Protective Effects of Prepubertal Genistein Exposure on Mammary Tumorigenesis Are Dependent on <i>BRCA1</i> Expression

Assis, Sônia de; Wärri, Anni; Benitez, Carlos; Helferich, William G.; Hilakivi‐Clarke, Leena

doi:10.1158/1940-6207.capr-10-0346

Cited by 29 publications

(20 citation statements)

References 52 publications

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“…It may thus participate in protecting the mammary epithelial cells from estrogeninduced adverse effects. We show that prepubertal exposure to E2 or other estrogenic compounds cause a persistent upregulation of BRCA1 in rats [31] and mice [80] .…”

Section: Data Obtained In Womenmentioning

confidence: 80%

Pregnancy hormonal environment and mother’s breast cancer risk

Hilakivi‐Clarke

Assis

Wärri

et al. 2012

Hormone Molecular Biology and Clinical Investigation

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Pregnancy can both reduce and increase lifetime breast cancer risk, and it also induces a short-term, transient increase in risk. Several biological mechanisms have been proposed to explain the protective effect, including pregnancy-induced increase in circulating estrogen levels leading to reduced estrogen receptor (ER) expression and activity. Persistent changes in ER-regulated gene expression may then alter the response of the breast to postpregnancy hormonal exposures originating, for example, from food. Understanding how pregnancy increases breast cancer risk has received less attention. Human studies indicate that those women who were exposed to an elevated pregnancy estrogenic environment, such as women who took the synthetic estrogen diethylstilbestrol or who had the highest circulating estrogen levels at the beginning or end of pregnancy, are at increased risk of developing breast cancer. There is also evidence that elevated leptin levels, for example, in pregnant women who gained excessive amount of weight, increase later breast cancer risk. This may reflect a close interaction between estradiol (E2), ER, and leptin. Our preclinical study suggests that an exposure to excess pregnancy E2 and leptin levels reverses the protective changes in genomic signaling pathways seen in the breast/mammary gland of parous women and rodents. Recent findings indicate that involution - the period after lactation when the breast regresses back to prepregnancy stage - may be related to some pregnancy-associated breast cancers. Importantly, in a preclinical model, the increase can be reversed by anti-inflammatory treatment, offering hope that the increase in lifelong breast cancer risk induced by late first pregnancy or by an exposure of pregnant women to an excessive hormonal environment may be reversible.

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Section: Data Obtained In Womenmentioning

confidence: 80%

Pregnancy hormonal environment and mother’s breast cancer risk

Hilakivi‐Clarke

Assis

Wärri

et al. 2012

Hormone Molecular Biology and Clinical Investigation

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“…Finally, several mechanisms for the protective effects of early isoflavone exposure have been proposed [242,243,244,245,246]. The protection afforded by isoflavones may be similar to the observed protective effect of early pregnancy against breast cancer [242].…”

Section: Breast Cancermentioning

confidence: 99%

Soy and Health Update: Evaluation of the Clinical and Epidemiologic Literature

2016

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Soyfoods have long been recognized as sources of high-quality protein and healthful fat, but over the past 25 years these foods have been rigorously investigated for their role in chronic disease prevention and treatment. There is evidence, for example, that they reduce risk of coronary heart disease and breast and prostate cancer. In addition, soy alleviates hot flashes and may favorably affect renal function, alleviate depressive symptoms and improve skin health. Much of the focus on soyfoods is because they are uniquely-rich sources of isoflavones. Isoflavones are classified as both phytoestrogens and selective estrogen receptor modulators. Despite the many proposed benefits, the presence of isoflavones has led to concerns that soy may exert untoward effects in some individuals. However, these concerns are based primarily on animal studies, whereas the human research supports the safety and benefits of soyfoods. In support of safety is the recent conclusion of the European Food Safety Authority that isoflavones do not adversely affect the breast, thyroid or uterus of postmenopausal women. This review covers each of the major research areas involving soy focusing primarily on the clinical and epidemiologic research. Background information on Asian soy intake, isoflavones, and nutrient content is also provided.

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“…Mammary tumors were induced in F1 an F2 female offspring by administration of 156 medroxyprogesterone acetate (MPA; 15 mg/100μl, subcutaneously) to 6 weeks of age female 157 offspring, followed by three weekly doses of 1 mg 7,12-dimethylbenz[a]anthracene (DMBA; 158 Sigma, St. Louis, MO) dissolved in peanut oil by oral gavage [27]. Tumors were detected by 159 palpation once per week, starting at week 2 after the last dose of DMBA.…”

Section: Mammary Tumor Induction 155mentioning

confidence: 99%

Paternal obesity and epigenetic inheritance of breast cancer: The role of systemic effects and transmission to the second generation

Fontelles¹,

Cruz²,

Gonsiewski³

et al. 2020

Preprint

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21Background: While genetics explains some familial breast cancer cases, we showed that 22 environmentally-induced epigenetic inheritance of breast cancer can also occur in rodent 23 models. We previously reported that paternal consumption of a high-fat diet and ensuing obesity 24 increased breast cancer susceptibility in the offspring (F1). Nevertheless, it is still unclear 25 whether paternal-induced programming of breast cancer in daughters is associated with systemic 26 alterations or mammary epithelium-specific factors. It also remains to be determined whether 27 the ancestrally programmed breast cancer predisposition in F1 progeny can be transmitted to 28 subsequent generations. 29Methods: Male mice (F0) were fed either a control (CO) diet or an obesity-inducing diet (OID) 30 for seven weeks and then mated with female mice (F0) reared on a CO diet. The resulting 31 offspring (F1), also exclusively fed CO diet, were either used for mammary gland and tumor 32 transplantation surgeries or to generate the F2 generation. To induce the mammary tumors, 33 female mice were treated with 7,12 dimethylbenz[a]anthracene (DMBA). Total RNA extracted 34 from F0 or F1 males sperm was used for small RNA-Seq analysis. 35Results: Mammary glands from F1 CO female offspring exhibited enhanced development when 36 transplanted into OID females [OID(CO-MG)], as shown by higher mammary gland area, 37 epithelial branching and elongation, compared to CO females that received a CO mammary 38 gland [CO(CO-MG)]. Similarly, mammary tumors from F1 CO female offspring transplanted 39 into OID females [OID(CO.T)] displayed improved growth with a higher proliferation/apoptosis 40 rate. We also found that granddaughters (F2) from the OID grand-paternal germline showed 41 accelerated tumor growth compared to COxCO granddaughters (F2). Transmission of breast 42 cancer predisposition to the F2 generation through OID male germline was associated with 43 alterations in specific sperm tRNA fragments (tRF) in both F0 and F1 males. 44 Conclusions:Our findings indicate that systemic metabolic and mammary stromal alterations 45 are the most significant contributors to paternal programming of mammary gland development 46 and cancer predisposition in female offspring rather than mammary epithelium confined factors. 47Our data also show breast cancer predisposition in OID daughters can be transmitted to 48 subsequent generations and could explain some familial cancers, if confirmed in humans. 49 50 Insulin tolerance test (ITT) was performed after the mice fasted for 6 h, according to the method 113 described by Takada et al [21]. The insulin load (75 mU/100 g body weight) was injected as a 114 bolus, and the blood glucose levels were determined at 0, 3, 6, 9, 12, and 30 minutes after 115 injection in female offspring. The area under the curve (AUC) was calculated according to the 116 trapezoid rule. Differences in ITT were analyzed using two-way ANOVA (group, time), 117 followed by post-hoc analyses.

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

Cited by 29 publications

References 52 publications

Pregnancy hormonal environment and mother’s breast cancer risk

Pregnancy hormonal environment and mother’s breast cancer risk

Soy and Health Update: Evaluation of the Clinical and Epidemiologic Literature

Paternal obesity and epigenetic inheritance of breast cancer: The role of systemic effects and transmission to the second generation

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