Breast cancer is the leading cancer diagnosed in women globally, with brain metastasis emerging as a major cause of death, particularly in human epidermal growth factor receptor 2 positive and triple-negative breast cancer subtypes. Comprehensive understanding of the molecular foundations of central nervous system metastases is imperative for the evolution of efficacious treatment strategies. Lipocalin-2 (LCN2), a secreted iron transport protein with multiple functions, has been linked to the progression of breast cancer brain metastasis (BCBM). In primary tumors, LCN2 promotes the proliferation and angiogenesis of breast cancer cells, triggers the epithelial-mesenchymal transition, interacts with matrix metalloproteinase-9, thereby facilitating the reorganization of the extracellular matrix and enhancing cancer cell invasion and migration. In brain microenvironment, LCN2 undermines the blood-brain barrier and facilitates tumor seeding in the brain by modulating the behavior of key cellular components. In summary, this review meticulously examines the fuel role of LCN2 in BCBM cascade, and investigates the potential mechanisms involved. It highlights the potential of LCN2 as both a therapeutic target and biomarker, indicating that interventions targeting LCN2 may offer improved outcomes for patients afflicted with BCBM.

Background: Melanoma brain metastasis is an lethal event. Investigating the molecules that potentially promoted melanoma metastasis is important for targeted therapy.Methods: The transcriptional profiles of totaling 7 melanoma samples, including 4 primary and 3 brain metastatic tissues were studied on the single-cell RNA sequencing level, and the expression of PLEKHA5 was examined in tumor clusters. Then PLEKHA5 expression was validated in brain Metastatic model by left ventricular injections in nude mice. The functional effect of PLEKHA5 isoforms (Long or Short) on proliferation and migration of melanoma was studied by RNA interference, overexpression by lentivirus vector, CCK8 test, colony formation test, transwell chamber assay. The targets and signal pathways that was potentially regulated by PLEKHA5 was studied by RNA-sequencing.Result: PLEKHA5 expression increased in brain metastatic melanoma at single cell level. PLEKH5 was constantly upregulated in brain metastatic tissue of melanoma in animal model. PLEKHA5-L had the potential for melanoma migration and proliferation by upregulating oncogenes such as HRAS, AKT3 etc. PLEKHA5-L also upregulated expression of PD-L1 and ABC transporters that were associated with therapy resistant.Conclusion: PLEKHA5-L was potential therapeutic target for metastatic melanoma.