Abstract 126: Defining how oxidative stress drives the evolution of aggressive breast cancers

Abstract Breast cancer is the most commonly diagnosed malignancy in women worldwide. It is a molecularly heterogeneous disease, which poses difficulties in the treatment of more advanced cancers. Despite this fact, the mechanisms contributing to the emergence of aggressive breast cancers remains poorly understood. We focus on reactive oxygen species (ROS), which are induced by a variety of stimuli in breast cancer cells. Moderately elevated ROS levels are tumor-promoting and facilitate the emergence of more aggressive tumours. Our laboratory has developed a unique model of HER2+ breast cancer that evolved to acquire more aggressive properties under conditions of chronic oxidative stress. We identified 20 transcription factors/co-regulators that were specifically overexpressed in these aggressive breast cancers, compared to their parental counterparts. We hypothesize that these transcription factors are central to the ability of breast tumors to adapt to chronic oxidative stress and acquire more aggressive properties. To test this, I have performed an in vivo functional shRNA screen to identify those transcriptional regulators that drive an aggressive phenotype. This will be followed by functional validation studies to interrogate whether and how these unique transcription factors overexpressed in aggressive breast cancers impact tumour growth, metastasis, and drug resistance. Mechanistically, we will explore whether and how these transcriptional responses mediate adaptive responses to tumor microenvironmental stressors, including altered metabolism, hypoxia, and tumor immune responses. This research will broaden our understanding of how breast cancers adapt to oxidative stress responses and represents a necessary first step in the development of novel therapeutics against these invulnerable malignancies. Citation Format: Caitlynn N. Mirabelli, Rachel La Selva, John Heath, Steven Hébert, Jutta Steinberger, Jialin Jiang, Claudia Kleinman, Sidong Huang, Josie Ursini-Siegel. Defining how oxidative stress drives the evolution of aggressive breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 126.