Abstract 5742: Identifying likely breast carcinogens using complementary mechanistic approaches

Abstract

Abstract Many commercial chemicals and environmental pollutants show chemical or mechanistic similarity with known breast carcinogens such as ionizing radiation, hormones, alcohol, and tobacco. Regulatory agencies like the US Environmental Protection Agency (EPA) are charged with evaluating these chemicals for safety, which requires predicting theoretical effects on cancer risk that are often small for any individual, but significant across the population because exposures are widespread. Current approaches to chemical screening and assessment are being re-envisioned, driven by innovations in chemical safety testing, new regulations, and demand for information on health effects. We reversed the usual direction of inquiry by beginning with an outcome - breast cancer - and using three complementary approaches to identify biological processes that could be the focus of chemical toxicity screening. First, an expert panel identified key processes whose perturbation may alter breast cancer risk, including cellular and molecular events, tissue changes, and factors that alter susceptibility. Comparison of these endpoints with those included in US EPA’s ToxCast and Endocrine Disruptor Screening Program identified important endpoints not currently evaluated by US testing programs, including altered mammary gland development, Her2 activation, progesterone receptor activity, prolactin effects, and aspects of estrogen receptor β activity. Second, investigation of the mechanistic basis for many known breast cancer risk factors indicates biological processes relevant to breast cancer. For example, the body of evidence indicates HRT as a tumor promoter in the breast, while studies of DES show that hormone exposure in utero alters breast development and subsequent breast cancer risk. Chemicals with similar properties and biological activity may also pose preventable risks. Third, we compiled chemicals shown to increase mammary tumors or alter mammary gland development in rodents and identified key modes of action. We used data from ToxCast – a project that screened over 1000 chemicals in almost 800 in vitro assays – for 75 rodent mammary carcinogens and 18 disruptors of mammary development to identify mechanisms of mammary carcinogenesis and highlight gaps. Our analysis confirms that many mammary carcinogens are genotoxic, estrogenic, or both. We also observed that mammary toxicants increased activation of glucocorticoid and androgen receptors, as well as of PXR and CYP19A1, xenobiotic metabolizing systems involved in steroid hormone synthesis and metabolism, compared to other chemicals in ToxCast. Taken together, these approaches identify mechanisms by which chemicals may alter breast cancer risk and can shape chemical testing programs to increase their relevance to breast cancer. This approach can be extended to identify biological processes and screening methods relevant for other common cancers. Citation Format: Ruthann A. Rudel, Janet M. Ackerman, Megan R. Schwarzman, Julia G. Brody. Identifying likely breast carcinogens using complementary mechanistic approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5742. doi:10.1158/1538-7445.AM2017-5742