Breast Cancer Risk In Offspring Research Articles

Can paternal environmental experiences affect the breast cancer risk in offspring? A systematic review

INTRODUCTION: Studies in recent years have shown that parental environmental experiences can affect their offspring’s risk of breast cancer (BC). We assessed the effect of different paternal factors on BC risk in offspring by reviewing the existing literature. METHOD: This systematic review followed the Joanna Briggs Institute’s (JBI) method for systematic reviews of qualitative evidence. The primary keywords were searched in reliable databases such as PubMed, Google Scholar, Elsevier, SID, and Wiley in English until 31 December 2021. Two authors independently examined the articles in terms of inclusion criteria and quality assessment of the articles. RESULTS: Of the 438 studies, 19 met the inclusion criteria of this systematic review and were included in the study. Paternal factors investigated in these studies included age at delivery, diet, occupational exposures, occupation type and education. The reported relationships between these factors and breast cancer varied among different studies. CONCLUSION: Studies considered in this article show that fathers’ age at the time of delivery of the child, dietary habits, overweight and occupational factors can affect the incidence of BC risk in the next generation.

Maternal obesity and resistance to breast cancer treatments among offspring: Link to gut dysbiosis.

About 50 000 new cases of cancer in the United States are attributed to obesity. The adverse effects of obesity on breast cancer may be most profound when affecting the early development; that is, in the womb of a pregnant obese mother. Maternal obesity has several long-lasting adverse health effects on the offspring, including increasing offspring's breast cancer risk and mortality. Gut microbiota is a player in obesity as well as may impact breast carcinogenesis. Gut microbiota is established early in life and the microbial composition of an infant's gut becomes permanently dysregulated because of maternal obesity. Metabolites from the microbiota, especially short chain fatty acids (SCFAs), play a critical role in mediating the effect of gut bacteria on multiple biological functions, such as immune system, including tumor immune responses. Maternal obesity can pre-program daughter's breast cancer to be more aggressive, less responsive to treatments and consequently more likely to cause breast cancer related death. Maternal obesity may also induce poor response to immune checkpoint inhibitor (ICB) therapy through increased abundance of inflammation associated microbiome and decreased abundance of bacteria that are linked to production of SCFAs. Dietary interventions that increase the abundance of bacteria producing SCFAs potentially reverses offspring's resistance to breast cancer therapy. Since immunotherapies have emerged as highly effective treatments for many cancers, albeit there is an urgent need to enlarge the patient population who will be responsive to these treatments. One of the factors which may cause ICB refractoriness could be maternal obesity, based on its effects on the microbiota markers of ICB therapy response among the offspring. Since about 40% of children are born to obese mothers in the Western societies, it is important to determine if maternal obesity impairs offspring's response to cancer immunotherapies.

Abstract 646: Pre conception paternal DDT exposure and programming of metabolic dysfunction and breast cancer risk in offspring

Abstract Background: Breast cancer is the most common cancer in American women, being the second leading cause of cancer-related death in this group. Exposure to environmental chemicals, such as the pesticide DDT (dichlorodiphenyltrichloroethane), has been long suspected to be a contributing factor in the development of metabolic disease and breast cancer. For instance, early life (in utero and early childhood) exposure to DDT has been associated with increased breast cancer risk in women, and these findings are supported by animal studies. While maternal DDT exposure in pregnancy has been linked to metabolic syndrome and breast cancer risk in offspring, the effects of paternal DDT exposure in male germ-line reprogramming and phenotypes in their progeny has not been investigated. Here, we evaluated the effects of pre-conception paternal exposure to DDT on offspring’s metabolism and susceptibility of breast cancer, using a mouse model. Methods: Male mice were exposed to DDT (1.7mg/kg body weight) by oral gavage for two weeks. At the end of this period, DDT and control-vehicle (CO) were housed with female mice, with free access to a standard chow diet, for three days. Pregnancy onset was assessed by the presence of a vaginal plug. The weight and number of pups per litter were determined two days after birth. Pups were weaned from mothers at 21 days of age, fed a standard chow diet for the extent of the study and weighed weekly. Mammary tumors were induced by subcutaneous administration of 15mg of medroxyprogesterone to six-week-old female offspring, followed by oral administration of 1mg 7,12-dimethylbenz[a]anthracene once-a-week for 3 weeks. Results: Paternal DDT exposure reprogramed the sperm small non-coding RNA content. In line with that, DDT offspring had decreased birthweight (p=0.04) and weaning weight (p=0.01) compared to CO. Further, ancestral DDT exposure caused metabolic dysfunction in offspring (p<0.05) at 7 and 22 weeks of age. Further, female offspring of DDT exposed fathers showed alterations in mammary gland development with a non-significant increase in numbers of terminal end buds and lower rates of apoptosis. In line with that, our preliminary data suggest that ancestral paternal exposures to DDT increases breast cancer risk in offspring: Compared to CO, the DDT offspring presented a non-significant increase in mammary tumor incidence and shorter latency to first-tumor onset. In addition, tumor growth (volume) was significantly increased in DDT offspring compared to CO (p<0.01). In conclusion, our findings support a role for DDT exposure from the paternal lineage in metabolic dysfunction and increased breast cancer risk in their offspring. Citation Format: Raquel Santana Da Cruz, Hong Cao, Camille Castilho Fontelles, Apsra Nasir, M Idalia Cruz, Sonia de Assis. Pre conception paternal DDT exposure and programming of metabolic dysfunction and breast cancer risk in offspring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 646.

Paternal programming of breast cancer risk in daughters in a rat model: opposing effects of animal- and plant-based high-fat diets.

BackgroundAlthough males contribute half of the embryo’s genome, only recently has interest begun to be directed toward the potential impact of paternal experiences on the health of offspring. While there is evidence that paternal malnutrition may increase offspring susceptibility to metabolic diseases, the influence of paternal factors on a daughter’s breast cancer risk has been examined in few studies.MethodsMale Sprague-Dawley rats were fed, before and during puberty, either a lard-based (high in saturated fats) or a corn oil-based (high in n-6 polyunsaturated fats) high-fat diet (60 % of fat-derived energy). Control animals were fed an AIN-93G control diet (16 % of fat-derived energy). Their 50-day-old female offspring fed only a commercial diet were subjected to the classical model of mammary carcinogenesis based on 7,12-dimethylbenz[a]anthracene initiation, and mammary tumor development was evaluated. Sperm cells and mammary gland tissue were subjected to cellular and molecular analysis.ResultsCompared with female offspring of control diet-fed male rats, offspring of lard-fed male rats did not differ in tumor latency, growth, or multiplicity. However, female offspring of lard-fed male rats had increased elongation of the mammary epithelial tree, number of terminal end buds, and tumor incidence compared with both female offspring of control diet-fed and corn oil-fed male rats. Compared with female offspring of control diet-fed male rats, female offspring of corn oil-fed male rats showed decreased tumor growth but no difference regarding tumor incidence, latency, or multiplicity. Additionally, female offspring of corn oil-fed male rats had longer tumor latency as well as decreased tumor growth and multiplicity compared with female offspring of lard-fed male rats. Paternal consumption of animal- or plant-based high-fat diets elicited opposing effects, with lard rich in saturated fatty acids increasing breast cancer risk in offspring and corn oil rich in n-6 polyunsaturated fatty acids decreasing it. These effects could be linked to alterations in microRNA expression in fathers’ sperm and their daughters’ mammary glands, and to modifications in breast cancer-related protein expression in this tissue.ConclusionsOur findings highlight the importance of paternal nutrition in affecting future generations’ risk of developing breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0729-x) contains supplementary material, which is available to authorized users.

Abstract LB-244: Paternal obesity alters daughters' mammary gland development and increases markers of breast cancer risk in a mouse model

Abstract Introduction: While several epidemiologic and animal studies indicate that maternal nutrition and body weight during pregnancy lead to reprogramming of breast cancer risk in the offspring, no studies have investigated the impact of fathers’ obesity or dietary habits on offspring's breast cancer risk. The goal of the current study is to investigate whether peri-conceptional paternal obesity can epigenetically reprogram father's germ-line and increase their daughters’ likelihood of developing breast cancer, using a carcinogen-induced mouse model of this disease. Methodology: Male mice were fed a control diet or obesity-inducing diet from weaning until sexual maturity; at this point, all males were switched to the control diet and housed together with female rats reared on control diet. Once a vaginal plug was detected, males were removed from female cages and euthanized for sperm collection. Pregnant dams were fed the control diet for the extent of pregnancy and after giving birth. Pups were weaned on postnatal day (PND)21 and fed the control diet throughout the experiment. Offspring's body weight was determined shortly after birth and at weaning. A subset of female offspring was euthanized on PND50 for mammary tissue harvesting. Mammary gland whole-mounts harvested on PND50 were processed and the number of TEBs and ductal elongation blindly examined. Using miRNA arrays, we also investigated whether misregulation of miRNAs expression is involved in mediating the effects of paternal obesity on offspring's mammary gland morphology. Another subset of female offspring was treated with 9,12-dimethylbenz[a]anthracene to induce mammary tumors and is currently being monitored. Results: We found that, compared to control offspring, the offspring of obese fathers had higher birth weight (p=0.02). Birth weight has been positively associated with breast cancer risk in epidemiologic and animal studies. Body weight of daughters (p=0.03), but not sons (p=0.6), of obese fathers were also higher at weaning. Daughters of obese fathers had higher numbers of terminal end buds (TEBs; p=0.03) _ which are targets for malignant transformation and markers of increased breast cancer risk_ in their mammary glands compared to control daughters. Mammary gland ductal elongation (p=0.004) in daughters of obese fathers was also increased. In addition, we found that paternal obesity led to changes in the miRNA expression profile in their sperm. Paternal obesity was also associated with changes in miRNA expression in daughters’ mammary tissue. Conclusions:This study provides critical evidence that fathers’ body weight around conception affects not only their daughters’ body weight at birth and weaning, but it also leads to changes in their daughters’ mammary gland development and miRNA expression profile, and likely their mammary cancer risk. Studies to confirm whether these findings are causally related to increased mammary cancer risk in daughters of obese fathers are currently underway. Citation Format: Chao Yin, Idalia Cruz, Leena Hilakivi-Clarke, Sonia M. de Assis. Paternal obesity alters daughters' mammary gland development and increases markers of breast cancer risk in a mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-244. doi:10.1158/1538-7445.AM2014-LB-244

Breast Cancer Risk in Opposite-Sexed Twins: Influence of Birth Weight and Co-Twin Birth Weight

Most, but not all, studies report a positive association between birth weight, as an indirect marker of prenatal hormone exposure, and offspring breast cancer risk, particularly premenopausal breast cancer. Females from opposite-sexed twin pairs may also be prenatally exposed to androgens from their twin brothers. A Swedish study of opposite-sexed twins with a small sample size found a very strong positive association between female birth weight and breast cancer risk. In this case-control study, nested within a cohort of female opposite-sexed twins, we included 543 breast cancer case subjects diagnosed in the period from 1972 to 2008 and 2715 matched control subjects. Conditional logistic regression estimated the breast cancer risk associated with birth weight and other birth characteristics, including gestational age and co-twin birth weight. All statistical tests were two-sided. There was no association between birth weight (odds ratio = 1.01; 95% confidence interval = 0.70 to 1.46) or twin brother's birth weight and risk of breast cancer, which suggests the previously reported strong positive association may have been a chance finding.

Abstract 835: Elevated in utero estrogenic environment may increase later breast cancer risk by down-regulating miRNAs

Abstract Objectives: High maternal estrogen levels during pregnancy increase a female offspring's breast cancer risk in women and in animal models. This increase is proposed to be mediated by epigenetic changes that involve DNA methylation. Dynamic changes in miRNA expression during fetal development also play a key role in setting gene transcription patterns that persist through the life-time. In this study, we investigated whether in utero exposure to excess estradiol (E2) causes persistent changes in the expression of miRNAs and their target genes. Methods: Pregnant Sprague Dawley rats were fed AIN93G diet supplemented with 0.1 ppm ethinyl estradiol between gestation days 13 and 20. Offspring's mammary glands were obtained on postnatal day 50, and miRNAs were measured using applied Biosystems TaqManR Array Rodent MicroRNA and mRNAs using RG_U34A Affymetrix platform. Data generated in the two arrays were analyzed by an integrated approach which uses a sequence-based TargetScan method to predict miRNA targets and then correlates these targets with mRNA data to identify targets specific to in utero E2 exposure. Results: Maternal E2 exposure during pregnancy increases carcinogen-induced mammary tumorigenesis in the offspring (final tumor incidence in controls: 56%, in E2 offspring: 82%, p<0.05). Fifteen miRNAs are significantly down-regulated in the mammary glands of adult rats exposed to E2 in utero, compared to the controls. Many of these are known to be down-regulated by E2 in MCF-7 human breast cancer cells including miR-21, miR-23ab, miR-27ab, and miR-200c. Some of these miRNAs and others that are down-regulated in the mammary glands of in utero E2 exposed rats (let-7, miR-26ab, miR-181, and miR-203), in turn, suppress the expression of estradiol-regulated genes, as defined by Cicatiello et al., 2010. We also found that of the known ER-α activated genes, more than 10% are significantly up-regulated in the E2 group. These genes included BCL2L1, CYP1B1, and IGF1R. Conclusions: Our findings indicate that maternal exposure to excess E2 during pregnancy may cause a persistent up-regulation of estrogen-regulated genes by suppressing miRNAs that target these genes. Of note is that some of the miRNAs found to be down-regulated in the E2 group suppress genes known to be involved in DNA methylation. For example, miR-21 targets DNMT1; our study indicates that mammary glands of rats exposed to excess E2 in utero express significantly elevated DNMT1 levels, compared to the controls. Thus, changes in miRNAs may also be involved in inducing DNA methylation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 835. doi:10.1158/1538-7445.AM2011-835

In utero exposure to methyl diet and epigenetic modification of breast cancer risk in offspring

Lipotropic nutrients contain methyl groups and affect DNA methylation, an epigenetic mechanism controlling expression of genes involved in cell growth and metabolism. Fuller differentiation of mammary gland during the first pregnancy has a protective effect against breast cancer. We studied a correlation between methyl metabolism-directed and pregnancy-related epigenetic modification of mammary gland development and reduction of breast cancer risk in female offspring. Female Sprague-Dawley rats were fed either control or lipotrope diet during pregnancy and lactation. At weaning, mammary tissues were analyzed for global DNA methylation level by quantitative DNA methylation and for expression of genes involved in mammary differentiation by real-time PCR. Half of the offspring were also used for the preceding purpose. Mammary cancer was induced in the remaining offspring by nitrosomethylurea protocol. The offspring in the lipotropic group showed a decrease in tumor incidence as compared to control diet group. Further, maternal lipotrope diet significantly reduced tumor volume (P<0.01) and tumor numbers (P<0.01) in offspring. However, there was no difference in global methylation level and gene expression in dams and offspring from each diet group. Our results suggest maternal methyl diet reduces chemically-induced mammary carcinogenesis in offspring. Supported by a US Department of Defense grant. Grant Funding Source: US Department of Defense

Intrauterine exposures, pregnancy estrogens and breast cancer risk: where do we currently stand?

Since 1990, when a hypothesis on intrauterine influences on breast cancer risk was published, several studies have provided supportive, indirect evidence by documenting associations of birth weight and other correlates of the prenatal environment with breast cancer risk in offspring. Recent results from a unique cohort of women with documented exposure to diethylstilbestrol in utero have provided direct evidence in support of a potential role of pregnancy oestrogens on breast cancer risk in offspring.

Maternal dietary exposure to fiber during pregnancy and mammary tumorigenesis among rat offspring

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.

Towards an integrated model for breast cancer etiology: The crucial role of the number of mammary tissue-specific stem cells

Perinatal events and conditions, notably birth weight, are associated with breast cancer risk in offspring, and correlates of mammary gland mass are predictors of breast cancer risk. These findings may be interpreted as indicating that high levels of estrogens and components of the insulin-like growth factor system during pregnancy favour the generation of mammary tissue-specific stem cells, and that the number of these cells, which is positively associated with mammary gland mass, is an important determinant of breast cancer risk. Perinatal events and conditions may also affect risk for other malignancies, but the evidence in the case of breast cancer is prominent, possibly because estrogens and the insulin-like growth factor system are both involved in breast cancer etiology and affect birth weight.