ZBTB1 Regulates Glycolysis and Chemotherapy Resistance Through Interacting with c-Myc in Triple Negative Breast Cancer

Background/Objectives: Our previous study identified ZBTB1 as a novel tumor suppressor in estrogen receptor-positive (ER+) breast cancer. Moreover, The Cancer Genome Atlas (TCGA) data analysis showed a much lower level of ZBTB1 in triple-negative breast cancer than in ER+ breast cancer. Triple negative breast cancer (TNBC) lacks effective targeted therapies and largely depends on chemotherapy, while chemotherapy resistance remains a major clinical challenge. This study aimed to explore the role of ZBTB1 in TNBC progression and chemotherapy resistance. Methods: We performed clinical survival analysis, in vitro and in vivo functional experiments, mass spectrometry screening, and mechanistic validation in TNBC and Adriamycin-resistant TNBC cells. Results: We found that ZBTB1 protein is downregulated in TNBC and this downregulation correlates with shorter patient survival. ZBTB1 regulates glycolysis and chemotherapy resistance in TNBC cells. Mechanistically, ZBTB1 interacts with c-Myc and suppresses its transcriptional activity in MDA-MB-231 and MDA-MB-453 but not in Adriamycin-resistant cells (MDA-MB-231/ADR and MDA-MB-453/ADR). LncRNA SAP30L-AS1 is required for maintaining the ZBTB1–c-Myc interaction in TNBC cells. SAP30L-AS1 is significantly depleted in Adriamycin-resistant cells, which disrupts the binding between ZBTB1 and c-Myc. Functional validation revealed that SAP30L-AS1 modulates glycolysis and chemotherapy resistance in TNBC cells in a ZBTB1-dependent manner. Conclusions: Collectively, our data indicate the key role of ZBTB1 in TNBC and ZBTB1 may serve as a novel approach for TNBC treatments.