Hypoxia fuels JAK/STAT-LIV1 signaling: A promising therapeutic avenue in triple-negative breast cancer.

Abstract

Triple-negative breast cancer remains one of the most aggressive and therapeutically challenging breast cancer subtypes because of its high metastatic potential, molecular heterogeneity and limited targeted treatment options. Hypoxia is a hallmark of TNBC tumor microenvironment and activates signaling cascades that promote tumor progression, metastasis, immune evasion, and therapeutic resistance. Although hypoxia, STAT3 signaling, LIV-1 (SLC39A6), and zinc homeostasis have been independently implicated in TNBC progression, the mechanistic crosstalk among these pathways and their integration into a unified, subtype specific model remains insufficiently understood. Emerging evidence suggests that LIV-1 functions not merely as a zinc transporter but as an active regulator of oncogenic signaling. Under hypoxia conditions, stabilization of hypoxia-inducible factor-1α (HIF-1α) promotes cytokine- mediated STAT3 activation, leading to increased LIV-1 expression and consequent intracellular zinc accumulation. Elevated zinc levels, in turn, may sustain STAT3 phosphorylation through inhibition of negative regulatory phosphatases, establishing a self-reinforcing feed-forward loop that enhances epithelial-mesenchymal transition, cancer stemness, immune modulation and treatment resistance. Current TNBC therapies, including chemotherapy and emerging immunotherapies show limited durable efficacy, underscoring the need for mechanistically grounded biomarkers and targets. Based on these observations, we propose the Hypoxia-STAT3-LIV-1-zinc signaling axis as a central regulatory node driving TNBC progression and a promising candidate for biomarker development and therapeutic targeting. This review integrates current evidence supporting this signaling network, identifies critical knowledge gaps, and outlines experimental strategies including hypoxia-mimetic models, LIV-1/STAT3 knockdown systems, and zinc chelation assays needed to validate this proposed mechanism and translate it into clinical application.