LKB1 contributes to miR-8072-driven aerobic glycolysis and tamoxifen resistance in ER-positive breast cancer

Estrogen receptor (ER)-positive breast cancer is the most common subtype of breast cancer, and endocrine therapy, particularly tamoxifen, remains a cornerstone of its treatment. However, a substantial proportion of patients eventually develop tamoxifen resistance, resulting in disease progression and poor clinical outcomes. The molecular mechanisms underlying tamoxifen resistance remain incompletely understood. We previously identified miR-8072 as a tumor suppressor in triple-negative breast cancer. In the present study, we investigated its context-dependent role in ER-positive breast cancer and endocrine therapy resistance. MTS, colony formation, and cytotoxicity assays, together with a xenograft mouse model, were used to evaluate the effects of miR-8072 or LKB1 on tumor growth and tamoxifen sensitivity in ER-positive breast cancer. A dual-luciferase reporter assay was performed to investigate the regulatory effect of miR-8072 on STK11 . Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), glucose consumption, and lactate production were measured to assess the effects of miR-8072/LKB1 on aerobic glycolysis in ER-positive breast cancer cells. miR-8072 was upregulated in breast cancer and negatively correlated with estrogen response signature. Under standard culture conditions, miR-8072 suppressed the growth of ER-positive breast cancer cells. Paradoxically, under endocrine-deprived or tamoxifen-treated conditions, miR-8072 promoted hormone-independent growth and enhanced tamoxifen resistance. Mechanistically, miR-8072 increased the expression of glycolytic enzymes and stimulated aerobic glycolysis in ER-positive breast cancer cells. STK11 , which encodes the serine/threonine kinase LKB1, was identified as a target of miR-8072. High STK11 expression was associated with improved overall survival in patients with ER-positive breast cancer but with poorer survival in those with ER-negative disease. Among patients with ER-positive breast cancer, high STK11 expression was associated with longer survival in those receiving endocrine therapy but shorter survival in those who did not receive endocrine therapy. Consistent with these clinical associations, LKB1 overexpression suppressed aerobic glycolysis and enhanced tamoxifen sensitivity, whereas LKB1 ​​​ silencing partially restored aerobic glycolysis and ​ tamoxifen resistance in miR-8072-inhibited cells. These findings reveal a context-dependent role of miR-8072 in ER-positive breast cancer and identify the miR-8072/LKB1 axis as a previously unrecognized mechanism linking metabolic reprogramming to tamoxifen resistance. Therapeutic targeting of this axis may provide a potential strategy for overcoming endocrine therapy resistance in ER-positive breast cancer.