Abstract IA14: High-throughput methods for screening for breast carcinogens

Abstract

Abstract The recognition that biologic activities of carcinogens extend beyond “carcinogen = DNA-damaging agent” creates a roadmap for improved approaches to test chemicals and predict which ones are likely to increase cancer risk, so we can avoid them. For breast cancer, for instance, the established risks from hormone treatment in utero or later in life are examples of the powerful influence of receptor-mediated effects in carcinogenesis. Breast cancer research also implicates other important biologic activities including inflammation, oxidative stress, epigenetic alterations, and DNA repair, while the sensitivity of the breast to DNA-damaging agents is demonstrated by effects of ionizing radiation. In addition, over 200 diverse chemicals that cause mammary gland tumors in rodents provide insight into important structural features and biologic activities for breast carcinogenesis. For example, these chemicals include many halogenated hydrocarbons, aromatic amino/nitro compounds, and epoxide-forming chemicals, as well as hormones. Also, the increased risk associated with in utero hormone exposure highlights that new models are needed to detect chemicals that produce these effects and to predict effects on risk. To protect public health, it is necessary to develop and apply rapid, sensitive, and cost-effective chemical toxicity screening for the thousands of chemicals in commercial use. The characteristics of carcinogens provide a useful set of biologic targets for such testing. As an example that applies this concept, we developed a 500-gene panel called BCScreen that includes genes associated with 14 characteristics of breast carcinogens. In MCF-7, expression patterns distinguish known estrogenic chemicals like BPA and genistein from PFOA, a highly fluorinated pollutant that has been shown to alter mammary gland development. An important consideration is that responses in common in vitro models, most of which are cancer cell lines, may be different from normal tissues. Normal tissue models may provide more relevant output but also pose challenges. For example, expression profiling of estradiol response in normal breast epithelial organoids that maintain ER function shows different responses compared with MCF-7, and organoids from different individuals also had distinct responses. Assays that can detect chemicals that activate estrogen receptor or increase synthesis of estradiol or progesterone also highlight chemicals of concern for breast cancer. While human studies have not been especially helpful for detecting cancer risk associated with thousands of commercial chemicals, approaches that determine the biologic activities of the known human carcinogens and flag chemicals with similar activities may provide a pathway to prevention, and new methods are needed to do this. Risk predictions for environmental chemicals also must take into account the cofactors that influence background cancer risk, including host susceptibility and coexposures. Citation Format: Ruthann Rudel. High-throughput methods for screening for breast carcinogens [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 IA14.