Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk
2013 Study Summary
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 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.
Maternal Exposure to DES During Pregnancy and Breast Cancer Risk Among Daughters
… Several studies have been published that investigate breast cancer risk in the daughters of DES mothers, the majority of which are cohort studies done in the US. The same cohort of daughters has been followed in many of these studies, and as the women in the cohort grew older, their breast cancer risk grew higher, compared with matched non-exposed controls [67, 70, 71, 73, 74]. These studies clearly indicate that when both groups of women are old enough to develop breast cancer, the incidence is at least 2-fold higher in the daughters of DES-exposed mothers.
Many pregnant women in Europe and Australia also used DES, but the peak exposure occurred later than in the USA. Fig. 2 shows that the peak exposure in the USA was in the early 50’s, while in France it was in the late 1960’s and early 70’s. The fact that the daughters of DES-exposed mothers in Europe are younger than the daughters in the USA 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 increased breast cancer risk. In summary, the findings in humans provide strong evidence that maternal DES exposure during pregnancy increases their daughters’ breast cancer risk. …
Findings in Animal Studies
Many animal studies have investigated the effect of in utero DES exposure on later mammary tumorigenesis [76–81]. The amount of DES given to pregnant mice or rat dams varied from study to study (0.2–12,000 µg/day, which translates in rats to approximately 1 µg/kg – 60 mg/kg DES per day; in pregnant women the DES dose ranged from 100 µg/kg to 2 mg/kg), as did the route of administration (subcutaneous injection or via feed) and mammary tumor model used (spontaneous, carcinogen-induced, or ACI rats which develop mammary tumors upon estrogen exposure). The animal studies show that the doses of DES relevant to pregnant women increased later risk of developing mammary tumors. The increase did not occur with the highest doses and exposures which started early in pregnancy [81, 82], probably because they prevented implantation or caused miscarriage in most of the exposed dams.
Women use estrogens for many purposes. During pregnancy, synthetic estrogen 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. The proposed sequence of events from the fetal estrogen exposure to an increase in breast cancer risk is illustrated in the featured image. 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.
- Full study (free access) : Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk, Journal of Mammary Gland Biology and Neoplasia, NCBI PubMed PMC3635108, 08 February 2013.
- Featured image Proposed sequence of events from maternal exposure to estrogens during pregnancy to an increase in daughter’s breast cancer risk PMC3635108/figure/F3.