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Development of an adverse outcome pathway network for breast cancer: a comprehensive representation of the pathogenesis, complexity and diversity of the disease


Adverse outcome pathways (AOPs), introduced in modern toxicology, intend to provide an evidence-based representation of toxicological effects and facilitate safety assessment of chemicals not solely based on laboratory animal in vivo experiments. However, some toxicological processes are too complicated to represent in one AOP. Therefore, AOP networks are developed that help understanding and predicting toxicological processes where complex exposure scenarios interact and lead to the emergence of the adverse outcome. In this study, we present an AOP network for breast cancer, developed after an in-depth survey of relevant scientific literature. Several molecular initiating events (MIE) were identified and various key events that link the MIEs with breast cancer were described. The AOP was developed according to Organization of Economic Co-Operation and Development (OECD) guidance, weight of evidence was assessed through the Bradford Hill criteria and confidence was tested by the OECD key questions. The AOP network provides a straightforward understanding of the disease onset and progression at different biological levels. It can be used to pinpoint knowledge gaps, identify novel therapeutic targets and act as a stepping stone for the development of novel in vitro test methods for hazard identification and risk assessment of newly developed chemicals and drugs.

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The authors acknowledge the use of Servier Medical Art as Figs. 13 were partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license. This research received no external funding.

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Conceptualization, GGD, IN and JDK; methodology, GGD, IN and JDK; investigation, GGD, IN, SPB, KS and BW; writing—original draft preparation, GGD, IN, YVH and JDK; writing—review and editing, GGD, IN, MR, TV, YVH and JDK; visualization, IN; supervision, YVH and JDK; funding acquisition, JDK. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Gigly G. Del’haye or Ine Nulmans.

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Del’haye, G.G., Nulmans, I., Bouteille, S.P. et al. Development of an adverse outcome pathway network for breast cancer: a comprehensive representation of the pathogenesis, complexity and diversity of the disease. Arch Toxicol 96, 2881–2897 (2022).

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  • Adverse outcome pathway
  • Risk assessment
  • Hazard identification
  • Breast cancer
  • Therapeutic target identification