Point-counterpoint: Soy Intake for Breast Cancer Patients

Integrative Cancer Therapies. Mar, 2002  |  Pubmed ID: 14664752

Do Estrogens Always Increase Breast Cancer Risk?

The Journal of Steroid Biochemistry and Molecular Biology. Feb, 2002  |  Pubmed ID: 11897501

The etiology of breast cancer is closely linked to the female hormone estrogen, with high life-time exposure being suggested to increase breast cancer risk [Nature 303 (1983) 767]. However, there appears to be a disparity between studies attempting to establish an association between high estrogen levels and breast cancer risk. This disparity becomes smaller by taking into consideration a timing factor, and we propose that estrogens can increase, decrease, or have no effect on breast cancer risk, depending on the timing of estrogen exposure. We further propose that the timing of estrogenic exposures may play at least as important a role in affecting breast cancer risk as life-time exposure.

Dietary Modulation of Pregnancy Estrogen Levels and Breast Cancer Risk Among Female Rat Offspring

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Nov, 2002  |  Pubmed ID: 12429652

Against the hypothesis that high estrogen levels in utero increase the risk of developing breast cancer in later life are data showing that pregnancy estrogen levels are significantly higher in Asian women who have low breast cancer risk than in Caucasian women. We investigated whether maternal dietary intake of genistein or n-3 polyunsaturated fatty acids (PUFAs), which are typical to Asian but not Caucasian diet, affect pregnancy estrogen levels and susceptibility to mammary tumorigenesis among offspring.

Cadmium Mimics the in Vivo Effects of Estrogen in the Uterus and Mammary Gland

Nature Medicine. Aug, 2003  |  Pubmed ID: 12858169

It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.

Antiestrogen Resistance in Breast Cancer and the Role of Estrogen Receptor Signaling

Oncogene. Oct, 2003  |  Pubmed ID: 14576841

Antiestrogens include agents such as tamoxifen, toremifene, raloxifene, and fulvestrant. Currently, tamoxifen is the only drug approved for use in breast cancer chemoprevention, and it remains the treatment of choice for most women with hormone receptor positive, invasive breast carcinoma. While antiestrogens have been available since the early 1970s, we still do not fully understand their mechanisms of action and resistance. Essentially, two forms of antiestrogen resistance occur: de novo resistance and acquired resistance. Absence of estrogen receptor (ER) expression is the most common de novo resistance mechanism, whereas a complete loss of ER expression is not common in acquired resistance. Antiestrogen unresponsiveness appears to be the major acquired resistance phenotype, with a switch to an antiestrogen-stimulated growth being a minor phenotype. Since antiestrogens compete with estrogens for binding to ER, clinical response to antiestrogens may be affected by exogenous estrogenic exposures. Such exposures include estrogenic hormone replacement therapies and dietary and environmental exposures that directly or indirectly increase a tumor's estrogenic environment. Whether antiestrogen resistance can be conferred by a switch from predominantly ERalpha to ERbeta expression remains unanswered, but predicting response to antiestrogen therapy requires only measurement of ERalpha expression. The role of altered receptor coactivator or corepressor expression in antiestrogen resistance also is unclear, and understanding their roles may be confounded by their ubiquitous expression and functional redundancy. We have proposed a gene network approach to exploring the mechanistic aspects of antiestrogen resistance. Using transcriptome and proteome analyses, we have begun to identify candidate genes that comprise one component of a larger, putative gene network. These candidate genes include NFkappaB, interferon regulatory factor-1, nucleophosmin, and the X-box binding protein-1. The network also may involve signaling through ras and MAPK, implicating crosstalk with growth factors and cytokines. Ultimately, signaling affects the expression/function of the proliferation and/or apoptotic machineries.

Prepubertal Estradiol and Genistein Exposures Up-regulate BRCA1 MRNA and Reduce Mammary Tumorigenesis

Carcinogenesis. May, 2004  |  Pubmed ID: 14729590

Prepubertal exposure to soy or its biologically active component genistein reduces later breast cancer risk in both animal models and human populations. We investigated whether that might be due to reported estrogenic properties of genistein. Our study indicated that daily prepubertal exposures between postnatal days 7 and 20 to 10 microg 17beta-estradiol (E2) reduced later risk of developing 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Assessment of mammary gland morphology revealed that both prepubertal E2 and genistein (50 microg daily) exposures reduced the size of mammary epithelial area and number of terminal end buds (TEBs) and increased the density of lobulo-alveolar structures, suggesting that these exposures induced elimination of targets for malignant transformation by differentiation. Next, the mechanisms mediating the protective effects of E2 and genistein were investigated. E2 is shown to up-regulate BRCA1, a tumor suppressor gene that participates in DNA damage repair processes and cell differentiation and that down-regulates the activity of estrogen receptor (ER)-alpha. The expression of BRCA1 mRNA was up-regulated in the mammary glands of rats exposed to E2 or genistein during prepuberty, when determined at the ages of 3, 8 and 16 weeks. Prepubertal E2 exposure reduced ER-alpha levels in the mammary gland, while prepubertal genistein exposure had an opposite effect. Our results suggest that prepubertal estrogenic exposures may reduce later breast cancer risk by inducing a persistent up-regulation of BRCA1 in the mammary gland.

Pregnancy Weight Gain and Breast Cancer Risk

BMC Women's Health. Oct, 2004  |  Pubmed ID: 15498103

BACKGROUND: Elevated pregnancy estrogen levels are associated with increased risk of developing breast cancer in mothers. We studied whether pregnancy weight gain that has been linked to high circulating estrogen levels, affects a mother's breast cancer risk. METHODS: Our cohort consisted of women who were pregnant between 1954-1963 in Helsinki, Finland, 2,089 of which were eligible for the study. Pregnancy data were collected from patient records of maternity centers. 123 subsequent breast cancer cases were identified through a record linkage to the Finnish Cancer Registry, and the mean age at diagnosis was 56 years (range 35 - 74). A sample of 979 women (123 cases, 856 controls) from the cohort was linked to the Hospital Inpatient Registry to obtain information on the women's stay in hospitals. RESULTS: Mothers in the upper tertile of pregnancy weight gain (>15 kg) had a 1.62-fold (95% CI 1.03-2.53) higher breast cancer risk than mothers who gained the recommended amount (the middle tertile, mean: 12.9 kg, range 11-15 kg), after adjusting for mother's age at menarche, age at first birth, age at index pregnancy, parity at the index birth, and body mass index (BMI) before the index pregnancy. In a separate nested case-control study (n = 65 cases and 431 controls), adjustment for BMI at the time of breast cancer diagnosis did not modify the findings. CONCLUSIONS: Our study suggests that high pregnancy weight gain increases later breast cancer risk, independently from body weight at the time of diagnosis.

Opposing Effects of Prepubertal Low- and High-fat N-3 Polyunsaturated Fatty Acid Diets on Rat Mammary Tumorigenesis

Carcinogenesis. Sep, 2005  |  Pubmed ID: 15888492

To determine whether dietary fat intake during childhood affects the later risk of developing breast cancer, we fed prepubertal rats between post-natal days 5 and 25 a low (16% energy) or high-fat (39% energy) diet composed mainly of n-6 or n-3 polyunsaturated fatty acids (PUFAs) originating either from corn oil or menhaden oil, respectively, in the ratios of 16-17:1 (n-6 PUFA diets) or 2-3:1 (n-3 PUFA diets). We also examined whether changes in risk are associated with perturbations in biological processes previously linked to fatty acid intake and breast cancer. Mammary tumorigenesis was induced by treating 50-day-old rats with the carcinogen 7,12-dimethylbenz[a]anthracene. When compared with the reference low-fat n-6 PUFA diet, prepubertal exposure to the low-fat n-3 PUFA diet decreased, whereas a high-fat n-3 PUFA diet increased mammary tumor incidence; the high-fat n-6 PUFA diet had no effect. Both the low and high-fat n-3 PUFA diets induced mammary epithelial differentiation by reducing the number of terminal end buds (TEBs) and increasing the presence of lobulo-alveolar structures. They also increased lipid peroxidation and reduced cyclooxygenase-2 activity. Prepubertal exposure to the low-fat n-3 PUFA diet increased apoptosis, determined using TUNEL assay, and reduced cell proliferation, determined using PCNA staining. In marked contrast, prepubertal exposure to the high-fat n-3 PUFA diet induced cell proliferation and inhibited apoptosis in the TEBs and lobular structures. The latter is consistent with the finding that pAkt, a survival factor that inhibits apoptosis, was elevated in their mammary glands. In summary, although prepubertal exposure to a low-fat n-3 PUFA diet reduced later mammary tumorigenesis in rats, high levels of this fatty acid can have adverse effects on the prepubertal mammary gland and increase subsequent breast cancer risk.

Steroid Hormone Levels in Pregnancy and 1 Year Postpartum Using Isotope Dilution Tandem Mass Spectrometry

Fertility and Sterility. Sep, 2005  |  Pubmed ID: 16169406

To establish normal, trimester-specific reference intervals for serum 17beta-estradiol, progesterone (P), 17alpha-hydroxyprogesterone, cortisol, 11-deoxycortisol, androstenedione, DHEA, and DHEAS, measured simultaneously using isotope dilution tandem mass spectrometry.

Mechanisms Mediating the Effects of Prepubertal (n-3) Polyunsaturated Fatty Acid Diet on Breast Cancer Risk in Rats

The Journal of Nutrition. Dec, 2005  |  Pubmed ID: 16317153

Dietary exposures during childhood may influence later breast cancer risk. We tested in an animal model the hypothesis that prepubertal intake of (n-3) PUFAs, present mainly in fish, reduces susceptibility to breast cancer. Between postnatal days 5 to 25, rat pups were fed (n-3) PUFA-containing diets at a 2:1 ratio of (n-6):(n-3) PUFAs (typical of prehistoric societies) or a control (n-6) PUFA diet at a 17:1 ratio of (n-6):(n-3) PUFAs (comparable with current Western societies). These fatty acids were given in a low- or high-fat context (16 or 39% energy from fat). The low-(n-3) PUFA diet reduced while the high-(n-3) PUFA diet increased carcinogen-induced mammary tumorigenesis. The low-(n-3) PUFA diet reduced mammary cell proliferation and increased apoptosis, particularly in the terminal end buds (the mammary source of malignant breast tumors). The high-(n-3) PUFA diet had opposite effects on these 2 key biomarkers and increased phospho-Akt levels, a survival factor. Microarray analyses identified genes that were permanently upregulated in the low-(n-3) PUFA-exposed glands and function in oxidative damage repair. Serum levels of 8-hydroxy-2'deoxyguanosine, a marker of DNA damage, were significantly reduced in these low-(n-3) PUFA-fed rats, and increased in the high-(n-3) PUFA-exposed group. The latter group exhibited reduced expression of BRCA1, a DNA repair gene. Our results indicate that the opposing susceptibilities to mammary tumorigenesis between the low- versus high-fat (n-3) PUFA-exposed groups were associated with altered DNA damage repair and gene expression linked to proliferation, survival, and differentiation.

Pregnancy Weight Gain and Premenopausal Breast Cancer Risk

The Journal of Reproductive Medicine. Nov, 2005  |  Pubmed ID: 16419626

To investigate whether excessive weight gain during pregnancy alters a woman's risk of developing premenopausal breast cancer.

Excessive Weight Gain During Pregnancy Increases Carcinogen-induced Mammary Tumorigenesis in Sprague-Dawley and Lean and Obese Zucker Rats

The Journal of Nutrition. Apr, 2006  |  Pubmed ID: 16549464

Excessive weight gain during pregnancy increases breast cancer risk in women. To determine whether this may be caused by increased pregnancy leptin levels, leptin receptor (Ob-Rb) mutant (fa/fa) and wild-type (FA/FA) female Zucker rats and Sprague-Dawley rats were fed during pregnancy an obesity-inducing high-fat diet (OID) that increased pregnancy weight gain, or a control diet. Because mutant Zucker rats do not readily become pregnant, their pregnancy was mimicked by exposing the rats to subcutaneous silastic capsules containing 150 microg of estradiol and 30 mg of progesterone for 3 wk. Sprague-Dawley rats underwent normal pregnancy. An assessment of hormone levels on gestation d 17 indicated that an exposure to the OID significantly elevated serum leptin concentration but did not affect those of estradiol or insulin-like growth factor 1 (IGF-1). Insulin and adiponectin levels were higher in the obese than lean Zucker rats, but were not related to pregnancy weight gain. Exposure to the OID during pregnancy increased 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis in all genetic backgrounds, including leptin receptor mutant Zucker rats. The results also indicated that obese Zucker rats that underwent mimicked pregnancy developed more palpable tumors and hyperplastic alveolar nodules that lean Zucker rats. Further, mammary epithelial cell proliferation assessed using PCNA staining was elevated in obese Zucker rats as was activation of mitogen-activated protein kinase (MAPK); however, neither of these 2 changes occurred in the context of excessive weight gain during pregnancy. It remains to be determined whether an increase in leptin levels was causally associated with an increase in the dams' mammary tumorigenesis, including in obese Zucker rats with dramatically reduced leptin signaling.

Meta-analysis of Soy Intake and Breast Cancer Risk

Journal of the National Cancer Institute. Apr, 2006  |  Pubmed ID: 16595782

High intake of soy foods has been proposed to contribute to the low breast cancer risk in Asian countries. However, results of epidemiologic studies of this association are highly variable, and experimental data suggest that soy constituents can be estrogenic and potentially risk enhancing. Thus, rigorous evaluation of available epidemiologic data is necessary before appropriate recommendations can be made, especially for women at high risk of breast cancer or those who have survived the disease.

High Birth Weight Increases Mammary Tumorigenesis in Rats

International Journal of Cancer. Journal International Du Cancer. Oct, 2006  |  Pubmed ID: 16646052

Epidemiological studies have investigated whether a high birth weight is associated with increased breast cancer risk, but the results remain inconclusive. This study was designed to determine whether high birth weight increases later susceptibility to carcinogen-induced mammary tumorigenesis in an animal model and to determine mechanisms mediating this association. Pregnant female Sprague Dawley rats were fed either a control or a high-fat diet during the extent of gestation. Maternal exposure to the high-fat diet increased pregnancy leptin levels and offspring's birth weight, but had no effect on pregnancy estradiol or insulin-like growth factor 1 levels. Changes in the offspring's mammary gland morphology and protein expression were assessed. The mammary epithelial tree of the high-birth-weight offspring was denser, contained more terminal end buds and exhibited higher number of proliferating cells. Further, their mammary glands expressed lower levels of ER-alpha, but higher levels of activated MAPK. No alterations in apoptosis were noted. High-birth-weight rats developed 7,12-dimethylbenz[a]anthracene-induced mammary tumors significantly earlier, and tumors grew larger than in the controls. The tumors in this group expressed higher levels of leptin receptor and activated Akt, and contained fewer apoptotic cells than those in the controls. Our results indicate that high birth weight is related to shortened latency to develop mammary tumors--perhaps reflecting an increase in activated MAPK levels and increased tumor growth--perhaps caused by a lower apoptotic response due to higher leptin receptor and activated Akt levels in the tumors.

Maternal Dietary Exposure to Fiber During Pregnancy and Mammary Tumorigenesis Among Rat Offspring

International Journal of Cancer. Journal International Du Cancer. Nov, 2006  |  Pubmed ID: 16921499

Maternal diet during pregnancy has been proposed to modify female offspring's later susceptibility to develop breast cancer; however, most of the dietary factors identified thus far have led to increased risk. To identify dietary factors that might reduce offspring's breast cancer risk, pregnant rat dams were fed diets containing 6% fiber originating either from cellulose (control), or oat, whole wheat or defatted flax flour. At birth, dams were switched to the AIN93 semi-purified diet. Mammary tumor incidence and multiplicity, induced by administering the offspring 5 mg 7,12-dimethylbenz[a]anthracene (DMBA) at the age of 50 days, was reduced in the whole wheat flour-exposed offspring and increased in the defatted flax-exposed offspring. To identify the mechanisms mediating the effects of in utero dietary exposures, changes in mammary gland morphology and gene expression were assessed before puberty onset (3 weeks of age) and at the time rats are most susceptible to malignant transformation (8 weeks of age). The number of terminal end buds (TEBs), i.e., the targets of malignant transformation, was reduced in the mammary glands of whole wheat- and oat flour-exposed offspring, as compared to the controls. Further, the number of apoptotic epithelial cells (based on ISOL assay) was elevated in the whole wheat flour offspring, but no changes in cell proliferation (PCNA), estrogen receptor alpha (ER-alpha) or cyclin D1 mRNA or protein levels were seen. The mRNA and/or protein levels of BRCA1 and p53 were significantly increased in the mammary glands of whole wheat flour offspring. Further, the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA damage, were significantly reduced in these rats, suggesting that maternal dietary exposure to whole wheat during pregnancy may reduce offspring's breast cancer risk by improving DNA damage repair mechanisms.

Differentiation of Mammary Gland As a Mechanism to Reduce Breast Cancer Risk

The Journal of Nutrition. Oct, 2006  |  Pubmed ID: 16988155

Fetal Origins of Breast Cancer

Trends in Endocrinology and Metabolism: TEM. Nov, 2006  |  Pubmed ID: 16997567

Susceptibility to breast cancer might be pre-determined in utero. Alterations in the fetal hormonal environment, caused by either maternal diet or exposure to environmental factors with endocrine activities, can modify the epigenome, and these modifications are inherited in somatic daughter cells and maintained throughout life. These epigenetic modifications might lead to changes in mammary gland development, such as increased vulnerability of epithelial targets for malignant transformation. According to this hypothesis, on post-pubertal exposure to an initiating factor, such as a carcinogen, high levels of hormones and radiation, the mammary epithelial targets, perhaps stem cells, in terminal end buds/terminal ductal lobular units would be at an increased risk of malignant transformation. The increased susceptibility for cancer initiation might result from high levels of cell proliferation, reduced apoptosis and/or altered stromal regulation. Thus, maternal diet and environmental exposure might increase the risk of breast cancer by inducing permanent epigenetic changes in the fetus that alter the susceptibility to factors that can initiate breast cancer. Identifying the epigenetically altered target genes and their ligands might lead to strategies to prevent this disease in some women.

Timing of Dietary Estrogenic Exposures and Breast Cancer Risk

Annals of the New York Academy of Sciences. Nov, 2006  |  Pubmed ID: 17261753

The same dietary component, such as fat or phytochemicals in plant foods, can have an opposite effect on breast cancer risk if exposed in utero through a pregnant mother or at puberty. Dietary exposures during pregnancy often have similar effects on breast cancer risk among mothers and their female offspring. High fat intake and obesity are illustrative examples: excessive pregnancy weight gain that increases high birth weight is associated with increased breast cancer risk among mothers and daughters. High body weight during childhood is inversely linked to later breast cancer risk. The main reason why the age when dietary exposures occur determines their effect on breast cancer risk likely reflects the extensive programming of the mammary gland during fetal life and subsequent reprogramming at puberty and pregnancy. Programming is a series of epigenetic/transcriptional modifications in gene expression that can be influenced by changes in the hormonal environment induced, for example, by diet. Because epigenetic modifications are inherited by daughter cells, they can persist throughout life if they occur in mammary stem cells or uncommitted mammary myoepithelial or luminal progenitor cells. Our results indicate that the estrogen receptor (ER), mitogen-activated protein kinase (MAPK), and the tumor suppressors BRCA1, p53, and caveolin-1 are among the genes affected by diet-induced alterations in programming/reprogramming. Consequently, mammary gland morphology may be altered in a manner that increases or reduces susceptibility to malignant transformation, including an increase/reduction in cell proliferation, differentiation, and survival, or in the number of terminal end buds (TEBs) or pregnancy-induced mammary epithelial cells (PI-MECs) that are the sites where breast cancer is initiated. Thus, dietary exposures during pregnancy and puberty may play an important role in determining later risk by inducing epigenetic changes that modify vulnerability to breast cancer.

Maternal Flaxseed Diet During Pregnancy or Lactation Increases Female Rat Offspring's Susceptibility to Carcinogen-induced Mammary Tumorigenesis

Reproductive Toxicology (Elmsford, N.Y.). Apr-May, 2007  |  Pubmed ID: 17398067

Flaxseed contains several dietary components that have been linked to low breast cancer risk; i.e., n-3 polyunsaturated fatty acids (PUFAs), lignans and fiber, but it also contains detectable levels of cadmium, a heavy metal that activates the estrogen receptor (ER). Since estrogenic exposures early in life modify susceptibility to develop breast cancer, we wondered whether maternal dietary intake of 5% or 10% flaxseed during pregnancy or lactation (between postpartum days 5 and 25) might affect 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis in the rat offspring. Our data indicated that both in utero and postnatal 5% and 10% flaxseed exposures shortened mammary tumor latency, and 10% flaxseed exposure increased tumor multiplicity, compared to the controls. Further, when assessed in 8-week-old rats, in utero 10% flaxseed exposure increased lobular ER-alpha protein levels, and both in utero and postnatal flaxseed exposures dose-dependently reduced ER-beta protein levels in the terminal end buds (TEBs) lobules and ducts. Exposures to flaxseed did not alter the number of TEBs or affect cell proliferation within the epithelial structures. In a separate group of immature rats that were fed 5% defatted flaxseed diet (flaxseed source different than in the diets fed to pregnant or lactating rats) for 7 days, cadmium exposure through the diet was six-fold higher than allowed for humans by World Health Organization, and cadmium significantly accumulated in the liver and kidneys of the rats. It remains to be determined whether the increased mammary cancer in rats exposed to flaxseed through a maternal diet in utero or lactation was caused by cadmium present in flaxseed, and whether the reduced mammary ER-beta content was causally linked to increased mammary cancer risk among the offspring.

Nutritional Modulation of Terminal End Buds: Its Relevance to Breast Cancer Prevention

Current Cancer Drug Targets. Aug, 2007  |  Pubmed ID: 17691906

Findings with experimental rodent models reveal that exposures to dietary factors during the in utero and pubertal periods when the mammary gland is undergoing extensive modeling and re-modeling, alter susceptibility to develop mammary tumors. Similar observations have been made in humans: childhood exposure to genistein in soy or to some other bioactive food components reduces later breast cancer risk, although they may have no effect if consumed during adulthood. Thus, food components may be more effective in affecting cancer risk in some periods of life than others. Many of these dietary exposures modify fetal and postnatal hormonal environment, including changing the concentrations of estrogens and leptin. The hormonal alterations then may induce persistent epigenetic changes by affecting gene promoter regions or by inducing histone modifications that affect chromatin transcription. The targets of epigenetic changes are likely to be the terminal end buds (TEBs), the structures where carcinogen-induced mammary tumors in rats and mice are initiated. More specifically, the site of these changes in TEBs may be the stem cells and their niche; this might explain how an exposure early in life affects the risk of breast cancer decades later. Similar structures in women, called terminal ductal lobular units, are the sites where most human breast cancers rise. According to this hypothetical model, cancer is initiated only when the epigenetically altered cells are exposed to carcinogens/radiation, etc. during adult life. In a "normal" stem cell or its niche, cancer initiating exposures do not necessarily cause cancer, because the cells can either repair the damage or undergo apoptosis. Thus, the most likely molecular targets of early life dietary exposures are genes that regulate DNA adduct formation, repair DNA damage or induce apoptosis, such as genes affecting cellular metabolism, tumor suppressor genes or genes promoting cell survival. It is possible that some of these epigenetic changes also explain why the number of TEBs generally, but not always, correlates with breast cancer risk. This hypothesis may imply that adult intake of some bioactive dietary components reduces cancer risk increased by early life dietary exposures or inhibits tumor growth by reversing epigenetic changes in various molecular targets.

Effects of Pre-pregnancy Physical Activity and Maternal BMI on Gestational Weight Gain and Birth Weight

Acta Obstetricia Et Gynecologica Scandinavica. 2008  |  Pubmed ID: 18446535

Western women frequently exhibit excessive gestational weight gain (GWG). The effects of maternal physical activity level (PAL) and body mass index (BMI) on the timing of GWG are insufficiently known.

Infant Feeding and the Incidence of Endometrial Cancer

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. Jun, 2008  |  Pubmed ID: 18541614

Biological mechanisms could support both an inverse and a direct association between exposure to breast milk in infancy and the risk of cancer. Having been breast-fed has been investigated in relation to the risk of breast and other cancer sites, and conflicting results have been reported. The association between infant feeding and the risk of endometrial cancer has not been explored. From 1976 to 2004, we followed 74,757 cancer-free participants in the Nurses' Health Study who had not undergone hysterectomy. Information on infant feeding was self-reported by study participants. A total of 708 incident cases of endometrial cancer were diagnosed during follow-up. After adjusting for age, family history of endometrial cancer, birth weight, premature birth, and birth order, the incidence of endometrial cancer was not associated with ever having been breast-fed (hazards ratio, 0.94; 95% confidence interval, 0.79-1.11) or duration of having been breast-fed [hazards ratio (95% confidence interval): 1.11 (0.80-1.54), 0.84 (0.62-1.13), 1.02 (0.79-1.31), respectively, for < or =3, 4-8, and > or =9 months of having been breastfed; P for trend = 0.88]. There was no significant effect modification by menopausal status, anthropometric factors (somatotype at age 5 or 10 years, body mass index at age 18 years, or current body mass index), or by other early-life exposures (birth weight, premature birth or exposure to parental smoking in childhood). Additional adjustment for adulthood risk factors of endometrial cancer did not materially change the results. Having been breast-fed was not associated with the incidence of endometrial cancer in this cohort, but statistical power for analyses restricted to premenopausal women was limited.

Gene Signaling Pathways Mediating the Opposite Effects of Prepubertal Low-fat and High-fat N-3 Polyunsaturated Fatty Acid Diets on Mammary Cancer Risk

Cancer Prevention Research (Philadelphia, Pa.). Dec, 2008  |  Pubmed ID: 19139003

In rats, prepubertal exposure to low-fat diet containing n-3 polyunsaturated fatty acids (PUFA) reduces mammary cell proliferation, increases apoptosis, and lowers risk of mammary tumors in adulthood, whereas prepubertal high-fat n-3 PUFA exposure has opposite effects. To identify signaling pathways mediating these effects, we performed gene microarray analyses and determined protein levels of genes related to mammary epithelial cell proliferation. Nursing female rats and rat pups were fed low-fat (16% energy from fat) or high-fat (39% energy from fat) n-3 or n-6 PUFA diets between postnatal days 5 and 24. cDNA gene expression microarrays were used to identify global changes in the mammary glands of 50-day-old rats. Differences in gene expression were confirmed by real-time quantitative PCR, and immunohistochemistry was used to assess changes in the peroxisome proliferator-activated receptor gamma and cyclin D1 levels. DNA damage was determined by 8-hydroxy-2'-deoxyguanosine assay. Expressions of the antioxidant genes thioredoxin, heme oxygenase, NADP-dependent isocitrate dehydrogenase, and metallothionein III, as well as peroxisome proliferator-activated receptor gamma protein, were increased in the mammary glands of 50-day-old rats prepubertally fed the low-fat n-3 PUFA diet. Prepubertal exposure to the high-fat n-3 PUFA diet increased DNA damage and cyclin D1 protein and reduced expression of BRCA1 and cardiotrophin-1. Reduction in mammary tumorigenesis among rats prepubertally fed a low-fat n-3 PUFA diet was associated with an up-regulation of antioxidant genes, whereas the increase in mammary tumorigenesis in the high-fat n-3 PUFA fed rats was linked to up-regulation of genes that induce cell proliferation and down-regulation of genes that repair DNA damage and induce apoptosis.

Dietary Fat Intake and Gestational Weight Gain in Relation to Estradiol and Progesterone Plasma Levels During Pregnancy: a Longitudinal Study in Swedish Women

BMC Women's Health. 2009  |  Pubmed ID: 19402915

Elevated pregnancy hormone levels, such as oestrogen and progesterone, may increase the risk of developing breast cancer both in mothers and offspring. However, the reasons for large inter-individual variations in estrogen and progesterone levels during pregnancy remain unknown. The objectives of this study were to investigate whether a) intakes of total dietary fat, types of fat (monounsaturated: MUFA, polyunsaturated: n-3 and n-6 PUFA, and saturated) and b) gestational weight gain are associated with estradiol and progesterone levels in plasma during pregnancy.

Early Intake Appears to Be the Key to the Proposed Protective Effects of Soy Intake Against Breast Cancer

Nutrition and Cancer. 2009  |  Pubmed ID: 20155618

There is a large variation in breast cancer incidence and mortality rates worldwide. Migration studies have indicated that this variation is primarily the result of lifestyle influences. Although there has been much research conducted, definitively identifying dietary factors that impact breast cancer risk has proven difficult. In part this may be because most clinical and epidemiologic studies have focused on adult dietary exposure. However, evidence suggests that childhood and/or adolescence is the period of life when the breast is most sensitive to dietary influences. Further, the available epidemiologic and animal data suggest that early soy intake reduces breast cancer risk. Soy foods are unique dietary sources of isoflavones, diphenolic compounds that exert estrogen-like effects under certain experimental conditions. The protection effects of soy may result from the soybean isoflavones stimulating differentiation of the breast in much the same way that the elevated estrogen levels do during pregnancy. More specifically, in rats, the primary isoflavone genistein reduces mammary tumorigenesis and increases mammary tissue differentiation by leading to a reduction in the number of terminal end buds (TEB) and an increase in the number of differentiated lobules. There is need and justification for continued investigation of the early soy intake hypothesis, particularly to determine the cellular targets of soy action and to identify the signaling pathways mediating the effects on mammary gland morphology and susceptibility to breast cancer.

Dietary N-3 Polyunsaturated Fatty Acids Fail to Reduce Prostate Tumorigenesis in the PB-ErbB-2 X Pten(+/-) Preclinical Mouse Model

Cell Cycle (Georgetown, Tex.). May, 2010  |  Pubmed ID: 20404514

Diet and obesity, and their associated metabolic alterations, are some of the fastest-growing causes of disease and death in America. Findings from epidemiological studies correlating obesity, the sources of dietary fat and prostate cancer (PCa) are conflicting. We have previously shown that 15% of PB-ErbB-2 x pten(+/-) mice developed PCa and exhibited increased phosphorylated 4E-BP1, but not the key PI3-kinase intermediary phospho-protein, mTOR, when maintained on unrefined mouse chow. We report herein that 100% of animals fed refined, westernized AIN-93-based diets containing corn oil developed PCa by 12 months of age. Increases in visceral fat and mTO R activation in the tumors were also observed. Furthermore, nuclear cyclin E levels were significantly induced by the AIN-93-corn oil-based diets versus chow. Replacing 50% of the corn oil with menhaden oil, with 21% of its triglycerides being n-3 PUFA's, had no effect on tumorigenesis, fat deposition, cyclin E or mTOR. Phosphorylated BAD levels were similar in the tumors of mice in all three diets. Our data demonstrated that in the context of our preclinical model, components of crude chow, but not dietary n-3 PUFAs, protect against PCa progression. In addition, these data establish phosphorylated mTOR, nuclear cyclin E and visceral fat deposits as possible biomarkers of increased dietary risk for PCa.

Dietary Vitamin D Exposure Prevents Obesity-induced Increase in Endometrial Cancer in Pten+/- Mice

Cancer Prevention Research (Philadelphia, Pa.). Oct, 2010  |  Pubmed ID: 20858763

The possibility that dietary vitamin D(3) (VD(3)) exposure inhibits endometrial carcinogenesis in an animal model and modifies the enhanced risk of endometrial carcinoma associated with obesity was investigated. At 4 weeks of age, Pten(+/-) and wild-type mice were each divided into four treatment groups and fed AIN93G control diet, or AIN93G-based diet containing either 25,000 international units of VD(3) per kilogram of diet, 58% fat to induce obesity (high fat), or high fat and 25,000 international units of VD(3) per kilogram of diet. Mice were kept on these diets until they were sacrificed at week 28. Although VD(3) did not affect endometrial cancer risk, it inhibited obesity-induced increase in endometrial lesions. Specifically, high-fat diet increased focal glandular hyperplasia with atypia and malignant lesions from 58% in the control diet-fed Pten(+/-) mice to 78% in obese mice. Dietary VD(3) decreased the incidence of endometrial pathology in obese Pten(+/-) mice to 25% (P < 0.001). VD(3) altered the endometrial expression of 25-hydroxylase, 1α-hydroxylase, and vitamin D receptor in the wild-type and Pten(+/-) mice. Estrogen receptor-α mRNA levels were higher (P < 0.014) and progesterone receptor protein levels in the luminal epithelium were lower (P < 0.04) in the endometrium of control diet-fed Pten(+/-) than wild-type mice, but the expression of these receptors was not affected by the dietary exposures. VD(3) reversed the obesity-induced increase in osteopontin (P < 0.001) and significantly increased E-cadherin expression (P < 0.019) in the endometrium of obese Pten(+/-) mice. Our data confirm the known association between obesity and endometrial cancer risk. Dietary exposure to VD(3) inhibited the carcinogenic effect of obesity on the endometrium. This protective effect was linked to a reduction in the expression of osteopontin and increase in E-cadherin.

Effect of Dietary Intervention on Serum Lignan Levels in Pregnant Women - a Controlled Trial

Reproductive Health. 2010  |  Pubmed ID: 20932282

ABSTRACT:

Is Soy Consumption Good or Bad for the Breast?

The Journal of Nutrition. Dec, 2010  |  Pubmed ID: 20980638

Genistein in soy activates estrogen receptor (ER)-α and ERβ and acts as an estradiol in multiple target tissues. Because estrogens increase breast cancer risk and genistein promotes the growth of ER-positive human breast cancer cells, it has remained unclear whether this isoflavone or soy is safe. Results reviewed here suggest that women consuming moderate amounts of soy throughout their life have lower breast cancer risk than women who do not consume soy; however, this protective effect may originate from soy intake early in life. We also review the literature regarding potential risks genistein poses for breast cancer survivors. Findings obtained in 2 recent human studies show that a moderate consumption of diet containing this isoflavone does not increase the risk of breast cancer recurrence in Western women, and Asian breast cancer survivors exhibit better prognosis if they continue consuming a soy diet. The mechanisms explaining the breast cancer risk-reducing effect of early soy intake or the protective effect in Asian breast cancer survivors remain to be established. We propose that the reduction in risk involves epigenetic changes that result in alterations in the expression of genes that regulate mammary epithelial cell fate, i.e. cell proliferation and differentiation. Lifetime soy consumption at a moderate level may prevent breast cancer recurrence through mechanisms that change the biology of tumors; e.g. women who consumed soy during childhood develop breast cancers that express significantly reduced Human epidermal growth factor receptor 2 levels. More research is needed to understand why soy intake during early life may both reduce breast cancer risk and risk of recurrence.

DDN: a CaBIG® Analytical Tool for Differential Network Analysis

Bioinformatics (Oxford, England). Apr, 2011  |  Pubmed ID: 21296752

Differential dependency network (DDN) is a caBIG® (cancer Biomedical Informatics Grid) analytical tool for detecting and visualizing statistically significant topological changes in transcriptional networks representing two biological conditions. Developed under caBIG®'s In Silico Research Centers of Excellence (ISRCE) Program, DDN enables differential network analysis and provides an alternative way for defining network biomarkers predictive of phenotypes. DDN also serves as a useful systems biology tool for users across biomedical research communities to infer how genetic, epigenetic or environment variables may affect biological networks and clinical phenotypes. Besides the standalone Java application, we have also developed a Cytoscape plug-in, CytoDDN, to integrate network analysis and visualization seamlessly. AVAILABILITY: The Java and MATLAB source code can be downloaded at the authors' web site http://www.cbil.ece.vt.edu/software.htm.

Effects of Maternal Exposure to Cow's Milk High or Low in Isoflavones on Carcinogen-induced Mammary Tumorigenesis Among Rat Offspring

Cancer Prevention Research (Philadelphia, Pa.). May, 2011  |  Pubmed ID: 21467133

We investigated whether maternal exposure during pregnancy to cow's milk containing endogenous estrogens and insulin-like growth factor 1 (IGF-1) and either high or low levels of isoflavones from dietary legumes (HIM and LIM, respectively) affected carcinogen-induced mammary carcinogenesis in female rat offspring. Pregnant Sprague-Dawley rats were given HIM, LIM, or tap water (control) from gestational day (GD) 11 until birth; hereafter all rats received tap water. Mammary tumorigenesis was induced by administrating 7,12-dimethylbenz[a]anthracene (DMBA) on postnatal day 50. No differences in maternal serum estradiol (P = 0.19) and IGF-1 levels (P = 0.15) at GD 19 or birth weight among the milk and water groups were seen, but estradiol, and IGF-1 levels and birth weight were numerically higher in the LIM group than in the HIM group. Puberty onset occurred earlier in the LIM offspring than in controls (P = 0.03). Although the high isoflavone content seemed to prevent the effect on circulating estradiol and IGF-1 levels and advanced puberty onset seen in the LIM group, HIM increased DMBA-DNA adducts in the mammary gland and tended to increase mammary tumorigenesis. In contrast, offspring exposed to LIM in utero, did not exhibit increased breast cancer risk, despite having higher estradiol and IGF-1 environment and consequently earlier puberty onset. These results indicate that the phytochemical content in the cow's milk, consumed by a pregnant dam, determines how milk affects the offspring.

Protective Effects of Prepubertal Genistein Exposure on Mammary Tumorigenesis Are Dependent on BRCA1 Expression

Cancer Prevention Research (Philadelphia, Pa.). Sep, 2011  |  Pubmed ID: 21680703

This study investigated whether prepubertal dietary exposure to genistein reduces mammary tumorigenesis by upregulating Brca1 expression in mice. Heterozygous Brca1(+/-) mice and their wild-type (WT) littermates were fed control AIN93G diet or 500 ppm genistein-supplemented AIN93G diet from postnatal day (PND) 15 to PND30 and then switched to AIN93G diet. Prepubertal dietary exposure to genistein reduced 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary incidence (P = 0.029) and aggressiveness of the tumors (P < 0.001) in the WT mice and upregulated the expression of Brca1 in their mammary glands (P = 0.04). In contrast, prepubertal genistein diet neither significantly reduced mammary tumorigenesis or tumor aggressivity nor increased Brca1 mRNA expression in the Brca1(+/-) mice. These results may be related to the opposing effects of prepubertal genistein diet on the expression of Rankl and CK5/CK18 ratio (marker of luminal epithelial cell differentiation) in the mammary gland and estrogen receptor (ER-α) and progesterone receptor (PgR) protein levels in the mammary tumor: these all were reduced in the WT mice or increased in Brca1(+/-) mice. Both the WT and Brca1(+/-) mice exhibited reduced levels of amphiregulin, CK5, and CK18, delayed ductal elongation and a reduction in terminal end bud number in the normal mammary gland, and reduced HER-2 protein levels in the mammary tumors; however, these effects were not sufficient to significantly reduce mammary tumorigenesis in Brca1(+/-) mice. Our results show that upregulation of Brca1 may be required for prepubertal dietary genistein exposure to reduce later mammary tumorigenesis, perhaps because in the absence of this upregulation, mice do not exhibit genistein-induced downregulation of ER-α, PgR, and Rankl.

Prepubertal Exposure to Cow's Milk Reduces Susceptibility to Carcinogen-induced Mammary Tumorigenesis in Rats

International Journal of Cancer. Journal International Du Cancer. Jan, 2011  |  Pubmed ID: 20232392

Cow's milk contains high levels of estrogens, progesterone and insulin-like growth factor 1 (IGF-1), all of which are associated with breast cancer. We investigated whether prepubertal milk exposure affects mammary gland development and carcinogenesis in rats. Sprague-Dawley rats were given either whole milk or tap water to drink from postnatal day (PND) 14 to PND 35, and thereafter normal tap water. Mammary tumorigenesis was induced by administering 7,12-dimethylbenz[a]anthracene on PND 50. Milk exposure increased circulating E2 levels on PND 25 by 10-fold (p < 0.001) and accelerated vaginal opening, which marks puberty onset, by 2.5 days (p < 0.001). However, rats exposed to milk before puberty exhibited reduced carcinogen-induced mammary carcinogenesis; that is, their tumor latency was longer (p < 0.03) and incidence was lower (p < 0.05) than in the controls. On PND 25 and 50, mammary glands of the milk-exposed rats had significantly less terminal end buds (TEBs) than the tap water-exposed controls (p < 0.019). ER-α protein levels were elevated in the TEBs and lobules of milk rats, compared to rats given tap water (p < 0.019), but no changes in cyclin D1 expression, cell proliferation or apoptosis were seen. IGF-1 mRNA levels were reduced on PND 50 in the mammary glands of rats exposed to milk at puberty. Our results suggest that drinking milk before puberty reduces later risk of developing mammary cancer in rats. This might be mediated by a reduction in the number of TEBs and lower expression of IGF-1 mRNA in the mammary glands of milk-exposed animals.

Influence of Berry-Polyphenols on Receptor Signaling and Cell-Death Pathways: Implications for Breast Cancer Prevention

Journal of Agricultural and Food Chemistry. Feb, 2012  |  Pubmed ID: 22300613

Breast cancer is the most commonly diagnosed cancer among women worldwide. Many women have become more aware of the benefits of increasing fruit consumption, as part of a healthy lifestyle, for the prevention of cancer. The mechanisms by which fruits, including berries, prevent breast cancer can be partially explained by exploring their interactions with pathways known influence cell-proliferation and evasion of cell-death. Two receptor pathways- estrogen receptor (ER) and tyrosine kinase receptors, especially the epidermal growth factor receptor (EGFR) family- are drivers of cell-proliferation and play a significant role in the development of both primary and recurrent breast cancer. There is strong evidence to show that several phytochemicals present in berries such as cyanidin, delphinidin, quercetin, kaempferol, ellagic acid, resveratrol and pterostilbene, interact with and alter the effects of these pathways. Further, they also induce cell death (apoptosis and autophagy) via their influence on kinase signaling. In this review, we summarize in vitro data regarding the interaction of berry polyphenols with the specific receptors and the mechanisms by which they induce cell death. Further, we also present in vivo data of primary breast cancer prevention by individual compounds and whole berries. Finally, we present a possible role for berries and berry compounds in the prevention of breast cancer and our perspective on the areas that require further research.