FOXA1 transcriptionally upregulates LMAN2 to promote breast cancer progression.
TL;DR
FoxA1 bound to the LMAN2 promoter to enhance its transcription, thereby promoting BC progression at least partially through ferroptosis suppression and malignant phenotype induction.
Abstract
Background
Breast cancer (BC), the most widespread malignancy in women globally, is characterized by complex and heterogeneous mechanisms. Lectin, mannose binding 2 (LMAN2), a potential oncogene highly expressed in BC, is linked to poor prognosis. The transcription factor forkhead box protein A1 (FOXA1) is often overexpressed in BC and tied to malignant phenotypes, but how it regulates LMAN2 to influence BC progression remains unclear.
Methods
LMAN2 expression in BC and its association with patient prognosis were analyzed via the GEPIA database. mRNA and protein levels were detected by qRT-PCR and Western blot. Cell proliferation, angiogenesis, invasion/migration, and apoptosis were evaluated using EdU, tube formation assay, Transwell, and flow cytometry. The ferroptosis status of cells was assessed by detecting ferroptosis-related indicators. The transcriptional regulatory effect of FOXA1 on LMAN2 was verified using JASPAR database, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. The in vivo effect of the FOXA1/LMAN2 axis on BC growth was validated using a nude mouse xenograft model, and related protein expression was detected by immunohistochemistry (IHC).
Results
LMAN2 was upregulated in BC, with high expression linked to poor survival. Silencing LMAN2 was associated with reduced BC cell proliferation, migration, invasion, and angiogenesis, concomitant with increased ferroptosis and apoptosis. FOXA1 binding sites were identified in the LMAN2 promoter; FOXA1 directly bound to this region to enhance LMAN2 transcription, and FOXA1 knockdown reduced LMAN2 expression. FOXA1 overexpression enhanced BC cell malignancy and suppressed ferroptosis, with these effects reversed by concurrent LMAN2 silencing. In vivo, FOXA1 knockdown restrained xenograft tumor growth, and this effect was reversed by concurrent LMAN2 overexpression.
Conclusion
FOXA1 bound to the LMAN2 promoter to enhance its transcription, thereby promoting BC progression at least partially through ferroptosis suppression and malignant phenotype induction.