Application of the Key Characteristics Framework to Identify Potential Breast Carcinogens Using Publicly Available in Vivo , in Vitro , and in Silico Data

Abstract

Background: Chemicals that induce mammary tumors in rodents or activate estrogen or progesterone signaling are likely to increase breast cancer (BC) risk. Identifying chemicals with these activities can prompt steps to protect human health. Objectives: We compiled data on rodent tumors, endocrine activity, and genotoxicity to assess the key characteristics (KCs) of rodent mammary carcinogens (MCs), and to identify other chemicals that exhibit these effects and may therefore increase BC risk. Methods: Using authoritative databases, including International Agency for Research on Cancer (IARC) Monographs and the US Environmental Protection’s (EPA) ToxCast, we selected chemicals that induce mammary tumors in rodents, stimulate estradiol or progesterone synthesis, or activate the estrogen receptor (ER) in vitro . We classified these chemicals by their genotoxicity and strength of endocrine activity and calculated the overrepresentation (enrichment) of these KCs among MCs. Finally, we evaluated whether these KCs predict whether a chemical is likely to induce mammary tumors. Results: We identified 279 MCs and an additional 642 chemicals that stimulate estrogen or progesterone signaling. MCs were significantly enriched for steroidogenicity, ER agonism, and genotoxicity, supporting the use of these KCs to predict whether a chemical is likely to induce rodent mammary tumors and, by inference, increase BC risk. More MCs were steroidogens than ER agonists, and many increased both estradiol and progesterone. Enrichment among MCs was greater for strong endocrine activity vs. weak or inactive, with a significant trend. Discussion: We identified hundreds of compounds that have biological activities that could increase BC risk and demonstrated that these activities are enriched among MCs. We argue that many of these should not be considered low hazard without investigating their ability to affect the breast, and chemicals with the strongest evidence can be targeted for exposure reduction. We describe ways to strengthen hazard identification, including improved assessments for mammary effects, developing assays for more KCs, and more comprehensive chemical testing. https://doi.org/10.1289/EHP13233

Investigating phenotypic plasticity due to toxicants with exposure disparities in primary human breast cells in vitro

“…Chemical hair straightening products, in particular, are disproportionately purchased by African American women and have been associated with premature breast development and increased risk of premenopausal breast cancer ( 10 ). While the mechanisms implicating disparate chemical exposures as drivers of aggressive breast cancer are poorly understood, it is becoming increasingly apparent that chemical exposures may impact breast cancer risk ( 11 , 12 ).…”

“…For estrogen receptor-negative breast cancers, such as TNBC, there is mounting evidence to suggest that chemical exposures may increase risk for breast cancer by inducing phenotypic plasticity. Recent studies have implicated cadmium, arsenic, and BPA as environmental chemicals capable of inducing phenotypic plasticity in normal human breast cells ( 1 – 3 , 5 – 7 , 9 , 11 , 12 , 14 – 16 , 18 , 19 , 22 – 49 ). The goal of the present study was to further characterize the association between exposure to chemicals with documented exposure disparities and phenotypic plasticity in primary normal breast cells from diverse donors.…”

Invited Perspective: New Motivations and Future Directions for Investigating Environmental Risk Factors for Breast Cancer

“…In this issue of Environmental Health Perspectives , Kay et al. 6 update their prior list 7 of mammary carcinogens by drawing upon the key characteristics framework developed by the International Agency for Research on Cancer. In doing so, they broadened the approach to identifying mammary carcinogens by incorporating information on chemical bioactivity, including both genotoxicity and endocrine disruption.…”

Comment on “Application of the Key Characteristics Framework to Identify Potential Breast Carcinogens Using Publicly Available in Vivo , in Vitro , and in Silico Data”

“…We read with interest the recent paper published by Kay et al. 1 We are particularly aware, through our work on breast cancer, of the need for strong and innovative research to characterize the contribution of the environment in the broad sense to the incidence of this disease, the leading cause of cancer deaths in women worldwide. 2 As Kay et al.…”