Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters, 2014
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.
In this review, findings related to in utero DES exposure and breast cancer are discussed for the purpose of weighing evidence as to whether fetal hormonal environment can impact breast cancer risk in women several decades later. Since causal studies can readily be performed using animal models, findings obtained in DES-exposed mouse and rat offspring also are discussed. Importantly, animal studies were done prior to any epidemiological studies addressing a possible link between maternal DES exposure and breast cancer risk among daughters could be performed. By the 1980s, exposed daughters in the cohorts began to be old enough to develop breast cancer and several human studies have been performed since to determine if maternal exposure to DES during pregnancy increases an offspring’s breast cancer risk.
…”The animal studies show that the doses of DES relevant to pregnant women increased later risk of developing mammary tumors. Specifically, female offspring of rat dams exposed to a total of 1.2 μg DES either on gestation week 2 or 3, to 0.6 μg or 4 μg DES on both gestation days 15 and 18 (all via injection), or via diet to 0.1, 1 or 10 ppm DES between gestation days 13 and 21 (week 3) exhibited increased mammary cancer risk. An increase in risk also was seen in rats exposed to a single dose of 0.1, 1 or 10 μg or less of DES at birth.” …
…”Importantly, in utero exposure to DES leads to an increase in terminal end buds (TEBs) numbers. It is thus possible that one of the mechanisms causing an increase in mammary cancer risk in DES offspring is an increase in the number of targets for malignant transformation.”…
…”Several published studies have investigated breast cancer risk in the daughters of DES mothers, the majority of which were cohort studies done in the US. As the women in the cohorts aged, their breast cancer risk grew higher, compared with matched non-exposed controls. The findings clearly indicate that after age 40 years the incidence of breast cancer is at least two-fold higher in the daughters of DES-exposed mothers. Many pregnant women in Europe and Australia also used DES, but the peak exposure occurred 10 to 20 years later than in the US, and this probably explains why a recent study done in Europe found a trend but not a significant increase in breast cancer risk among them. Once the European daughters reach the age when breast cancer is more commonly detected, they too are likely to exhibit a significant increase in breast cancer risk.”…
To summarize, animal and human studies have generated similar findings and indicate that there is a causal link between maternal exposure to DES during pregnancy and increased breast cancer risk among female offspring. According to animal studies, the increase in risk may reflect the presence of a higher number of TEBs in the mammary epithelium in the DES offspring. Baik and colleagues have proposed that the increase in mammary epithelial cells in in utero estrogen-exposed females is caused by a high number of mammary stem cells or an increase in their potential to generate daughter cells. Our unpublished data support this conclusion”
Epigenetic alterations induced by in utero diethylstilbestrol exposure
We and others have observed that the expression of DNA methyltransferases (DNMTs) is persistently altered in estrogen-regulated tissues following estrogenic exposures during early life. In utero exposure to DES is reported to increase the expression of DNMT1 in the epididymis and uterus. We found that DNMT1 expression is increased in the mammary glands of adult rat offspring of dams exposed to ethinyl estradiol during pregnancy. These changes provide a key regulatory layer to influence gene expression in the mammary gland and perhaps breast tumors of individuals exposed to DES or other estrogenic compounds in utero.
The effects of maternal diethylstilbestrol exposure are not limited to the F1 generation?
Some researchers have begun to investigate whether the effects of maternal DES exposure during pregnancy extend to the third generation in humans. Although there is no evidence that DES granddaughters have cervical and ovarian abnormalities similar to DES daughters, there is evidence that they may have more menstrual irregularities and a higher rate of infertility than non-exposed granddaughters. In addition, DES granddaughters may have a slightly higher risk of ovarian cancer. The granddaughters are still too young to assess whether they might also be at an increased risk of developing breast cancer.
Millions of women in the US, Europe and Australia have been exposed to DES in the womb, and consequently exhibit about a two times higher breast cancer risk than unexposed women. The increase in risk may not be limited to the DES-exposed daughters, but could also increase breast cancer risk in granddaughters and great granddaughters. Such outcome would be consistent with the findings we obtained in studies using a synthetic estrogen ethinyl estradiol (EE2). If DES has similar effects to ethinyl estradiol on the transgenerational increase in breast cancer risk, it is urgent to find ways to stop the cycle of inheritance, and also prevent breast cancer in DES-exposed granddaughters and great granddaughters.
To achieve this goal, we need to understand how maternal DES exposure during pregnancy increases a daughter’s breast cancer risk. A plausible model is proposed in the featured image. It is evident from studies done in animal models that in utero DES exposure induces epigenetic changes in reproductive tract tissues and the breast. DES exposure might also have induced epigenetic changes in primordial germ cells and consequently germ cells, and further be detectable in the somatic cells in granddaughters and great granddaughters. We are not aware of any study that has compared epigenetic changes in germ cells and the next generation somatic cells in individuals exposed to DES or other endocrine disruptors in utero. Second, we should investigate whether the transgenerational increase in breast cancer risk can be prevented with drugs that reverse epigenetic modifications. Our preliminary studies in mice suggest that this is achievable in daughters by using the well-tolerated and non-toxic histone deacetylase inhibitor valproic acid and DNMT inhibitor hydralazine. However, whether these compounds also prevent an increase in granddaughters and great granddaughters in experimental models remains to be investigated.
- Full study (free access) : Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters, Breast cancer research : BCR, NCBI PubMed PMC4053091, 2014.
- Featured image : Proposed model to explain an increase in breast cancer risk in daughters, and possibly granddaughters and great granddaughters, of mothers who took diethylstilbestrol during pregnancy. DES, diethylstilbestrol; TDLU, terminal ductal lobular unit; TEB, terminal end bud. PMC4053091/figure/F1.