This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Early-life stromal estrogen receptor activation by endocrine disrupting chemicals in the mammary gland leading to enhanced cancer risk
- Andrea Hindman
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite||Under Development||1.79||Included in OECD Work Plan|
This AOP was last modified on January 09, 2020 08:10
This adverse outcome pathway (AOP) links gestational EDC exposure to enhanced breast cancer risk. The molecular initiating event (MIE) is gestational estrogen receptor (ER) activation; particularly, stromal activation at in utero time of exposure. The ER is a master transcriptional regulator, with proliferation as its primary effect, and is the main mediator of breast development [24, 25]. Human-relevant EDC exposure triggers transcriptional activity that promotes altered signaling between the epithelial and stromal tissue compartments leading to disrupted tensional homeostasis  and tissue architecture. Inflammation and altered cellular differentiation are major cell- and tissue-level key events (KEs) mediating these disruptions. The pathway converges on the following mammary gland adverse outcomes (AOs) at the tissue- and organ-levels: altered density, structure and hormone sensitivity along with hyperplasia. Epigenetic alterations are a cellular-level AO that propagate gestational EDC exposure to later-life risk through cellular memory that directs ER-mediated gene expression and altered mammary development. Risk of tumorigenesis follows from these AOs.
The industrial estrogen, bisphenol A (BPA) is one of the most data-rich chemicals related to breast cancer and altered mammary gland development . As such, studies in model rodent strains following gestational EDC exposure to bisphenol A (BPA) or DES provide experimental support for this AOP and human-relevance. A thorough search of the literature yielded experimental evidence for this AOP as directed by a mix of natural and MeSH term search logic specifying rodents and non-human primates (population); human-relevant, in utero exposure to BPA or DES (exposure); and mammary gland AOs (outcome) [27-32] (see PECO statement, Table 1 below). Most studies investigating EDC-effects on mammary development heavily describe altered growth and structure, resulting in limited mechanistic understanding. This AOP integrates knowledge and tools from investigations of established breast cancer risk factors such as density and obesity to enhance understanding of the molecular- and cellular-driven etiologies of altered mammary structure and growth. Integrating this knowledge promotes the development of in vitro assays capable of predicting high-risk phenotypes and offers efficient alternatives to in vivo mammary gland evaluation. Ultimately, making these links in the knowledge base will improve screening to identify chemicals that act on gestational development and will more specifically target chemical contributions to later-life breast cancer risk in toxicity testing. Productive intermediate testing endpoints would follow ER-binding, -activation and steroidogenesis (OECD TG-455; EDSP TG-890[33, 34]), precede carcinogenicity (OECD TG-451, and -453) and connect these with EDC-effects on breast cancer due to prenatal exposure (OECD TG-414, -415, -416, -422, -443). This AOP will also describe ‘missed opportunities’ in the existing evidence; not reporting or measuring traditional toxicity testing endpoints, like uterine weight and body weight alongside more sensitive mammary gland growth and structural changes. Failure to do this in parallel within the same study undermines the sensitivity of these endpoints to predict later-life breast cancer risk.
Table 1. PECO statement [27, 28]. A statement of the Population, Exposure, Comparators and Outcomes was prepared to direct objective experimental study collection for this AOP synthesis on breast cancer risk from early-life EDC exposure. The Organization for Economic Co-operation and Development does not cite systematic review methods or objective identification of included evidence in its guidance for AOP development. A narrowed survey of review articles in PubMed, published after 2006 and until November 2018, was performed to assess the state of mechanistic evidence connecting EDC exposure to breast cancer risk and altered mammary gland growth and structure. This step assisted problem formulation by situating human-relevant EDC exposures in the hallmarks of cancer via ‘important reviews.’ There were no systematic reviews. This initial survey of the review literature assisted search logic development and supported an initial sketch of the AOP.
Population (Experimental animal, in vivo studies)
Breast cancer risk background: Breast cancer is a significant health concern as the second leading cause of death in women . Only 5-10% of breast cancers are attributable to genetic predisposition and substantial evidence indicates many lifestyle and environmental factors contribute to lifetime risk [2-5]. Early-life developmental disruption by hormone-like, or endocrine disrupting chemicals (EDCs), heightens age-related breast cancer risk. A human model of this disruption emerges from the treatment of pregnant women with synthetic estrogen, diethylstilbestrol (DES), beginning in the 1940’s with the intent to prevent miscarriages. This practice ceased when women exposed in gestation – “DES Daughters” – had a 40x increased incidence of cervical and vaginal cancers [6, 7], highlighting in utero development as a critical window of exposure. The later finding that “DES Daughters” also had a 2-fold increased incidence of breast cancer only detected in women ≥30 years post-exposure, underscores the latency of this disruption in causing disease [7-9]. Studies of the reproductive tract and mammary gland of rodent models have recapitulated these increased risks [10-12]. While synthetic estrogens are no longer prescribed to pregnant women, human biomonitoring data show widespread exposure to EDCs that include weak estrogens [13, 14] and their ability to cross the placental barrier [14-18]. Many EDCs are present at human-relevant exposures in the environment, but these chemicals can act together on the same adverse health outcomes , including estrogen action as a relevant target for breast cancer [20-23]. Taken together, this evidence raises concerns that early-life EDC exposure enhances later-life breast cancer risk.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
Considerations for Potential Applications of the AOP (optional)
1. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer Statistics, 2017. CA Cancer J Clin, 2017. 67(1): p. 7-30.
2. Kim, B.J. and S.H. Kim, Prediction of inherited genomic susceptibility to 20 common cancer types by a supervised machine-learning method. Proc Natl Acad Sci U S A, 2018. 115(6): p. 1322-1327.
3. Lichtenstein, P., et al., Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med, 2000. 343(2): p. 78-85.
4. Foulkes, W.D., Inherited susceptibility to common cancers. N Engl J Med, 2008. 359(20): p. 2143-53.
5. Peto, J., et al., Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst, 1999. 91(11): p. 943-9.
6. Herbst, A.L. and R.E. Scully, Adenocarcinoma of the vagina in adolescence. A report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas). Cancer, 1970. 25(4): p. 745-57.
7. Hatch, E.E., et al., Cancer risk in women exposed to diethylstilbestrol in utero. Jama, 1998. 280(7): p. 630-4.
8. Hoover, R.N., et al., Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med, 2011. 365(14): p. 1304-14.
9. Palmer, J.R., et al., Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev, 2006. 15(8): p. 1509-14.
10. Newbold, R.R., W.N. Jefferson, and E. Padilla-Banks, Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod Toxicol, 2007. 24(2): p. 253-8.
11. Soto, A.M., et al., 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, 2013. 18(2): p. 199-208.
12. Boylan, E.S. and R.E. Calhoon, Transplacental action of diethylstilbestrol on mammary carcinogenesis in female rats given one or two doses of 7,12-dimethylbenz(a)anthracene. Cancer Res, 1983. 43(10): p. 4879-84.
13. Calafat, A.M., et al., Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004. Environ Health Perspect, 2008. 116(1): p. 39-44.
14. Woodruff, T.J., A.R. Zota, and J.M. Schwartz, Environmental chemicals in pregnant women in the United States: NHANES 2003-2004. Environ Health Perspect, 2011. 119(6): p. 878-85.
15. Gerona, R.R., et al., Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in midgestation umbilical cord serum in a northern and central California population. Environ Sci Technol, 2013. 47(21): p. 12477-85.
16. Chen, M., et al., Determination of bisphenol-A levels in human amniotic fluid samples by liquid chromatography coupled with mass spectrometry. J Sep Sci, 2011. 34(14): p. 1648-55.
17. Balakrishnan, B., et al., Transfer of bisphenol A across the human placenta. Am J Obstet Gynecol, 2010. 202(4): p. 025.
18. Nishikawa, M., et al., Placental transfer of conjugated bisphenol A and subsequent reactivation in the rat fetus. Environ Health Perspect, 2010. 118(9): p. 1196-203.
19. Goodson, W.H., 3rd, et al., Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis, 2015. 36(1).
20. Dairkee, S.H., et al., A Ternary Mixture of Common Chemicals Perturbs Benign Human Breast Epithelial Cells More Than the Same Chemicals Do Individually. Toxicol Sci, 2018. 165(1): p. 131-144.
21. Goodson, W.H., 3rd, et al., Activation of the mTOR pathway by low levels of xenoestrogens in breast epithelial cells from high-risk women. Carcinogenesis, 2011. 32(11): p. 1724-33.
22. Silva, E., N. Rajapakse, and A. Kortenkamp, Something from "nothing"--eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol, 2002. 36(8): p. 1751-6.
23. Charles, G.D., et al., Analysis of the interaction of phytoestrogens and synthetic chemicals: an in vitro/in vivo comparison. Toxicol Appl Pharmacol, 2007. 218(3): p. 280-8.
24. Couse, J.F., et al., Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology, 1997. 138(11): p. 4613-21.
25. Feng, Y., et al., Estrogen receptor-alpha expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice. Proc Natl Acad Sci U S A, 2007. 104(37): p. 14718-23.
26. Northey, J.J., L. Przybyla, and V.M. Weaver, Tissue Force Programs Cell Fate and Tumor Aggression. Cancer Discov, 2017. 7(11): p. 1224-1237.
27. Vandenberg, L.N., et al., A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals. Environ Health, 2016. 15(1): p. 016-0156.
28. Rochester, J.R., A.L. Bolden, and C.F. Kwiatkowski, Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis. Environ Int, 2018. 114: p. 343-356.
29. Lewis, S.J., et al., Developing the WCRF International/University of Bristol Methodology for Identifying and Carrying Out Systematic Reviews of Mechanisms of Exposure-Cancer Associations. Cancer Epidemiol Biomarkers Prev, 2017. 26(11): p. 1667-1675.
30. Ertaylan, G., et al., A Comparative Study on the WCRF International/University of Bristol Methodology for Systematic Reviews of Mechanisms Underpinning Exposure-Cancer Associations. Cancer Epidemiol Biomarkers Prev, 2017. 26(11): p. 1583-1594.
31. Kushman, M.E., et al., A systematic approach for identifying and presenting mechanistic evidence in human health assessments. Regul Toxicol Pharmacol, 2013. 67(2): p. 266-77.
32. Higgins, J.P.T.a.G.S., Cochrane Handbook for Systematic Reviews of Interventions. Vol. Version 5.1.0 [updated March 2011]. 2011: The Cochrane Collaboration, 2011.
33. OECD, Test No. 455: Performance-Based Test Guideline for Stably Transfected Transactivation In Vitro Assays to Detect Estrogen Receptor Agonists and Antagonists. 2016.
34. EPA, Endocrine Disruptor Screening Program Tier 1 Assays: Considerations for Use in Human Health and Ecological Risk Assessments, O.o.C.S.a.P.a.P.O.a.O.o.P.P. (OPP), Editor. 2013, Environmental Protection Agency: Washington, DC 20460.