Abstract 3807: Exposure to environmental chemicals leads to extensive branching and expression of cancer-promoting proteins in human mammary gland organoids

Abstract Bisphenol A (BPA) is a chemical compound used as a plasticizer in a variety of plastic goods. Environmental chemicals like BPA haven been detected in the blood of women and girls. Yet, they are thought to interact with the endocrine system, thereby having carcinogenic effects on the tissue. While BPA is removed from many commercial products because of its potential carcinogenic effect, surprisingly little is known about its replacement chemicals, such as bisphenol S (BPS) and bisphenol F (BPF). In this study, we aim to link the exposure to those environmental chemicals to changes in human mammary gland morphology and to the underlying alterations at the protein level. We established organoid cultures from non-malignant primary human mammary gland tissue as advanced disease model. Human breast organoids were treated with physiological levels of various environmental chemicals, includingBPA, BPF, BPS, 17-β-estradiol (E2), or DMSO as vehicle control. Effects on organoid morphology were studied using brightfield and confocal microscopy. We analyzed relative protein abundances by quantitative mass spectrometry to define proteome changes between the different treatments. The exposure to the environmental chemicals as well as E2 resulted in altered branching morphology while organoid size was not affected. It is already known that BPA has oncogenic potential. Surprisingly, in our study, BPA has the least severe effects when compared to the other bisphenols. BSF or BPS treatment lead to more extensive branching and changed morphology.On protein level, each environmental chemical resulted in distinct protein profiles which show proteins alterations independent of endocrine signaling. Moreover, the exposure to the different bisphenols resulted in the upregulation of proteins which are involved in carcinogenesis, tumor progression and metastasis in various cancer types including breast cancer and thus may support tumor development. In this study, we identified BPS and BPF as potential carcinogens. Not only BPA, but also BPF and in particular BPS alter branching morphology of mammary organoids and influence various biological processes that are distinct from endocrine signaling. Our study highlights the desperate need of a thorough characterization of environmental chemicals to prevent the development of breast cancer caused by the exposure to potential harmful and carcinogenic substances. Citation Format: Johanna H. Hinrichs, Juliane Winkler, Pengyuan Liu, Nassim Ataii, Susan Fisher, Zena Werb. Exposure to environmental chemicals leads to extensive branching and expression of cancer-promoting proteins in human mammary gland organoids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3807.