Microsomal Epoxide Hydrolase Variants Are Not Associated with Risk of Breast Cancer

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. Dec, 2002  |  Pubmed ID: 12496064

Effects of Maternal Hypercholesterolemia on Pregnancy and Development of Offspring

Pediatric Nephrology (Berlin, Germany). Apr, 2003  |  Pubmed ID: 12700957

The effect of maternal hypercholesterolemia on the course of pregnancy and the development of offspring was investigated. Rats were fed either an enriched-cholesterol diet (HC) or a standard diet (control) from 1 week before mating until weaning of offspring. Compared with the control group, HC dams showed a fourfold increase in abortions, a twofold increase in neonatal mortality, smaller litter size, and lower birth weight of pups. At weaning, Na(+),K(+)-ATPase activity in the outer renal medulla was reduced in HC pups compared with control pups, suggesting retarded or impaired development of medullary nephron segments. At this point, to better examine the adverse effects of maternal hypercholesterolemia, the HC pups were divided into two groups: one fed a cholesterol-enriched diet (HC/hc) and the other a standard diet (HC/nc), while control pups were maintained on the standard diet. In adulthood, the HC/hc group showed growth impairment and reduced renal function, demonstrated by low creatinine clearance (0.24+/-0.04 ml/min per 100 g body weight) and high fractional excretion of sodium, potassium, and water ( P<0.05 vs. control). These effects were partially reversed in the HC/nc group. In this study, neither dams nor offspring developed hypertension. Thus, maternal hypercholesterolemia adversely affected pregnancy outcomes and the development of offspring by inducing abnormalities and thereby reducing renal function.

Genetic and Epigenetic Alterations in Sentinel Lymph Nodes Metastatic Lesions Compared to Their Corresponding Primary Breast Tumors

Cancer Genetics and Cytogenetics. Oct, 2003  |  Pubmed ID: 14499694

The accumulation of genetic and epigenetic changes plays a pivotal role in tumor development and progression. In this study, we investigated these changes using comparative genomic hybridization and bisulfite polymerase chain reaction analysis for CpG island hypermethylation of the following genes: TP16, THBS2, E-Cadherin (ECAD), RARbeta2, MINT1, MINT2, and MINT31 in six paired primary breast tumors and their matched sentinel lymph nodes (SLN). The most frequent chromosomal alterations observed were the following: losses of 6q13 approximately q23 and 13q13 approximately q32 and gains of 9q31 approximately qter, 11p15 approximately q21, 12q23 approximately qter, and 20q12 approximately qter. Gain of 6p21 approximately pter was observed in the SLN but in none of the primary tumors. Overall, 71% (30/42) of the methylation measurements were identical between the primary tumors and the SLN. Of the six cases, two showed no differences between the primary tumors and SLN, one tumor with 4 of 7 genes hypermethylated in the primary tumor showed loss of all four hypermethylation events in the SLN, and the remaining three tumors showed loss of one methylation event and simultaneous gain of one to two methylation changes in the SLN. This is the first study reporting genetic and epigenetic alterations in breast sentinel lymph nodes compared to their corresponding primary tumors. Characterization of such alterations may lead to identification of initial events associated with the metastatic dissemination process.

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.

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.

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.

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.

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.