DES Daughter

Prenatal DES exposure in relation to breast size

2013 Study Abstract

PURPOSE:

Prenatal DES exposure has been associated with increased risk of breast cancer, but the mechanisms are unknown. Larger bra cup size has also been associated with increased breast cancer risk, although not consistently. We investigated the relation of prenatal DES exposure to mammary gland mass, as estimated by bra cup size.

METHODS:

In 2006, 3,222 DES-exposed and 1,463 unexposed women reported their bra cup size, band size (chest circumference), and weight at age 20. Prevalence ratios (PR) were calculated for DES exposure in relation to large bra cup size, with control for year of birth and study cohort. Primary analyses were carried out among women who reported a chest circumference of no more than 32 inches because their cup size would be less influenced by fat mass.

RESULTS:

Within this group, DES-exposed women had an estimated 45% increased prevalence (95% CI 0.97-2.18) of large cup size (C or greater) relative to unexposed women. The PR was further increased among women in this group who had a body mass index of < 21 at age 20: PR = 1.83 (95% CI 1.11-3.00). The PR for high-dose DES exposure relative to no exposure was 1.67, 95% CI 1.02-2.73, whereas there was no association of bra cup size with low-dose exposure.

CONCLUSIONS:

These results provide support for the hypothesis that in utero DES exposure may result in greater mammary gland mass. Taken together with previous research on bra size and breast cancer risk, these findings suggest a mechanism for a possible association of in utero DES exposure with increased risk of breast cancer.

Sources

Prenatal DES exposure in relation to breast size, NCBI PMID23775027, Palmer JR1, Boggs DA, Hatch EE, Troisi R, Titus-Ernstoff L, Strohsnitter WC, Adam E, Hoover RN. Cancer Causes Control. 2013 Sep;24(9):1757-61. doi: 10.1007/s10552-013-0248-3. Epub 2013 Jun 18.

Full study, springer: Cancer Causes & Control September 2013, Volume 24, Issue 9, pp 1757-17619, 10.1007%2Fs10552-013-0248-3.

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Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters

2014 Study Abstract

The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression.Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.

Sources

Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters, NCBI PMC25032259, Hilakivi-Clarke L. Breast Cancer Res. 2014;16(2):208.

Full study, Breast Cancer Research : BCR. 2014;16(2):208. doi:10.1186/bcr3649, PMC4053091.

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Does Cancer start in the Womb? Predisposition to Breast Cancer due to in utero Exposure to DES, EDCs

2013 Study Abstract

We are now witnessing a resurgence of theories of development and carcinogenesis in which the environment is again being accepted as a major player in phenotype determination. Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood. For example, gestational exposure to diethylstilbestrol (DES) resulted in clear cell carcinoma of the vagina and breast cancer.

In this review the effects of the endocrine disruptor bisphenol A (BPA) on mammary development and tumorigenesis in rodents is used as a paradigmatic example of how altered prenatal mammary development may lead to breast cancer in humans who are also widely exposed to it through plastic goods, food and drink packaging, and thermal paper receipts. Changes in the stroma and its extracellular matrix led to altered ductal morphogenesis. Additionally, gestational and lactational exposure to BPA increased the sensitivity of rats and mice to mammotropic hormones during puberty and beyond, thus suggesting a plausible explanation for the increased incidence of breast cancer.

Excerpts

“… Breast cancer risk at 40 years of age and older is 2.5 fold higher in DES-exposed women than in unexposed women of the same age. In rats, prenatal exposure to DES also resulted in increased mammary cancer incidence during adulthood when these animals were challenged with the chemical carcinogen dimethylbenzanthracene (DMBA) at puberty. DES was administered to rats at pharmacological doses to mimic its medical use… ”

“… The causal link between fetal exposure to estrogens and the development of breast cancer that was first suggested by epidemiologists has now been confirmed by the increased risk to develop breast cancer during adulthood of women exposed to DES during their fetal life. Fetal and neonatal exposures to EDCs cause persistent alterations in the mammary glands of rodents, including pre- and neoplastic lesions, long after the exposure ended. In the case of BPA, mammary neoplasias may have their origin in the altered mammary morphogenesis that occurs during fetal and neonatal exposure. The data obtained from laboratory animals support the extrapolation that exposure to BPA and other xenoestrogens during organogenesis in humans contributes to the increase in the incidence of breast cancer observed over recent decades….”

Sources

Does cancer start in the womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors, J Mammary Gland Biol Neoplasia, NCBI PMC23702822, Soto AM1, Brisken C, Schaeberle C, Sonnenschein C. 2013 Jun;18(2):199-208. doi: 10.1007/s10911-013-9293-5. Epub 2013 May 24..

Full study, Journal of mammary gland biology and neoplasia, PMC3933259.

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Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk

2013 Study Abstract

Women are using estrogens for many purposes, such as to prevent pregnancy or miscarriage, or to treat menopausal symptoms. Estrogens also have been used to treat breast cancer which seems puzzling, since there is convincing evidence to support a link between high lifetime estrogen exposure and increased breast cancer risk. In this review, we discuss the findings that maternal exposure to the synthetic estrogen diethylstilbestrol (DES) during pregnancy increases breast cancer risk in both exposed mothers and their daughters. In addition, we review data regarding the use of estrogens in oral contraceptives and as postmenopausal hormone therapy and discuss the opposing effects on breast cancer risk based upon timing of exposure. We place particular emphasis on studies investigating how maternal estrogenic exposures during pregnancy increase breast cancer risk among daughters. New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations.

2013 Study Conclusion

Women use estrogens for many purposes. During pregnancy, synthetic strogen DES was used to prevent miscarriage and promote healthy pregnancy, although it turned out to cause the opposite. During the reproductive years when a woman’s own estrogen levels are high, women use synthetic estrogens as contraceptives. Since estrogens play an important role in normal physiological functions in women, some menopausal and postmenopausal women use estrogen supplementation to regain the benefits of natural estrogens.

The effects of estrogens on breast cancer risk differ depending upon when during a woman’s life time they are used. Maternal exposure to DES during pregnancy increases breast cancer risk in mothers and their daughters. The adverse effects of synthetic estrogen exposure during pregnancy may not be limited to mothers and their daughters. Our preclinical study in rodents showed that maternal exposure to EE2 increases breast cancer risk in daughters, granddaughters, and great granddaughters. The first generation of OCs increased breast cancer risk at the time women were taking them, but the increase in risk was not permanent. The current, third generation contraceptives do not increase breast cancer risk. Menopausal and postmenopausal HT, if it contains both estrogens and progestin, increases a woman’s breast cancer risk, and recent data suggest that tumors developing during therapy are more aggressive than those in women not using HT. Estrogen-only HT does not increase breast cancer risk, and might even reduce it. However, due to other adverse effects of estrogen-only HT, it is not recommended beyond using it to control the most severe menopausal symptoms.

We are beginning to understand how the increase in breast cancer risk following in utero exposures to synthetic estrogens occurs. It most likely involves long-term epigenetic changes in genes that are important in determining the risk for breast cancer development, such as tumor suppressor genes, PcTGs and oncogenes. Briefly, an exposure to synthetic estrogens during the fetal period induces modifications in the epigenetic reprogramming of the genome, leading to changes in mammary gland morphology, and gene and protein expression. Some of these changes are transient, such as an increase in the number of TEBs in rodents, and some persist, such as an altered gene and protein expression involving tumor suppressor genes and oncogenes. Together, epigenetically induced modifications in the mammary gland morphology and gene expression increase the likelihood that environmental carcinogens and radiation induce malignant transformation, and evetually breast cancer. The next challenge is to determine whether the increase in risk can be reversed by reversing epigenetic changes that occur as a consequence of early life exposure to synthetic estrogens.

Sources

Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk, NCBI PMC3635108, Hilakivi-Clarke L, de Assis S, Warri A. Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk. Journal of mammary gland biology and neoplasia. 2013;18(1):25-42. doi:10.1007/s10911-013-9274-8.

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Mammography screening behaviors of women exposed prenatally to diethylstilbestrol

2015 Study Abstract

BACKGROUND: In utero diethylstilbestrol (DES) exposure is a risk factor for rare development of vaginal and cervical cancer and may potentially be a risk factor for breast cancer. Mammography use in this population is relatively unknown; therefore, this study aims to determine if in utero DES exposure is associated with the frequency of mammography screening examinations while considering demographic and clinical factors.

METHODS: Using combined DES cohort questionnaire data, self-reported mammography screening over the past 5 years (2001-2006) was analyzed in women aged ≥45 years. Binary logistic regression assessed if DES exposure was associated with mammography use after adjustment for benign breast disease (BBD), previous cancer diagnosis, and whether insurance access influenced screening use.

RESULTS: Overall, the frequency of mammography examinations was similar for both DES-exposed and unexposed women. DES-exposed (n=2986) and unexposed women (n=1397) over the age of 44 reported receiving ≥3 mammography examinations in the past 5 years (73.8% and 74.0%, respectively). After adjustment, DES exposure was not associated with ≥3 mammograms in the past 5 years compared to ≤2 examinations (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.86-1.17), p=0.99).

CONCLUSIONS: In utero DES exposure was not associated with mammography use, nor was health insurance status or a BBD or cancer diagnosis. Because of the potential elevated risk for breast cancer in women exposed prenatally to DES, continued monitoring of standard mammography recommendations is recommended for this group, which is predominantly over the age of 45.

Sources

Mammography screening behaviors of women exposed prenatally to diethylstilbestrol, NCBI 22150213, J Womens Health (Larchmt). 2012 Feb;21(2):209-14. doi: 10.1089/jwh.2011.2741. Epub 2011 Dec 8.

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In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer

2010 Study Abstract

Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that epigenetic alterations would precede the increased risk of breast neoplasia after in utero exposure to endocrine disruptors. Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that has been linked to breast cancer risk and epigenetic regulation of tumorigenesis. We examined the effect of BPA and DES on EZH2 expression and function in MCF-7 cells and in mammary glands of mice exposed in utero. DES and BPA treatment approximated human exposure. EZH2 functional activity was assessed by measuring histone H3 trimethylation. Treatment of MCF-7 cells with DES or BPA led to a 3- and 2-fold increase in EZH2 mRNA expression, respectively (p < 0.05) as well as increased EZH2 protein expression. Mice exposed to DES in utero showed a >2-fold increase in EZH2 expression in adult mammary tissue compared with controls (p 

Sources

In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer, NCBI PMID 21761357, Horm Cancer. 2010 Jun;1(3):146-55. doi: 10.1007/s12672-010-0015-9.

Full text: PMC3140020 Hormones & cancer 2010;1(3):146-155. doi:10.1007/s12672-010-0015-9.

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Prenatal diethylstilbestrol exposure and risk of breast cancer

DES Follow-up Study Summary

One of the main purposes of our study is to examine whether prenatal diethylstilbestrol (DES) exposure influences risk of breast cancer or other cancers in addition to cancers of the vagina and cervix. Results from our most recent analysis of prenatal DES exposure and breast cancer were published in the scientific journal Cancer Epidemiology Biomarkers and Prevention.

Questionnaire data collected in 2001, 1997, and 1994 were used to examine this issue among daughters participating in the study. 4,817 study participants whose mothers took DES while pregnant with them were compared with 2,073 participants who were unexposed. Medical records were obtained to confirm cancer diagnoses. A total of 102 participants were diagnosed with invasive breast cancer. Comparisons of exposed and unexposed women took into account differences in age and other factors such as number of births, age at first birth, and age at first menstruation that are related to breast cancer risk.

Before age 40, women exposed to DES prenatally were not at higher breast cancer risk compared to unexposed women. However, at ages 40 and older, DES-exposed women had two times the breast cancer risk of unexposed women. It appeared that the increase for exposed relative to unexposed women continued to rise with increasing age, but most study participants were still under 50 when the last questionnaire was completed and it is too early for definitive results. Data from the 2006 follow-up questionnaire will provide better information on this question. The association of DES exposure with breast cancer risk was present regardless of whether a participant had a family history of breast cancer or had used female hormone supplements.

Although breast cancer is the most common cancer in U.S. women, most women will never develop breast cancer. That is still the case for women exposed to DES prenatally – most will never develop breast cancer. Based on U.S. cancer registry data, for every 1,000 DES-exposed women aged 45-49, we would expect 4 new cases of breast cancer each year, compared to 2 new cases per year in 1,000 unexposed women.

Under American Cancer Society recommendations, all women who are 40 years or older are advised to undergo yearly mammograms to screen for early breast cancers. Women who were exposed to DES should follow this screening guideline if they are not already doing so.

2006 Study Abstract

It has been hypothesized that breast cancer risk is influenced by prenatal hormone levels. Diethylstilbestrol (DES), a synthetic estrogen, was widely used by pregnant women in the 1950s and 1960s. Women who took the drug have an increased risk of breast cancer, but whether risk is also increased in the daughters who were exposed in utero is less clear. We assessed the relation of prenatal DES exposure to risk of breast cancer in a cohort of DES-exposed and unexposed women followed since the 1970s by mailed questionnaires. Eighty percent of both exposed and unexposed women completed the most recent questionnaire. Self-reports of breast cancer were confirmed by pathology reports. Cox proportional hazards regression was used to compute incidence rate ratios (IRR) for prenatal DES exposure relative to no exposure. During follow-up, 102 incident cases of invasive breast cancer occurred, with 76 among DES-exposed women (98,591 person-years) and 26 among unexposed women (35,046 person-years). The overall age-adjusted IRR was 1.40 [95% confidence interval (95% CI), 0.89-2.22]. For breast cancer occurring at ages >or=40 years, the IRR was 1.91 (95% CI, 1.09-3.33) and for cancers occurring at ages >or=50 years, it was 3.00 (95% CI, 1.01-8.98). Control for calendar year, parity, age at first birth, and other factors did not alter the results. These results, from the first prospective study on the subject, suggest that women with prenatal exposure to DES have an increased risk of breast cancer after age 40 years. The findings support the hypothesis that prenatal hormone levels influence breast cancer risk.

Sources

Prenatal diethylstilbestrol exposure and risk of breast cancer, NCBI PMID: 16896041, Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1509-14.

Full text: aacrjournals doi: 10.1158/1055-9965.EPI-06-0109 Cancer Epidemiol Biomarkers Prev August 2006 15; 1509.

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Birth weight and breast cancer risk

Exploring whether the positive association between birth weight and breast cancer risk differs by other breast cancer risk factors may help inform speculation about biological mechanism. In these data, high birth weight was associated with breast cancer risk in younger and in more educated women, but was not associated overall.

Birth weight was not associated with attained age, age at first birth/parity, menopausal status, or family history of breast cancer, but was inversely associated with mother’s smoking status and use of DES during pregnancy. An inverse association between birth weight and age at menarche was also suggested.

Sources

Birth weight and breast cancer risk, NCBI PMC2361301, Br J Cancer. Jun 5, 2006; 94(11): 1734–1737. doi: 10.1038/sj.bjc.6603122

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Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy

The use of diethylstilbestrol (DES) for high risk pregnancy has exposed millions of mothers to an increased risk of breast cancer, and also resulted in a generation of women with genital tract abnormalities, such as vaginal adenosis. It is still too early to say that exposure to DES will also result in an increased risk of breast cancer in the offspring, though there is some preliminary evidence to support this. The employment of optimal hormonal therapy (for breast cancer) in this special population may be hampered by the fact that agents with oestrogen agonistic activity (such as tamoxifen) may be contraindicated. Though some of the newer hormonal agents, such as the pure anti-oestrogen Fulvestrant and the aromatase inhibitors, could be considered interesting alternatives for postmenopausal patients, their safety in this population has never been evaluated. Finally, the prevalence prenatal exposure to DES may have been underestimated patients diagnosed with breast cancer, though this information might have major implications in their management. We report on the interesting example of a young woman with a history of vaginal adenosis, who was also diagnosed with early breast cancer.

Sources

Management of breast cancer in patients prenatally exposed to diethylstilbestrol: are we prepared?, NCBI PMID: 16216745, Breast. 2005 Oct;14(5):408-10.

Full text: S0960-9776(04)00230-9 TheBreastOnline, November 11, 2004.

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