Abstract A034: TET1 Orchestrates Glucose Metabolism and Counteracts TNBC Aggressiveness under the Oncogenic stress

Abstract The role of epigenetic mechanisms in silencing tumor suppressor genes and promoting triple-negative breast cancer (TNBC) progression and metastasis remain unclear. Multiple Copies in T-cell malignancy 1 (MCT-1) also known as malignant T-cell-amplified sequence 1 (MCTS1) is an oncoprotein overexpressed in TNBC and invasive BC. Our new findings reveal that MCT-1 upregulates DNA methyltransferase 1 (DNMT1) and downregulates ten-eleven translocation methylcytosine dioxygenase 1 (TET1) via the interleukin-6 (IL-6)/nuclear factor kappa B (NF-κB) pathway, causing hypermethylation and suppression of the miR-34a gene promoter. Higher miR-34a and TET1 expression levels are correlated with better survival of BC patients. Overexpression of TET1 suppresses TNBC cell growth, motility, stemness, and M2 macrophage activity driven by the MCT-1 oncogenic activity. Conversely, silencing TET1 or using the selective inhibitor NSC-370284 exacerbates TNBC malignancies. Clinically, TET1 is inversely correlated with MCT-1, IL-6 and NF-κB but not with DNMT1 in metastatic breast cancer. TET1 and miR-34a both reduce MCT-1-promoted glucose uptake and lactate production. Consistently, RNA- sequencing and metabolomics analyses show that TET1 counters MCT-1 effects on inducing the glycolytic metabolites and metabolism profiling. Elevated TET1 levels efficiently limits primary TNBC growth and the postoperative metastasis, which MCT-1 otherwise promotes. Significantly, depleted TET1 and induced MCT-1 synergistically aggravate TNBC metastasis to the lungs, liver, and bones. Collectively, TET1 modulates aggressiveness, metabolism, and immunity of TNBC under the oncogenic stress. Citation Format: Pao-Pao Yang, Aushia Tanzih . Al Haq, Hong-Yu Tseng, Jou-Ho Shih, Li-Mei Chen, Michael P. Snyder, Hsin-Ling Hsu. TET1 Orchestrates Glucose Metabolism and Counteracts TNBC Aggressiveness under the Oncogenic stress [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A034.