Abstract 3086: TFAP2C promotes mitochondrial fitness required for sustained kinase reprogramming in endocrine therapy resistance in breast cancer

Abstract Endocrine therapy resistance (ETR) remains a formidable challenge in the treatment of estrogen receptor-positive (ER+) luminal breast cancer, frequently leading to therapeutic failure. Our previous research identified the transcription factor TFAP2C as a key regulator of the antioxidant enzyme glutathione peroxidase 1 (GPX1), as well as c-ErbB2/HER2, RET, and EGFR, which lead to ERK/MAPK activation and promote ETR. Here, we aimed to elucidate the role of TFAP2C in the redox regulation of kinase reprogramming in acquired ETR. Our current study reveals that TFAP2C acts as a metabolic switch, triggering cellular reprogramming and redox modulation of kinase signaling through post-translational cysteine modifications. TFAP2C knockdown in tamoxifen-resistant cell lines and patient-derived organoids induces mitophagy, leading to reduced mitochondrial content, metabolic reprogramming, and altered Reactive oxygen species (ROS) profiles via GPX1 and SOD1 signaling. This disruption enhances phosphatase activity in the PI3K and MAPK pathways, resulting in cell cycle arrest and attenuated HER2- and EGFR-mediated signaling, both of which are pivotal for sustaining ETR. This study not only underscores the role of TFAP2C as a central player in maintaining the metabolic and signaling adaptations required for kinase reprogramming associated with ER+ targeting therapies, but also highlights the broader implications of mitochondrial redox signaling in the etiology of ETR, providing a novel avenue for therapeutic intervention. Citation Format: Attila Szenasi, Austin Whitman, Santiago Haase, Philip Spanheimer. TFAP2C promotes mitochondrial fitness required for sustained kinase reprogramming in endocrine therapy resistance in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3086.