Quantifying early biomarkers of mammary carcinogenesis with multiplexed spatial biology

PROJECT SUMMARY/ ABSTRACT Dr. Jennifer Kay is a tenure track-equivalent Research Scientist at Silent Spring Institute, an independent, non- profit research center dedicated to uncovering environmental causes of breast cancer and other women’s health issues. Dr. Kay develops new approaches to identify chemical exposures that increase breast cancer risk and quantify their effects by integrating mechanistic evidence with experimental and observational studies in animals and humans. Genotoxicity and/or endocrine activity are features of most known human breast carcinogens, and the combination of cancer initiation by genotoxicity and promotion by endocrine signaling is predicted to increase risk compared to either alone. Drawing on her experience studying mechanisms of mutagenesis and carcinogenesis in the liver, intestines, and lung, with this K01 career development award, she will investigate the mechanistic interactions of estrogenicity and genotoxicity in breast cancer using a rodent model and novel multiplexed spatial biology approaches. This award will provide Dr. Kay the opportunity to 1) hone grantsmanship and project management skills, 2) become a leader in breast cancer prevention and toxicology, and 3) generate new mechanistic knowledge that can support hazard and risk prediction. Dr. Kay’s primary mentor, Ruthann Rudel, Research Director of Silent Spring Institute, will help her design research that can shape cancer risk assessment and prevention strategies, and she will help Dr. Kay translate findings to national and international scientific organizations, government decision makers, and lay audiences. Co-mentor Dr. Laura Vandenberg of University of Massachusetts Amherst—an expert in rodent mammary gland biology and carcinogenesis—will train her in diverse techniques for studying chemical effects on the breast using rats. The proposed project, “Quantifying early biomarkers of mammary carcinogenesis with multiplexed spatial biology,” will characterize the mechanistic interactions between genotoxicity and estrogenicity in chemically induced mammary carcinogenesis. Biomarkers of effect will be tracked in mammary tissue structures and epithelial cell types in the days and weeks after exposure to chemicals that are genotoxic, estrogenic, or both, preceding tumor development. Expanding upon her previous experience with spatial biology and quantitative bioimaging, Dr. Kay will integrate molecular markers measured via multiplexed immunofluorescence with microscopic alterations to tissue morphology in adjacent histopathological sections and structural effects in whole-mount tissues. In addition, this project will, for the first time, measure the ability for chemical exposures to alter estradiol levels in mammary tissue as well as serum. This research advances NIEHS goals by enhancing mechanistic understanding of endocrine disruption and genotoxicity in breast cancer, laying a foundation for assessing carcinogenic effects of mixtures and predicting risk with toxicological methods that are matched to the underlying processes. The tools developed here can be applied to study molecular effects of carcinogens that act via other mechanisms in a wide range of tissues.