present with this malignancy have no established risk factors other than age and living in a western society [2]. When women migrate from a region of low incidence for breast cancer to one with a high incidence their risk does not immediately assume the rate in the host country. However, the risk in their descendants approaches that of their adopted country after two to three generations, which indicates that environmental factors are of greater importance than genetic factors [4, 5, 8, 9]. Nevertheless, breast cancer is known to cluster in families and having a first-degree relative (mother, sister, daughter) with breast cancer, especially at a young age, can double the risk of developing this cancer. Two high-penetrant genes, BRCA1 and BRCA2 account for the majority of inherited breast cancer, however, mutations in these and other low-penetrant susceptibility genes account for less than 5 to 10% of breast cancer cases [5, 10].

From the mass of epidemiological data generated over the years, characteristics of a woman’s reproductive history provide the most consistent evidence for the risk of breast cancer. Early onset of menarche, a late menopause, delayed childbirth, nulliparity and low cumulative lactation time all increase the risk of breast cancer [2, 4,5]. It is believed these factors reflect a longer lifetime exposure to endogenous steroid hormones. This is supported by observations that women with bilateral oophorectomy at an early age have a decreased risk of breast cancer compared with women who had a natural menopause [4, 11]. Further, there is a small increase in risk of breast cancer associated with long-term use of oral contraceptives and hormone replacement therapy (HRT) [3–5]. However, most of these risk factors are weak and the relative risk (RR) or odds ratio (OR), indices used to indicate the strength of risk, are seldom much greater than the null value of 1 [11].

A number of other important, although minor, risk factors have been noted. Women exposed to excessive levels of radiation, especially at a young age, are at increased risk of breast cancer [5, 12]. Increased mammographic breast density is associated with increased risk [5, 13]. Obesity is associated with a decreased risk of breast cancer in premenopausal women and an increased risk in postmenopausal women [4, 11,14]. Physical activity decreases risk [4, 5]. Height is a risk factor [4], and risk increases with increasing birth weight [15]. Most of this group of risk factors may influence or be influenced by steroid hormones. Although the role of diet in the etiology of breast cancer has been studied extensively there is no clear indication that any dietary item, apart from alcohol, is associated with breast cancer risk [16].

Special interest groups, media articles, books and some scientific papers have suggested that dairy product consumption can increase the risk of developing breast cancer. The rationale for this claim is that dairy products are a source of fat, including saturated fatty acids; insulin-like growth factor, a mitogen; estrogenic hormones, which are weak carcinogens and mutagens, and growth hormone [17–20]. The validity of these assertions is now examined.

	DAIRY PRODUCT CONSUMPTION AND BREAST CANCER RISK: EPIDEMIOLOGY

TOP ABSTRACT INTRODUCTION DAIRY PRODUCT CONSUMPTION AND... FAT, FAT TYPE AND... INSULIN-LIKE GROWTH FACTOR AND... SEX HORMONES AND BREAST... GROWTH HORMONE COMPONENTS OF MILK WITH... CONCLUSION REFERENCES

 
Some 41 case-control studies together with 12 cohort and case-control studies nested within cohort studies have determined the associations between total dairy product or specific dairy item consumption and the risk of breast cancer. Knekt and Jarvinen [21] give a description and results of studies published up to 1998, and summarize in table form the strength of association for the various studies. As part of a meta-analysis on dietary fat and breast cancer risk, Boyd et al. [22] included two dairy categories, milk (16 studies) and cheese (12 studies), which showed ORs with associated 95% confidence intervals (CIs) of 1.12 (0.88–1.43) and 1.26 (0.96–1.66), respectively. Missmer et al. [23] conducted a pooled analysis of primary data from eight large prospective studies as part of the Pooling Project of Prospective Studies of Diet and Cancer. No relation was found with dairy products analyzed as total dairy fluids, total dairy solids, ten sub-groups, or seven specific dairy foods and the risk of breast cancer.

Recently, Moorman and Terry [24] summarized the results of ten cohort and 36 case-control studies that evaluated the association between dairy product consumption and breast cancer risk. They concluded that the available epidemiological evidence dose not support a strong association between the consumption of milk or other dairy products and the risk of breast cancer. Since this report [24] results have appeared for two case-control studies and two cohort studies. One case-control study found a significant negative association between high milk intake and breast cancer risk [25]. The other study [26] found a significant negative association between a high intake of total dairy and low-fat dairy intake and the risk of breast cancer, but high-fat dairy consumption was nonsignificantly associated with risk. In the Nurses’ Health Study II [27] women with a high consumption of low-fat dairy products during their premenopausal years had a nonsignificant negative association with breast cancer risk. However, total dairy intake was nonsignificantly associated, and high-fat dairy intake was positively associated with risk. The other cohort study [28] assessed the risk of adolescent diet and the risk of breast cancer and will be discussed separately.

Adolescent Diet and the Risk of Breast Cancer
Exposure to initiating events during childhood, adolescence and early adulthood, when the mammary gland is attaining adult-stage morphology, may influence the risk of breast cancer in later life. Indeed, several studies show that the risk of breast cancer associated with alcohol consumption and cigarette smoking increases with decreasing age at which exposure to these practices commenced [29]. For women treated with high doses of ionising radiation for tuberculosis, acute postpartum mastitis, enlarged thymus and Hodgkin’s disease, the risk of breast cancer increased with decreasing age at exposure [12]. Long-term follow-up studies of the incidence of breast cancer among atomic bomb survivors from Hiroshima and Nagasaki also show increased risk with decreasing age at exposure [12].

Three cohort and four case-control studies have examined the consumption of dairy products during adolescence and the subsequent risk of breast cancer. The results of these studies are presented in Table 1. Of the 12 associations listed, ten showed a negative association between intake of dairy products and the risk of breast cancer, but only one achieved statistical significance.

	FAT, FAT TYPE AND BREAST CANCER RISK

TOP ABSTRACT INTRODUCTION DAIRY PRODUCT CONSUMPTION AND... FAT, FAT TYPE AND... INSULIN-LIKE GROWTH FACTOR AND... SEX HORMONES AND BREAST... GROWTH HORMONE COMPONENTS OF MILK WITH... CONCLUSION REFERENCES

It is now realized that in cancer studies there is an interrelationship between dietary fat and calories. In studies using rodent models of carcinogenesis in which the effects of calorie intake were separated from those of the fat content, the fat content of the diet did not significantly influence tumor development. On the other hand, calorie restriction inhibited tumor development [30, 31]. Because fat intake is highly correlated with energy intake it is essential to adjust for energy intake in epidemiological studies that assess associations between dietary fat intake and the risk of breast cancer.

Most international comparison (ecologic) studies show strong positive correlation between per capita fat consumption and mortality from breast cancer [32, 33]. Ecological studies are a poor format for determining causality. Dietary information based on national food disappearance data is a poor reflection of individual consumption and tells nothing about the diets of individuals who develop cancer and those who do not. Other dietary, environmental and reproductive patterns can vary widely between countries, and are not adjusted for in this type of study [34].

Within-population epidemiological studies can avoid much of the confounding found in ecological studies. Goodwin and Boyd [35] reviewed the published results from 14 case-control studies that examined the relationship between the intake of total fat or fat containing foods and the risk of breast cancer. Eight studies examined the relationship between total fat intake and breast cancer risk. Only one study found a statistically significant positive association. Results were inconsistent in the six studies that examined the risk for various fat containing foods. Howe et al. [36] conducted a pooled analysis of the original data from 12 case-control studies of diet and breast cancer that represented 4427 cases. The RR for the highest vs. lowest quintile of total fat was 1.13 (non-significant) for premenopausal women and 1.48 (significant) for postmenopausal women. This analysis did not include the then largest study of 2024 cases [37], or a subsequent study with 2564 cases [38], both of which did not find an association between fat intake and the risk of breast cancer.

The accuracy of associations generated by case-control studies can be affected by dietary measurement error due to unreliable nutrient databases, inaccurate assessment of past diet, and dietary recall bias by subjects who have breast cancer. Inappropriate selection of control subjects can also introduce bias [34]. Prospective (cohort) studies largely overcome these biases, because diet is assessed before cancer diagnosis, and at a time closer to its initiation. In addition, control subjects belong to the same community as cases [34].

Hunter et al. [39] conducted a collaborative-pooled analysis of original data from seven large prospective studies published up to 1995 that represented 4980 cases. The analysis found no evidence of an association between the intake of cholesterol or total, saturated, monounsaturated or polyunsaturated fat and the risk of breast cancer. There was no reduction in risk among women whose energy intake from fat was less than 20% of total energy intake. What is more, for the small number of women reporting less than 15% of energy from fat, the risk of breast cancer increased more than two-fold. A follow-up pooled analysis by Smith-Warner et al. [40], with 7,329 cases, confirmed the lack of association between total fat, fat class or animal or vegetable fat intake and the risk of breast cancer. In addition, no survival advantage was found for consumption of a low fat diet or type of fat, after diagnosis of breast cancer in participants from the Nurses’ Health Study [41]. High correlations between various dietary fatty acids in epidemiological studies reduce the ability to detect an independent association with cancer risk. Nevertheless, there is no convincing evidence from epidemiological studies that any individual fatty acid is associated with the risk of breast cancer [42].

Of the dietary items thought to protect against breast cancer, fruit and vegetables and fiber have received the most attention. However, a pooled analysis of cohort studies suggests that fruit and vegetable consumption, at least during adulthood, is not significantly associated with reduced breast cancer risk [43]. Likewise, evidence from well-conducted epidemiological studies does not suggest a protective effect for dietary fiber [16]. In contrast, there is consistent epidemiological evidence that alcohol consumption is positively associated with breast cancer risk [16]. Overall, there is no convincing evidence that fat intake is associated with the risk of breast cancer. The RRs and related confidence intervals associated with nearly all dietary items in the epidemiological studies are close to the null value of 1. This suggests that diet does not play an important role in the etiology of breast cancer.

	INSULIN-LIKE GROWTH FACTOR AND BREAST CANCER

TOP ABSTRACT INTRODUCTION DAIRY PRODUCT CONSUMPTION AND... FAT, FAT TYPE AND... INSULIN-LIKE GROWTH FACTOR AND... SEX HORMONES AND BREAST... GROWTH HORMONE COMPONENTS OF MILK WITH... CONCLUSION REFERENCES

 
The Insulin-Like Growth Factor System
Insulin-like growth factors (IGFs) belong to a larger family of insulin related peptides, which include insulin, IGF-1 and IGF-2. Together with binding proteins, binding protein proteases and receptors they form the IGF system. IGFs are mitogens that play an important function in almost every organ of the body, where they regulate cell proliferation, differentiation and apoptosis [44, 45]. IGFs, particularly IGF-1, are required for normal mammary gland development, but it is also implicated in breast cancer development [46, 47]. IGF-1 exerts its biological actions by interacting with a specific type 1 IGF-1 receptor (IGF-IR) associated with the cell membrane [45, 46]. The bioactivity of IGF-1 depends on complex physiological regulation. Only a small portion circulates in the free form; the remainder is regulated by a series of six IGF-binding proteins (IGFBP-1 through IGFBP-6), which have a somewhat stronger affinity for IGF-1 than the receptor. More than 90% of serum IGF-1 is bound in a ternary complex with IGFBP-3 and an acid-labile subunit (ALS). This complex cannot leave the circulation and serves to both increase the half-life of IGF-1 and at the same time inhibit its mitogenic effect. The presence of IGFBP proteases in tissues can cleave the binding protein and liberate free IGF-1 [44, 45,47–49]. IGFBP-3 can also modulate the IGF-1 signaling pathway independently of its IGF-1-binding ability. In mammary tissue, IGFBP-3 may interact with its own membrane receptor to inhibit growth, induce apoptosis and mediate cell growth arrest induced by other molecules [47–50].

Most IGF-1 and IGFBPs are produced in the liver under control of growth hormone, and levels can be influenced by nutritional factors. Non-hepatic tissues can also produce IGF-1 and IGFBP-3, where they exert autocrine and paracrine effects [44, 45]. In the breast, IGF-1 is expressed in stromal cells adjacent to normal or malignant epithelial cells. The extent to which circulating versus endogenously produced IGF-1 is important for mammary gland development and in tumorigenesis is still to be resolved [46, 51, 52].

Determinants of Circulating IGF-1 and IGFBP-3 Levels
Serum IGF-1 levels are low at birth, rise during childhood and reach a peak at puberty. Thereafter, values decline with age. The age-specific distribution of IGFBP-3 and ALS is similar to the distribution for IGF-1 [44, 47,53]. There is considerable heterogeneity in adult serum IGF-1 levels, with a range of 80 to 425 µg/L [53], however, an individual’s circulating level of IGF-1 and IGFBP-3 is relatively constant. Thissen et al. [54] and Yu and Rohan [47] have reviewed the determinants of circulating IGF and IGFBPs. The most consistent determinant of IGF-1 levels is dietary protein. Levels are markedly lowered by severe protein and energy restriction, with essential amino acid deficiency having a severe depressive effect. Over nutrition has the opposite effect, but not to the same extent as under nutrition. There have been few studies on dietary micro- and macronutrients, and the results are conflicting. Associations between serum IGF-1 levels and other factors, such as physical activity, energy intake within normal limits, smoking, BMI and anthropometric indices have provided divergent results [47, 54].

Epidemiological Studies
Many epidemiological studies have examined the association between circulating levels of IGF-1 and IGFBP-3 and the risk of breast cancer. Recently, three meta-analyses of these studies, using different exclusion criteria, were published [55–57]. Overall, there was a marginally significant association between high levels of circulating IGF-1 and increased risk of breast cancer in premenopausal women, but not in postmenopausal women. Surprisingly, there was no protective effect for IGFBP-3, and high levels were associated with a marginally increased risk of premenopausal breast cancer.

Breast cancer cells can produce IGF-1 [46, 47,58]. Also, because breast cancer cells secrete IGFBP-3 proteases, this can alter circulating levels of free IGF-1 without increasing its production [59], and breast cancer tissue exhibits higher IGF-1R levels than adjacent normal tissue [44, 46,47]. An interesting sequential serum IGF-1 study was conducted in a nested case-control of prostate cancer, a hormone-related epithelial malignancy with a common pathogenic framework to breast cancer. In the prostate cancer cases serum IGF-1 levels were significantly higher at the time of diagnosis than in previous samples drawn 2 to 5 years before diagnosis [60]. Thus elevated IGF-1 levels in breast cancer patients may be a marker of, rather than a cause of the disease. Further, the positive association between serum IGFBP-3 levels and the risk of breast cancer may be a consequence of the production of IGFBP-3 by breast cancer cells [61].

IGF-1 in Milk
The IGF-1 content of bovine milk varies with the stage of lactation. A recent study showed colostrum had a level of 300ng/mL and the content dropped to 7ng/mL at 1 week postpartum. Thereafter the levels dropped further to below 2ng/mL. IGFBP-3, which inhibits the mitogenic effect of IGF-1, is by far the most abundant binding protein in milk and content varies throughout lactation in a manner similar to IGF-1 [62]. At any given stage of lactation, IGF-1 levels can vary widely between cows due to many factors including parity and farm practise [63]. The level of IGF-1 in milk is not affected by pasteurisation [64].

Milk IGF-1 and Breast Cancer
Because milk contains IGF-1, which has an identical amino acid sequence to human IGF-1 [65], it has been suggested its consumption may be linked to breast cancer [17, 18]. The evidence presented to justify this connection does not stand up to serious scientific scrutiny. Firstly, the amount of IGF-1 consumed daily from milk products is minute compared to endogenous production. Based on a milk content of 4ng/mL, milk product consumption equivalent to 1.5L milk/day would contribute 6,000ng IGF-1 to the gastrointestinal tract. The gastrointestinal tract also receives considerable exogenous IGF-1 from saliva, biliary fluid, pancreatic juice and secretions from the intestinal mucosa, estimated to total 380,000ng/day [66, 67]. In addition, it is estimated that in adults the liver and extra-hepatic tissues produce 10⁷ng IGF-1/day [68]. Thus, milk-derived IGF-1 would contribute less than 0.06% of total daily IGF-1 production if it escaped proteolysis during intestinal passage, and was absorbed by the intestine and passed to the circulation. This is unlikely, as considerable, if not total, digestion of IGF-1 should take place in the small intestine [69].

Studies cited to justify absorption of IGF-1 from the intestine [17] used suckling rats. This is an inappropriate model, because neonates do not have a fully developed protease/peptidase system and intestinal closure has not occurred, which allows enhanced permeability of macromolecules. Even so, evidence from neonatal animal studies suggests that feeding IGF-1 results in negligible intestinal absorption [70]. Of greater significance, recent studies that fed human adults up to 60g/d of a concentrated bovine colostrum protein powder for up to 8 weeks did not find an increase in serum IGF-1 levels [71–73]. These studies provide compelling evidence that IGF-1 in dairy products is not implicated in the etiology of breast cancer.

Diet and Serum IGF-1 Levels
In an oft-cited study by Heaney et al. [74], subjects with habitual low dairy product consumption consumed their usual diet or their usual diet plus three servings of dairy per day. After 12 weeks serum IGF-1 levels increased by 12% in the milk drinkers, and decreased by 2% in the non-milk drinkers. However, the increase in IGF-1 levels in milk drinkers was accompanied by an increase in total protein intake and energy compared to non-milk drinkers. Total energy intake and protein consumption are the major determinants of circulating IGF-1 [47–54]. In a nested case-control study from the Physician’s Health Study there was a modest increase in serum IGF-1 levels with increasing skim or low-fat milk consumption. Nonsignificant increases were found for poultry and fish consumption [75]. In a randomised double blind study, healthy men consumed 40g of soy protein (often associated with protection from breast cancer) or milk protein daily for 3 months. Serum IGF-1 levels increased from baseline with both protein supplements, but were significantly higher only for soy protein [76]. Animal studies suggest that the essential amino acid content of dietary protein may be the important determinant for IGF-1 level [77].

	SEX HORMONES AND BREAST CANCER

TOP ABSTRACT INTRODUCTION DAIRY PRODUCT CONSUMPTION AND... FAT, FAT TYPE AND... INSULIN-LIKE GROWTH FACTOR AND... SEX HORMONES AND BREAST... GROWTH HORMONE COMPONENTS OF MILK WITH... CONCLUSION REFERENCES

 
Established risk factors for breast cancer are predominantly associated with a woman’s reproductive history, which suggests they are markers for exposure to endogenous ovarian hormones, the estrogens and progestins [3, 14]. Support for the concept that cumulative exposure to estrogens is a major determinant of breast cancer risk comes from several epidemiological studies and clinical observations. Women with bilateral oophorectomy have a lower risk of breast cancer than women who have a natural menopause. The younger the age of oophorectomy, the lower the risk [3, 4,11]. The antiestrogenic drug tamoxifen is successful in the prevention and treatment of breast cancer, especially in women with estrogen receptor (ER) positive tumours [78]. In addition, aromatase inhibitors, which prevent the aromatase enzyme catalysing the final step in estrogen biosynthesis, are also successful in the prevention and treatment of breast cancer [79].

Use of oral contraceptives slightly increases the risk of breast cancer in young women. The risk increases with increasing duration of use, and after age 45 years. [3–5,80] Epidemiological studies show there is a modest increase in risk of breast cancer associated with hormone replacement therapy (HRT). Combined estrogen and progestogen use appears to be related to a higher risk for breast cancer than estrogen alone. Overall, the risk associated with HRT use for a year is comparable to delayed menopause for the same period of time. Risk is higher for long-term users, but risk falls when use ceases [3, 81,82].

Estrogens as Carcinogens
A number of lines of evidence suggest that estradiol, the most potent estrogen, is a weak carcinogen and mutagen, although the molecular mechanisms are still incompletely understood [83–85]. Estrogens function in cells by diffusing passively through cell membranes binding to nuclear ERs and stimulating transcription of genes involved in cell proliferation. This increases the opportunity for accumulation of DNA damage that may lead to carcinogenesis. There is also accumulating evidence that estradiol can be metabolised to genotoxic compounds like 16-hydroxy estradiol and the catechol estrogen quinones that directly damage DNA [83, 85]. Estrogens act in concert and interact synergistically with elements of the IGF-1 axis. In breast cancer cells estrogens induce the expression of IGF-1 and enhance its mitogenic effect. Estrogens stimulate production of IGF-1Rs, repress synthesis of IGFBP-3 and increase the synthesis of cathepsin D, an IGFBP-3 protease. [47, 86,87].

Serum Sex Hormone Level and Breast Cancer Risk
Because of the important role for sex hormones in the etiology of breast cancer, numerous studies have investigated the association between circulating sex hormone levels, particularly estradiol, and the risk of breast cancer. The physiologically significant estrogens in order of potency are estradiol (17ß-estradiol), estrone and estriol in a ratio of about 100:10:4. Most circulating estradiol is bound to plasma proteins, sex hormone-binding globulin (SHBG) or albumin, which renders them biologically inactive [14].

Premenopausal Women.
Key [88] lists four prospective studies that reported on estrogens and breast cancer in premenopausal women. Together, they do not suggest that a higher level of serum estradiol is associated with an increased risk of breast cancer. However, a single blood sample may not represent a woman’s habitual hormone status because of large variation in hormone level during the menstrual cycle. Estradiol level varies from 6ng/100mL in the early follicular phase to 33 to 70ng/100mL in the late follicular phase, and a value around 20ng/100mL in the mid luteal phase [89].

Postmenopausal Women.
About three-quarters of diagnosed breast cancer occurs in postmenopausal women. After menopause ovarian estrogen production ceases and the major circulating estrogen is estrone (30pg/mL), which is formed by aromatization of the steroid hormone androstenedione in peripheral tissues, primarily adipose tissue. Some estrone, in turn, is metabolized to estradiol (15pg/mL) [14, 90].

The Endogenous Hormones and Breast Cancer Collaborative Group [91] conducted a pooled analysis of the original data from nine prospective studies. In postmenopausal women they found a statistically significant increase in the risk of breast cancer with increasing concentrations of all sex hormones examined. Interestingly, the association between the different levels of estrogens and breast cancer risk was stronger in never uses of HRT than users.

Determinants of Serum Estrogen Levels
Overweight, obese and sedentary postmenopausal women have elevated concentrations of circulating estrogens, and lower concentrations of SHBG [14, 92]. Exercise can reduce serum estrogen and increase SHBG levels, but the effect is dependent on loss of body fat [92]. There is no clear association between obesity and estrogen levels in premenopausal women [14]. Many studies have investigated the role of diet on serum estrogen levels, but the results are inconclusive [14]. A relationship between dietary fat and serum estrogen levels is unclear [14, 34]. Dietary fiber intake may be inversely related to concentrations of serum estrogen [14].

Estrogen Metabolism in Breast Tissue
Are high circulating levels of estrogens a cause of breast cancer, or a correlate, or a consequence of the disease? There is no simple linear relationship between serum levels and tissue concentrations of estrogens [93, 94]. The levels of estradiol in normal and malignant breast tissue are similar for both premenopausal and postmenopausal women, even though serum estrogen levels are up to 50-fold lower in postmenopausal women [93, 95,96]. However, estradiol levels are significantly higher in breast cancer tissue than in normal tissue for both premenopausal and postmenopausal women [93]. Levels of estrone sulphate, the major form of circulating estrogen in postmenopausal women, were significantly higher in their breast tumors than in those of premenopausal women [94].

The concentration of estrogens in breast tissue is far higher than in circulating plasma [94, 97,98], which suggests that local production of estrogens in breast tissue is far more important than uptake of estrogens from the circulation [85, 99]. Breast tissue contains all the enzymes necessary to synthesize the biologically active estradiol from circulating precursors. Firstly, aromatase, which converts androstenedione to estrone; secondly, estrone sulfatase that hydrolyses biologically inactive estrone sulphate to estrone; and thirdly 17ß-hydroxysteroid dehydrogenase, which reduces the weakly bioactive estrone to estradiol [85]. Human breast cancer cells can adapt to a deprivation in estradiol stimulation by developing enhanced estrogen sensitivity to the residual levels of estradiol present [100] or to the precursors of estrogen by increasing the levels of estrogen synthesizing enzymes [96].

Contribution of Milk Estrogens to Circulating Levels in Women
Steroid hormones are widely distributed in the animal and vegetable products we consume [101]. Milk contains estrone and estradiol, but the concentration varies considerably during the estrous cycle and during pregnancy, especially in estrone sulfate [102, 103].

As part of a German market basket survey Hartman et al. [101] purchased samples of dairy products and determined their content of estrone and estradiol. Based on previously published national nutritional data they calculated that a woman would consume about 0.05µg/day of estrogens from dairy products, with about 90% represented by the weakly bioactive estrone. These estrogens are largely conjugated and a large proportion of injested hormones are inactivated by the first-pass effect of the liver [101]. In contrast, during the late follicular phase of the menstrual cycle a woman produces up to 1mg/day of estradiol and 0.7 mg/day of estrone [89]. Postmenopausal women produce between 40 and 200µg/day of estrone from androstenedione, depending on their weight [90]. Thus, the contribution of dairy product consumption to a woman’s estrogen status is infinitesimal and cannot be considered a risk for breast cancer.

	GROWTH HORMONE

TOP ABSTRACT INTRODUCTION DAIRY PRODUCT CONSUMPTION AND... FAT, FAT TYPE AND... INSULIN-LIKE GROWTH FACTOR AND... SEX HORMONES AND BREAST... GROWTH HORMONE COMPONENTS OF MILK WITH... CONCLUSION REFERENCES

 
Growth hormone (GH) or somatotropin is secreted by the anterior pituitary gland, and regulates growth in most tissues from birth to puberty, although GH still has important metabolic effects in adults. GH levels are low in infancy, increase slightly during childhood and peak during puberty. Thereafter levels progressively decrease with age, but there is considerable inter-individual variation. There is also considerable intra- individual variation in GH levels, which are low during most of the day with bursts occurring after meals, exercise and emotional stress, but mostly during the first few hours of sleep. This pulsatile pattern of GH release by the pituitary gland is controlled by the hypothalamic factors; growth hormone-releasing hormone, which stimulates release of GH, and growth hormone-inhibitory hormone (somatostatin) that inhibits the release of GH [104].

GH is an essential factor in the development of the mammary gland. Acting through its receptor, GH induces stromal cells to synthesize IGF-1, which can stimulate proliferation and differentiation in adjacent epithelial cells in a paracrine manner [105]. Estradiol enhances the stimulatory effect of GH and IGF-1 on mammary gland development and in breast cancer cells [51, 87]. The GF/IGF-1 axis also plays a role in mammary tumorigenesis. GH binds to receptors in the liver to induce IGF-1, thereby elevating circulating IGF-1 levels. On the other hand, GH also increases IGFBP-3 levels [106]. Autocrine production of GH in mammary carcinoma cells can promote cell proliferation, transcriptional activation and prevention of apoptosis. Autocrine produced GH is believed to be a more potent stimulator of mammary carcinoma cell spreading than exogenously administered GH [107].

Despite the mitogenic activity of GH, relatively few studies have addressed the role of GH in the etiology of breast cancer. Animal studies using transgenic mice that over or under express GH show that GH deficiency is associated with less tumor growth, whereas over expression of GH increases tumor development [87, 108,109]. Serum GH levels in breast cancer patients were higher than in control subjects in what appears to be the only study that examined the relationship between GH level and the risk of breast cancer [110]. However, an independent role for GH in breast cancer etiology is difficult to establish because of its effect on the GH/IGF-1 axis.

Milk Derived GH
Commercial use of recombinant bovine GH (rbGH) to increase milk yield and efficiency in dairy cows commenced in the United States in 1994 [111]. This event provoked considerable debate among special interest groups, the media and in the scientific literature, as to whether milk from treated cows would cause adverse health effects [17, 18,112–114].

Bovine milk naturally contains less than 1ng/mL of GH [115], whereas humans secrete 500 to 875 µg of GH per day [104]. There is no significant increase in bGH levels in milk from cows treated with rbGH [113, 115]. Pasteurization of milk destroys about 90% of bGH [113]. Because bGH is a protein it is hydrolyzed in the intestinal tract during the digestion process. Should any bGH survive digestion it will have no effect on human biology, because the human GH receptor does not respond to bGH [63, 116].

Administration of rbGH to cows increases the level of IGF-1 in milk, but overall the impact is minimal when considered against the large variations influenced by stage of lactation, parity, nutrition and herd environment [63, 111,113]. What is more, when IGF-1 levels increase so do the levels of IGFBP-3 and ALS [111]. The unlikely survival of dietary IGF-1 in the intestinal tract to produce a biological response in humans was discussed in a previous section.

	COMPONENTS OF MILK WITH THE POTENTIAL TO PREVENT BREAST CANCER

TOP ABSTRACT INTRODUCTION DAIRY PRODUCT CONSUMPTION AND... FAT, FAT TYPE AND... INSULIN-LIKE GROWTH FACTOR AND... SEX HORMONES AND BREAST... GROWTH HORMONE COMPONENTS OF MILK WITH... CONCLUSION REFERENCES

 
The assertion that consumption of milk and its products could increase the risk of developing breast cancer because of their content of fat, IGF-1, estrogens and GH is ill founded. On the other hand, milk contains a number of components with the potential to help prevent breast cancer.

Calcium and Vitamin D
Both calcium and vitamin D play an important role in the regulation of cell growth. In addition, vitamin D, through its active metabolite 1,25-dihydroxy vitamin D₃(1,25(OH)₂D₃), is important for calcium homeostasis and absorption into cells [117, 118]. Animal studies suggest that hyperproliferation and hyperplasia in mammary epithelial cells can be reduced by dietary calcium and vitamin D [117].

There are a number of possible mechanisms for the antiproliferative action of calcium. Calcium may neutralize fatty acids and mutagenic bile acids, which can rapidly pass from the intestine to the breast where they can affect ERs and induce estrogen-regulated protein in a manner similar to estradiol [119]. Human breast cancer cells express elevated levels of fatty acid synthase [FAS], the major enzyme required for endogenous fatty acid biosynthesis, a process that has been linked to cell proliferation. Treatment of breast cancer cell lines with cerulenin, an inhibitor of FAS activity, resulted in rapid growth inhibition that was associated with apoptosis [120]. Zemel [121] recorded that high-calcium diets suppressed 1,25(OH)₂D₃-induced calcium influx into adipocytes - the predominant cells in the breast - and inhibited FAS activity.

Increased mammographic breast density is strongly associated with the risk of breast cancer [5]. A recent study showed that an increased intake of calcium and vitamin D was associated with decreases in mammographic breast density [13]. Boyapati et al. [122] recently reported that dietary calcium intake was negatively associated with the risk of breast cancer in both premenopausal and postmenopausal women. These authors also tabulated the results of seven other case-control and two cohort studies, all of which found negative associations between calcium intake and the risk of breast cancer. In the Nurses’ Health Study both calcium and dairy product intake was associated with a survival benefit for women with breast cancer [41].

Rumenic and Vaccenic Acids
Rumenic acid (RA) is the predominant natural isomer of conjugated linoleic acid (CLA), and milk fat is the richest natural source. Vaccenic acid (VA), the major trans-monounsaturated fatty acid in milk fat can be converted to RA in animals and humans by the enzyme ⁹ - desaturase [123]. In normal rat mammary epithelial cells, RA inhibited cell growth and induced apoptosis [124]. At physiological concentrations RA, VA and milk fat all arrested cell growth in breast cancer cells [125, 126]

When added to the diet of rats at a level of 1% or less, RA is a potent inhibitor of mammary tumor development. Tumor inhibition is independent of the amount or type (saturated or polyunsaturated) of fat in the diet, and is particularly effective when fed only during the period of mammary gland development to adult stage morphology. Feeding RA during this period resulted in a decrease in epithelial density associated with a reduced proliferation of the epithelial cells within the terminal end buds and lobular epithelium, areas where most tumors develop [124]. The anti-tumor action of RA is possibly additionally mediated by induction of apoptosis and inhibition of angiogenesis associated with decreased serum and glandular levels of vascular endothelial growth factor and its receptor Flk-1 [124, 127]. RA is a potent inhibitor of FAS in human breast cancer cell lines [128, 129]. As part of a CLA mixed isomer supplement, RA reduced serum IGF-1 levels in rats [130].

Epidemiological Studies.
The initial case-control study found a significant inverse association between dietary intake of RA and the risk of breast cancer in Finnish postmenopausal women. Serum levels of RA and VA also showed a significant inverse relationship to breast cancer risk [131]. A study conducted in New York [132] found that there was a nonsignificant inverse association between intake of RA and incidence of breast cancer in premenopausal but not postmenopausal women. The benefit was more apparent in women with the more aggressive ER negative tumors. Three other studies did not find a relationship between RA and breast cancer risk. The methodological limitations in these, and other RA/VA studies, have been discussed [123].

Branched-Chain Fatty Acids
Branched long-chain fatty acids (BCFA) are synthesized by rumen bacteria, and iso- and anteiso-BCFAs, particularly those with a chain length of 13 to 17 carbon atoms, are found in milk fat [123]. Initially, Yang et al. [133] reported that 13-methyltetradecanoic acid (13-MTDA) induced cell death in human breast cancer cells by rapid induction of apoptosis. Recently, Wongtangtintharn et al. [129] tested the antitumour activity of a series of iso-BCFA in two human breast cancer cell lines. The highest antitumour activity was found with iso-16:0, and the activity decreased with an increase or decrease in chain-length from iso-16:0. Anteiso-BCFAs were also cytotoxic. Interestingly, cytotoxicity of 13-MTDA was comparable to RA. Both 13-MTDA and RA inhibited FAS.

Butyric Acid
Butyric acid, uniquely present in milk fat, is a potent anticancer agent, which induces differentiation and apoptosis and inhibits proliferation and angiogenesis. Although butyrate has a short half-life in the circulation this can be increased when butyrate is present as a derivative. In the case of milk fat, butyrate is esterified as a triacylglycerol, and about one-third of all milk fat triglycerides contain butyrate. Synergy with other dietary anticancer agents like vitamin A, vitamin D and resveratrol reduce the plasma concentration of butyrate required to modulate cell growth [123]. Two studies showed that dietary butyrate significantly inhibited chemically induced mammary tumor development in rats [134, 135].

Milk Proteins
Evidence from animal studies and in vitro studies with human breast cancer cells suggest that milk proteins, especially those associated with the whey fraction, have anticarcinogenic properties [136, 137]. Whey protein is a rich source of cysteine, which is essential for the synthesis of glutathione. Glutathione is a potent cellular antioxidant and also acts by itself or by its related enzymes as a detoxifying agent that facilitates the elimination of mutagens, carcinogens and other xenobiotics from the body [136]. Results from a recent nested case-control study from within the prospective Nurses’ Health Study [138] show that women with higher plasma concentrations of cysteine had a significantly reduced risk of breast cancer.

	CONCLUSION

TOP ABSTRACT INTRODUCTION DAIRY PRODUCT CONSUMPTION AND... FAT, FAT TYPE AND... INSULIN-LIKE GROWTH FACTOR AND... SEX HORMONES AND BREAST... GROWTH HORMONE COMPONENTS OF MILK WITH... CONCLUSION REFERENCES

 
The etiology of breast cancer is still largely undetermined, although a woman’s reproductive history is considered an important determinant. A role for diet in breast cancer is not well established. An examination of the results from more than 40 case-control studies and 12 cohort studies does not support an association between dairy product consumption and the risk of breast cancer. The research that addresses theories about an association between dairy product consumption and breast cancer via fat, IGF-1, GH and estrogens was examined, however, the weight of evidence does not support a link. Although estrogens and the GH/IGF-1 axis play a critical role in the development of the mammary gland and in breast cancer, the mechanisms are complex and cancer is probably influenced more by autocrine/paracrine secretion than by circulating levels. Nevertheless, the daily contribution of these factors from dairy product consumption is far too small compared to daily endogenous secretion to exert a physiological effect. The presence of rumenic, vaccenic, butyric and branched chain fatty acids, cysteine-rich whey proteins, calcium and vitamin D in milk has the potential to help prevent breast cancer.

Received September 9, 2005.

	REFERENCES

TOP ABSTRACT INTRODUCTION DAIRY PRODUCT CONSUMPTION AND... FAT, FAT TYPE AND... INSULIN-LIKE GROWTH FACTOR AND... SEX HORMONES AND BREAST... GROWTH HORMONE COMPONENTS OF MILK WITH... CONCLUSION REFERENCES

 

1. Greenlee RT, Murray T, Bolden S, Wingo PA: Cancer statistics, 2000.CA Cancer J Clin50 :7 –33,2000 .
   
   
2. Fisher B, Osborne CK, Margolese R, Bloomer W: Neoplasms of the breast. In Holland JF, Frei E, Bast RC, Kufe DW, Morton DL, Weichselbaum RR (eds): "Cancer Medicine," 3rd ed. Philadelphia: Lee and Febiger,pp 1706 –1774,1993 .
   
   
3. Pike MC, Spicer DV, Dahmoush L, Press MF: Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk.Epidemiol Rev15 :17 –35,1993 .
   
   
4. Kuller LH: The etiology of breast cancer - From epidemiology to prevention.Public Health Rev23 :157 –213,1995 .
   
   
5. Kelsey JL, Bernstein L: Epidemiology and prevention of breast cancer.Annu Rev Public Health17 :47 –67,1996 .
   
   
6. Lacey JV, Devesa SS, Brinton LA: Recent trends in breast cancer incidence and mortality.Environ Mol Mutagen39 :82 –88,2002 .
   
   
7. Marsden J: The menopause, hormone replacement therapy and breast cancer.J Steroid Biochem Mol Biol83 :123 –132,2003 .
   
   
8. Ziegler RG, Hoover RN, Pike MC, Hildesheim A, Nomura AMY, West DW, Wu-Williams AH, Kolonel LN, Horn-Ross PL, Rosenthal JF, Hyer MB: Migration patterns and breast cancer risk in Asian-American women.J Natl Cancer Inst85 :1819 –1827,1993 .
   
   
9. Lopez-Otin C, Diamandis EP: Breast and prostate cancer: an analysis of common epidemiological, genetic, and biochemical features.Endocr Rev19 :365 –396,1998 .
   
   
10. Dunning AM, Healey CS, Pharoah PDP, Teare MD, Ponder BAJ, Easton DF: A systematic review of genetic polymorphisms and breast cancer risk.Cancer Epidemiol Biomarkers Prev8 :843 –854,1999 .
    
    
11. Harris JR, Lippman ME, Veronesi U, Willett WC: Breast cancer.N Engl J Med327 :319 –328,1992 .
    
    
12. Land CE: Studies of cancer and radiation dose among atomic bomb survivors.JAMA274 :402 –407,1995 .
    
    
13. Berube S, Diorio C, Verhoek-Oftedahl W, Brisson J: Vitamin D, calcium, and mammographic breast densities.Cancer Epidemiol Biomarkers Prev13 :1466 –1472,2004 .
    
    
14. Bernstein L, Ross RK: Endogenous hormones and breast cancer risk.Epidemiol Rev15 :48 –65,1993 .
    
    
15. Michels KB, Trichopoulos D, Robins JM, Rosner BA, Manson JE, Hunter DJ, Colditz GA, Hankinson SE, Speizer FE, Willett WC: Birthweight as a risk factor for breast cancer.Lancet348 :1542 –1546,1996 .
    
    
16. Willett WC: Diet and Breast Cancer.J InternMed 249 :395 –411,2001 .
    
    
17. Outwater JL, Nicholson A, Barnard, N: Dairy products and breast cancer: the IGF-1, estrogen, and bGH hypothesis.Med Hypoth48 :453 –461,1997 .
    
    
18. Epstein SS: Re; Role of the insulin-like growth factors in cancer development and progression.J Natl Cancer Inst93 :238 ,2001 .
    
    
19. Li XM, Ganmaa D, Sato A: The experience of Japan as a clue to the etiology of breast and ovarian cancers: relationship between death from both malignancies and dietary practices.Med Hypoth60 :268 –275,2003 .
    
    
20. Qin L-Q, Xu J-Y, Wang P-Y, Ganmaa D, Li J, Wang J, Kaneko T, Hoshi K, Shirai T, Sato A: Low-fat milk promotes the development of 7,12-dimethylbenz(a)anthracine (DMBA)-induced mammary tumors in rats.Int J Cancer110 :491 –496,2004 .
    
    
21. Knekt P, Jarvinen R: Intake of dairy products and breast cancer risk. In Yurawecz MP, Mossoba MM, Kramer JKC, Pariza MW, Nelson GJ (eds): "Advances in Conjugated Linoleic Acid Research, Volume1," Champaign, Illinois:AOAC Press ,pp 444 –470,1999
    
    
22. Boyd NF, Stone J, Vogt KN, Connelly BS, Martin LJ, Minkin S: Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature.Br J Cancer89 :1672 –1685,2003 .
    
    
23. Missmer SA, Smith-Warner SA, Spiegelman D, Yaun S-S, Adami H-O, Beeson W.L., van den Brandt PA, Fraser GE, Freudenheim JL, Goldbohm RA, Graham S, Kushi LH, Miller AB, Potter JD, Rohan TE, Speizer FE, Toniolo P, Willett WC, Wolk A, Zeleniuch-Jacquotte A, Hunter D J: Meat and dairy food consumption and breast cancer: a pooled analysis of cohort studies.Int J Epidemiol31 :78 –85,2002 .
    
    
24. Moorman PG, Terry PD: Consumption of dairy products and the risk of breast cancer: a review of the literature.Am J Clin Nutr80 :5 –14,2004 .
    
    
25. Hirose K, Takezaki T, Hamajima N, Miura S, Tajima K: Dietary factors protective against breast cancer in Japanese premenopausal and postmenopausal women.Int J Cancer107 :276 –282,2003 .
    
    
26. Shannon J, Cook LS, Stanford JL: Dietary intake and risk of postmenopausal breast cancer.Cancer Causes Control14 :19 –27,2003 .
    
    
27. Cho E, Spiegelman D, Hunter DJ, Chen WY, Stampfer MJ, Colditz GA, Willett WC, Premenopausal fat intake and risk of breast cancer.J Natl Cancer Inst.95 :1079 –1085,2003 .
    
    
28. Frazier AL, Li L, Cho E, Willett WC, Colditz GA: Adolescent diet and risk of breast cancer.Cancer Causes Control15 :73 –82,2004 .
    
    
29. Colditz GA, Frazier AL: Models of breast cancer show that risk is set by events of early life: prevention efforts must shift focus.Cancer Epidemiol Biomark Prev4 :567 –571,1995 .
    
    
30. Beth M, Berger MR, Aksoy M, Schmahl, D: Comparison between the effects of dietary fat level and of calorie intake on methylnitrosourea-induced mammary carcinogenesis in female SD rats.Int J Cancer39 :737 –744,1987 .
    
    
31. Ip C: Quantitative assessment of fat and calorie as risk factors in mammary carcinogenesis in an experimental model. In Mettlin CJ, Aoki K (eds): "Recent Progress in Research on Nutrition and Cancer." New York: Wiley-Liss, Inc,pp 107 –117,1990 .
    
    
32. Carroll KK: Experimental evidence of dietary factors and hormone-dependent cancers.Cancer Res35 :3374 –3383,1975 .
    
    
33. Rose DP, Boyar AP, Wynder EL: International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption.Cancer58 :2363 –2371,1986 .
    
    
34. Willett WC: "Nutritional Epidemiology," 2nd ed. Oxford: Oxford University Press,1998 .
    
    
35. Goodwin PJ, Boyd NF: Critical appraisal of the evidence that dietary fat intake is related to breast cancer risk in humans.J Natl Cancer Inst79 :473 –485,1987 .
    
    
36. Howe GR, Hirohata T, Hislop TG, Iscovich JM, Yuan J-M, Katsouyanni K, Lubin F, Marubini E, Modan B, Rohan T, Toniolo P, Shunzhang Y: Dietary factors and risk of breast cancer: combined analysis of 12 case-control studies.J Natl Cancer Inst82 :561 –569,1990 .
    
    
37. Graham S, Marshall J, Mettlin C, Rzepka T, Nemoto T, Byers T: Diet in the epidemiology of breast cancer.Am J. Epidemiol116 :68 –75,1982 .
    
    
38. La Vecchia C, Negri E, Franceschi S, Decarli A, Giacosa A, Lipworth L: Olive oil, other dietary fats, and the risk of breast cancer (Italy).Cancer Causes Control6 :545 –550,1995 .
    
    
39. Hunter DJ, Spiegelman D, Adami H-O, Beeson L, van den Brandt PA, Folson AR, Fraser GE, Goldbohm RA, Graham S, Howe GR, Kushi LH, Marshall JR, McDermott A, Miller AB, Speizer FE, Wolk A, Yaun S-S, Willett WC: Cohort studies of fat intake and the risk of breast cancer.N Engl J Med334 :356 –361,1996 .
    
    
40. Smith-Warner SA, Spiegelman D, Adami H-O, Beeson WL, van den Brandt PA, Folsom AR, Fraser GE, Freudenheim JL, Goldbohm RA, Graham, S, Kushi LH, Miller AB, Rohan TE, Speizer FE, Toniolo P, Willett WC, Wolk A, Zeleniuch-Jacquotte A, Hunter DJ: Types of dietary fat and breast cancer: a pooled analysis of cohort studies.Int. J Cancer92 :767 –774,2001 .
    
    
41. Holmes MD, Stampfer MJ, Colditz GA, Rosner B, Hunter DJ, Willett WC: Dietary factors and the survival of women with breast carcinoma.Cancer86 :826 –835,1999 .
    
    
42. Willett WC: Specific fatty acids and risks of breast and prostate cancer: dietary intake.Am J Clin Nutr66 :1557S –1563S,1997 .
    
    
43. Smith-Warner SA, Spiegelman D, Yaun, S-S, Adami H-O, Beeson WL, van den Brandt PA, Folsom AR, Fraser GE, Freudenheim JL, Goldbohm RA, Graham S, Miller AB, Potter JD, Rohan TE, Speizer FE, Toniolo P, Willett WC, Wolk A, Zeleniuch-Jacquotte A, Hunter DJ: Intake of fruit and vegetables and risk of breast cancer.JAMA285 :769 –776,2001 .
    
    
44. Le Roith D: Insulin-like growth factors.N Engl J Med336 :633 –640,1997 .
    
    
45. Jones JI, Clemmons DR: Insulin-like growth factors and their binding proteins: biological actions.Endocr Rev16 :3 –34,1995 .
    
    
46. Rajaram S, Baylink DJ, Mohan S: Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and function.Endocr Rev18 :801 –831,1997
    
    
47. Yu H, Rohan T: Role of the insulin-like growth factor family in cancer development and progression.J Natl Cancer Inst92 :1472 –1489,2000 .
    
    
48. Ricort J-M, Binoux M: Insulin-like growth factor (IGF) binding protein-3 inhibits type 1 IGF receptor activation independently of its IGF binding affinity.Endocrinology142 :108 –113,2 001.
    
    
49. Oh Y, Muller HL, Lamson G, Rosenfeld RG: Insulin-like growth factor (IGF)-independent action of IGF-binding protein-3 in Hs578T human breast cancer cells.J Biol Chem268 :14964 –14971,1993 .
    
    
50. Ruan W, Kleinberg DL: Insulin-like growth factor 1 is essential for terminal end bud formation and ductal morphogenesis during mammary development.Endocrinology140 :5075 –5081,1999 .
    
    
51. Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE: The effects of insulin-like growth factors on tumorigenesis and neoplastic growth.Endocr Rev21 :215 –244,2000 .
    
    
52. Wood TL, Yee D: IGFs and IGFBPs in the normal mammary gland and in breast cancer.J Mammary Gland Biol Neoplasia5 :1 –5,2000 .
    
    
53. Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K, Skakkebaek NE: Serum insulin-like growth factor-1 in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index.J Clin Endocrinol Metab78 :744 –752,1994 .
    
    
54. Thissen J-P, Ketelslegers J-M, Underwood LE: Nutritional regulation of the insulin-like growth factors.Endocr Rev15 :80 –101,1994 .
    
    
55. Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M: Insulin-like growth factor (IGF)-1, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis.Lancet363 :1346 –1353,2004 .
    
    
56. Shi R, Yu H, McLarty J, Glass J: IGF-1 and breast cancer: a meta-analysis.Int J Cancer111 :418 –423,2004 .
    
    
57. Sugumar A, Liu Y-C, Xia Q, Koh Y-S, Matsuo K: Insulin-like growth factor (IGF)-1 and IGF-binding protein 3 and the risk of premenopausal breast cancer: a meta-analysis of literature.Int J Cancer111 :293 –297,2004 .
    
    
58. Sachdev D, Yee D: The IDF system and breast cancer.Endocr Relat Cancer8 :197 –209,2001 .
    
    
59. Salahifar H, Baxter RC, Martin JL: Insulin-like growth factor binding protein (IGFBP)-3 protease activity secreted by MCF-7 breast cancer cells: Inhibition by IGFs does not require IGF-IGFBP interaction.Endocrinology138 :1683 –1690,1997 .
    
    
60. Woodson K, Tangrea JA, Pollak M, Copeland TD, Taylor PR, Virtamo J, Albanes D: Serum insulin-like growth factor 1: Tumor marker or etiologic factor? A prospective study of prostate cancer among Finnish mean.Cancer Res63 :3991 –3994,2003 .
    
    
61. Martin JL, Coverley JA, Pattison ST, Baxter RC: Insulin-like growth factor-binding protein-3 production by MCF-7 breast cancer cells: stimulation by retinoic acid and cyclic adenosine monophosphate and differential effects of estradiol.Endocrinology136 :1219 –1226,1995 .
    
    
62. Sejrsen K, Pedersen LO, Vestergaard M, Purup S: Biological activity of bovine milk. Contribution of IGF-1 and IGF binding proteins.Livest Prod Sci70 :79 –85,2001 .
    
    
63. Etherton TD, Bauman DE: Biology of somatotropin in growth and lactation of domestic animals.Physiol Rev78 :745 –761,1998 .
    
    
64. Collier RJ, Miller MA, Hildebrandt JR, Torkelson AR, White TC, Madsen KS, Vicini JL, Eppard PJ, Lanza GM: Factors affecting insulin-like growth factor-1 concentration in bovine milk.J Dairy Sci74 :2905 –2911,1991 .
    
    
65. Honegger A, Humbel RE: Insulin-like growth factors I and II in fetal and adult bovine serum.J Biol Chem261 :569 –575,1986 .
    
    
66. Chaurasia OP, Marcuard SP, Seidel ER: Insulin-like growth factor 1 in human gastrointestinal exocrine secretions.Regul Pept50 :113 –119,1994 .
    
    
67. FAO/WHO Joint Expert Committee on Food Additives (JECFA): Toxicological evaluation of certain veterinary drug residues in food, WHO Food Additives Series 41,pp 125 –146,1998 .
    
    
68. Guler H-P, Zapf J, Schmid C, Froesch ER: Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates.Acta Endocrinol (Copenh)121 :753 –758,1989 .
    
    
69. Alpers DH: Digestion and absorption of carbohydrates and proteins. In Johnson LR (ed): "Physiology of the Gastrointestinal Tract," 3rd ed. New York: Raven Press,pp 1723 –1749,1994 .
    
    
70. Burrin DG: Is milk-borne insulin-like growth factor-1 essential for neonatal development?J Nutr127 :975S –979S,1997 .
    
    
71. Coombes JS, Conacher M, Austen SK, Marshall PA: Dose effects of oral bovine colostrums on physical work capacity in cyclists.Medicine & Science in Sports & Exercise34 :1184 –1188,2002 .
    
    
72. Kuipers H, van Breada E, Verlaan G, Smeets R: Effects of oral bovine colostrum supplementation on serum insulin-like growth factor-1 levels.Nutrition18 :566 –567,2002 .
    
    
73. Buckley JD, Brinkworth GD, Abbott MJ: Effect of bovine colostrum on anaerobic exercise performance and plasma insulin-like growth factor I. J. Sports Sci21 :577 –588,2003 .
    
    
74. Heaney RP, McCarron DA, Dawson-Hughes B, Oparil S, Berga SL, Stern JS, Barr SI, Rosen CJ: Dietary changes favorably affect bone remodeling in older adults.J Am Diet Assoc99 :1228 –1233,1999 .
    
    
75. Ma J, Giovannucci E, Pollak M, Chan JM, Gaziano JM, Willett WC, Stampfer MJ: Milk intake, circulating levels of insulin-like growth factor-1, and risk of colorectal cancer in men.J Natl Cancer Inst93 :1330 –1336,2001 .
    
    
76. Khalil DA, Lucas EA, Juma S, Smith BJ, Payton ME, Arjmandi BH: Soy protein supplementation increases serum insulin-like growth factor-1 in young and old men but does not effect markers of bone metabolism.J Nutr132 :2605 –2608,2002 .
    
    
77. Ammann P, Laib A, Bonjour J-P, Meyer JM, Ruegsegger P, Rizzoli R: Dietary essential amino acid supplements increase bone strength by influencing bone mass and bone microarchitecture in ovariectomized adult rats fed on isocaloric low-protein diet.J Bone Miner Res17 :1264 –1272.
    
    
78. Jordan VC: Estrogens and antiestrogens. In Holland JF, Frei E, Bast RC, Kufe DW, Morton DL, Weichselbaum RR (eds): "Cancer Medicine," 3rd ed. Philadelphia: Lee and Febiger, pp 857–865, 1993.
    
    
79. Campos SM: Aromatase inhibitors for breast cancer in postmenopausal women.Oncologist9 :126 –136,2004 .
    
    
80. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies.Lancet347 :1713 –1727,1996 .
    
    
81. Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer.Lancet350 :1047 –1059,1997 .
    
    
82. Stahlberg C, Pedersen AT, Lynge E, Ottesen B: Hormone replacement therapy and risk of breast cancer: the role of progestins.Acta Obstet Gynecol Scand82 :335 –344,2003 .
    
    
83. Liehr JC: Is estradiol a genotoxic mutagenic carcinogen?Endocr Rev21 :40 –54,2000 .
    
    
84. Clemons M, Goss P: Estrogens and the risk of breast cancer.N Engl J Med334 :276 –285,2001 .
    
    
85. Russo J, Russo IH: Genotoxicity of steroidal estrogens.Trends Endocrinol Metab15 :211 –214,2004 .
    
    
86. Martin MB, Stoica A: Insulin-like growth factor-1 and estrogen interactions in breast cancer.J Nutr132 :3799S –3801S,2002 .
    
    
87. Laban C, Bustin SA, Jenkins PJ: The GH-IGF-1 axis and breast cancer.Trends Endocrinol Metab14 :28 –34,2003 .
    
    
88. Key TJ: Serum oestradiol and breast cancer risk.Endocr Relat Cancer6 :175 –180,1999 .
    
    
89. Hsueh AJW, Billig H: Ovarian hormone synthesis and mechanism of action. In DeGroot LJ (ed): "Endocrinology," 3rd ed. Philadelphia: WB Saunders,pp 2019 –2030,1995 .
    
    
90. Odell WD: The menopause and hormone replacement. In DeGroot LJ (ed): "Endocrinology," 3rd ed. Philadelphia: WB Saunders,pp 2128 –2139,1995 .
    
    
91. The Endogenous Hormones and Breast Cancer Collaborative Group: Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies.J Natl Cancer Inst94 :606 –616,2002 .
    
    
92. McTiernan A, Tworoger SS, Ulrich CM, Yasui Y, Irwin ML, Rajan KB, Sorensen B, Rudolph RE, Bowen D, Stanczyk FZ, Potter JD, Schwartz RS: Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial.Cancer Res.64 :2923 –2928,2004 .
    
    
93. Thijssen JHH, van Landeghem AAJ, Poortman J: Uptake and concentration of steroid hormones in mammary tissue.Ann NY Acad Sci464 :106 –116,1986 .
    
    
94. Pasqualini JR, Chetrite G, Blacker C, Feinstein M-C, Delalonde L, Talbi M, Maloche C: Concentrations of estrone, estradiol, and estrone sulphate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients.J Clin Endocrinol Metab81 :1460 –1464,1996 .
    
    
95. van Landeghem AAJ, Poortman J, Nabuurs M, Thijssen JHH: Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue.Cancer Res45 :2900 –2906,1985 .
    
    
96. Yue W, Santner SJ, Masamura S, Wang J-P, Demers LM, Hamilton C, Santen RJ: Determinants of tissue estradiol levels and biological responsiveness in breast tumors.Breast Cancer Res Treat49 :1S –7S,1998 .
    
    
97. Geisler J: Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators.J Steroid Biochem Mol Biol86 :245 –253,2003 .
    
    
98. Nakata T, Takashima S, Shiotsu Y, Murakata C, Ishida H, Akinaga S, Li P-K, Sasano H, Suzuki T, Saeki T: Role of steroid sulfatase in local formation of estrogen in post-menopausal breast cancer patients.J Steroid Biochem Mol Biol86 :455 –460,2003 .
    
    
99. Yue W, Santen RJ, Wang J-P, Hamilton CJ, Demers LM: Aromatase within the breast.Endocrine-Related Cancer6 :157 –164,1999 .
    
    
100. Masamura S, Santner SJ, Heitjan DF, Santen RJ: Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells.J Clin Endocrinol Metab80 :2918 –2925,1995 .
     
     
101. Hartmann S, Lacorn M, Steinhart H: Natural occurrence of steroid hormones in food.Food Chem62 :7 –20,1998 .
     
     
102. Henderson KM, Karanikolas M, Kenealy L, Macmillan KI: Concentrations of oestrone sulphate during pregnancy in milk from Jersey and Friesian dairy cows differing in milk yield and composition.NZ Vet J42 :89 –92,1994 .
     
     
103. Wilson SJ, Marion RS, Spain JN, Spiers DE, Keisler DH, Lucy MC: Effects of controlled heat stress on ovarian function of dairy cattle.1. Lactating cows.J Dairy Sci81 :2124 –2131,1998 .
     
     
104. Biller BMK, Daniels GH: Neuroendocrine regulation and diseases of the anterior pituitary and hypothalamus. In Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL (eds): "Harrison’s Principles of Internal Medicine," 14th ed. New York: McGraw-Hill,pp 1972 –1999,1998 .
     
     
105. Walden PD, Ruan W, Feldman M, Kleinberg DL: Evidence that the mammary fat pad mediates the action of growth hormone in mammary gland development.Endocrinology139 :659 –662,1998 .
     
     
106. Cohen P, Clemmons DR, Rosenfeld RG: Does the GH-IGF axis play a role in cancer pathogenesis? Growth Hormone & IGF Res10 :297 –305,2000 .
     
     
107. Kaulsay K, Zhu T, Bennett WF, Lee K-O, Lobie PE: The effects of autocrine human growth hormone (hGH) on human mammary carcinoma cell behavior are mediated via the hGH receptor.Endocrinology142 :767 –777,2001 .
     
     
108. Yang X-F, Beamer WG, Huynh H, Pollak M: Reduced growth of human breast cancer xenografts in hosts homozygous for the lit mutation.Cancer Res.56 :1509 –1511,1996 .
     
     
109. Swanson SM, Unterman T: The growth hormone-deficient spontaneous dwarf rat is resistant to chemically induced mammary carcinoma.Carcinogenesis23 :977 –982,2002 .
     
     
110. Emerman JT, Leahy M, Gout PW, Bruchovsky N: Elevated growth hormone levels in sera from breast cancer patients.Horm Metabol Res17 :421 –424,1985 .
     
     
111. Bauman DE: Bovine somatotropin and lactation: from basic science to commercial application.Domest Anim Endocrinol17 :101 –116,1999 .
     
     
112. Daughaday WH, Barbano DM: Bovine somatotropin supplementation of dairy cows. Is milk safe?JAMA264 :1003 –1005,1990 .
     
     
113. Juskevich JC, Guyer CG: Bovine growth hormone: human food safety evaluation.Science249 :875 –884,1990 .
     
     
114. Collier RJ, Bauman DE: Re: Re: Role of the insulin-like growth factors in cancer development and progression.J Natl Cancer Inst93 :876 , 2001.
     
     
115. Torkelson AR, Dwyer KA, Rogan GJ, Ryan RL: Radioimmunoassay of somatotropin in milk from cows administered recombinant bovine samatotropin. J Dairy Sci 70 (Suppl 1):146 ,1987 .
     
     
116. Souza SC, Frick GP, Wang X, Kopchick JJ, Lobo RB, Goodman HM: A single arginine residue determines species specificity of the human growth hormone receptor.Proc Natl Acad Sci USA92 :959 –963,1995 .
     
     
117. Lipkin M, Newmark HL: Vitamin D, calcium and prevention of breast cancer: a review.J Am Coll Nutr18 :392S –397S,1999 .
     
     
118. Colston KW, Hansen CM: Mechanisms implicated in the growth regulatory effects of vitamin D in breast cancer.Endocr Relat Cancer9 :45 –59,2001 .
     
     
119. Javitt NB, Budai K, Miller DG, Cahan AC, Raju U, Levitz M: Breast-gut connection: origin of chenodeoxycholic acid in breast cyst fluid.Lancet343 :633 –635,1994 .
     
     
120. Pizer ES, Jackisch, C, Wood FD, Pasternack GR, Davidson NE, Kuhajda FP: Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells.Cancer Res56 :2745 –2747,1996 .
     
     
121. Zemel MB, Role of dietary calcium and dairy products in modulating adiposity.Lipids38 :139 –146,2003 .
     
     
122. Boyapati SM, Shu XO, Jin F, Dai Q, Ruan Z, Gao Y-T, Zheng W: Dietary calcium intake and breast cancer risk among Chinese women in Shanghai.Nutr Cancer46 :38 –43,2003 .
     
     
123. Parodi PW: Milk fat in human nutrition.Aust J Dairy Technol59 :3 –59,2004 .
     
     
124. Ip MM, Masso-Welch PA, Ip C: Prevention of mammary cancer with conjugated linoleic acid: role of stroma and the epithelium.J Mammary Gland Biol Neoplasia8 :103 –118,2003 .
     
     
125. O’Shea M, Devery R, Lawless F, Murphy J, Stanton C: Milk fat conjugated linoleic acid (CLA) inhibits growth of mammary MCF-7 cancer cells.Anticancer Res20 :3591 –3602,2000 .
     
     
126. Miller A, McGrath E, Stanton C, Devery R: Vaccenic acid (t11–18:1) is converted to c9,t11-CLA in MCF-7 and SW480 cancer cells.Lipids38 :623 –632,2003 .
     
     
127. Masso-Welch PA, Zangani D, Ip C, Vaughan MM, Shoemaker SF, McGee SO, Ip MM: Isomers of conjugated linoleic acid differ in their effects on angiogenesis and survival of mouse mammary adipose vasculature.J Nutr134 :299 –307,2004 .
     
     
128. Oku H, Wongtangtintharn S, Iwasaki H, Toda T: Conjugated linoleic acid (CLA) inhibits fatty acid synthetase activity in vitro.Biosci Biotechnol Biochem67 :1584 –1586,2003 .
     
     
129. Wongtangtintharn S, Oku H, Iwasaki H, Toda T: Effect of branched-chain fatty acids on fatty acid biosynthesis of human breast cancer cells.J Nutr Sci Vitaminol50 :137 –143,2004 .
     
     
130. Buison A, Ordiz F, Pellizzon M, Jen K-LC: Conjugated linoleic acid does not impair fat regain but alters IGF-1 levels in weight-reduced rats.Nutr Res20 :1591 –1601,2000 .
     
     
131. Aro A, Mannisto S, Salminen I, Ovaskainen M-L, Kataja V, Uusitupa M: Inverse association between dietary and serum conjugated linoleic acid and risk of breast cancer in post menopausal women.Nutr Cancer38 :151 –157,2000 .
     
     
132. McCann SE, Ip C, Ip MM, McGuire MK, Muti P, Edge SB, Trevisan M, Freudenheim JL: Dietary intake of conjugated linoleic acids and risk of premenopausal and postmenopausal breast cancer, Western New York Exposures and Breast Cancer Study (WEB Study).Cancer Epidemiol Biomark Prev13 :1480 –1484,2004 .
     
     
133. Yang Z, Liu S, Chen X, Chen H, Huang M, Zheng J: Induction of apoptotic cell death and in vivo growth inhibition of human cancer cells by a saturated branched-chain fatty acid,13-methyltetradecanoic acid.Cancer Res60 :505 –509,2000 .
     
     
134. Yanagi S, Yamashita M, Imai S: Sodium butyrate inhibits the enhancing effect of high fat diet on mammary tumorigenesis.Oncology50 :201 –204,1993 .
     
     
135. Belobrajdic DP, McIntosh, GH: Dietary butyrate inhibits NMU-induced mammary cancer in rats.Nutr Cancer36 :217 –223,2000 .
     
     
136. Parodi PW: A role for milk proteins in cancer prevention.Aust J Dairy Technol.53 :37 –47,1998 .
     
     
137. Hakkak R, Korourian S, Shelnutt SR, Lensing S, Ronis MJJ, Badger TM: Diets containing whey proteins or soy protein isolate protect against 7,12-dimethylbenz(a)anthracine-induced mammary tumors in female rats.Cancer Epidemiol Biomark Prev9 :113 –117,2000 .
     
     
138. Zhang SM, Willett WC, Selhub J, Manson JE, Colditz GA, Hankinson SE: A prospective study of plasma total cysteine and risk of breast cancer.Cancer Epidemiol Biomark Prev12 :1188 –1193,2003 .
     
     
139. Shin M-H, Holmes MD, Hankinson SE, Wu K, Colditz GA, Willett WC: Intake of dairy products, calcium, and Vitamin D and risk of breast cancer.J Natl Cancer Inst94 :1301 –1311,2002 .
     
     
140. Hjartaker A, Laake P, Lund E: Childhood and adult milk consumption and risk of premenopausal breast cancer in a cohort of 48,844 women - the Norwegian Women and Cancer Study.Int J Cancer93 :888 –893,2001 .
     
     
141. Shu XO, Jin F, Dai Q, Wen W, Potter JD, Kushi LH, Ruan Z, Gao Y-T, Zheng W: Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women.Cancer Epidemiol Biomark Prev10 :483 –488,2001 .
     
     
142. Potischman N, Weiss HA, Swanson CA, Coates RJ, Gammon MD, Malone KE, Brogan D, Stanford JL, Hoover RN, Brinton LA: Diet during adolescence and risk of breast cancer among young women.J Natl Cancer Inst90 :226 –233,1998 .
     
     
143. Pryor M, Slattery ML, Robison LM, Egger M: Adolescent diet and breast cancer in Utah.Cancer Res49 :2161 –2167,1989 .
     
     
144. Hislop TG, Coldman AJ, Elwood JM, Brauer G, Kan L: Childood and recent eating patterns and risk of breast cancer.Cancer Detect Prev9 :47 –58,1986 .
     

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