Abstract A51: Mechanistic pathways for breast carcinogens can highlight early effects as predictive endpoints for chemical safety testing: Case studies for ionizing radiation and for in utero exposure to estrogens such as DES

Abstract

Abstract Knowledge about established breast carcinogens can support improved 21st-century toxicologic testing by identifying key mechanistic events. To clarify mechanisms, we developed adverse outcome pathways (AOPs) for two well-established breast carcinogens: ionizing radiation (IR) and the pharmaceutical hormone diethylstilbestrol (DES). The AOP for ionizing radiation includes these elements: IR increases production of reactive oxygen and nitrogen species (RONS), and directly and indirectly causes DNA damage. DNA damage leads to mutations and proliferation, leading to increased breast cancer. RONS also increases inflammation, contributing to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS, and separately increases breast cancer risk through increased proliferation of cells and increased tumor growth and invasion. Estrogen and progesterone also influence the risk of breast cancer from ionizing radiation, as does developmental stage. For in utero estrogens like DES, the AOP links gestational estrogen exposure to transcriptional activity that promotes altered signaling between the epithelial and stromal tissue compartments, leading to disrupted development, including altered tensional homeostasis and tissue architecture, inflammation, and altered cellular differentiation. These key events lead to several adverse outcomes at the tissue and organ level that increase susceptibility to breast cancer, including altered density, structure, and hormone sensitivity along with hyperplasia. Epigenetic alterations are a cellular-level outcome that propagates gestational estrogen exposure to later-life risk through cellular memory that directs ER-mediated gene expression and altered mammary development. Increased susceptibility to breast cancer follows from these adverse outcomes. Dose-response and developmental timing of exposure are discussed in both AOPs. These AOPs provide a framework for evaluating the potential for mechanistically similar stressors—e.g., genotoxicants/RONS-inducers may act like IR, or estrogenic chemicals in utero may act like DES—to affect breast cancer risk. Citation Format: Jessica Helm, Andrea Hindman, Ruthann A. Rudel. Mechanistic pathways for breast carcinogens can highlight early effects as predictive endpoints for chemical safety testing: Case studies for ionizing radiation and for in utero exposure to estrogens such as DES [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A51.