It is suggested that targeting LINC01929 to regulate TFRC-mediated ferroptosis could represent a promising therapeutic strategy for BC, positioning both LINC01929 and TFRC as potential biomarkers and therapeutic targets.
Abstract
Breast cancer (BC) remains the most prevalent malignancy among women worldwide, with persistent challenges such as drug resistance and tumor progression despite significant therapeutic advancements. The roles of ferroptosis and long non-coding RNAs (lncRNAs) in BC are not yet fully elucidated, underscoring the need for novel therapeutic targets. In this study, we investigated the function of LINC01929 in BC through a combination of in vitro and in vivo experiments, bioinformatics analysis, RNA pull-down mass spectrometry, and clinical tissue validation. We found that LINC01929 is significantly overexpressed in BC tissues and is associated with poor patient prognosis. Mechanistically, LINC01929 promoted malignant phenotypes in BC cells and was associated with reduced ferroptosis-related stress, with these effects being at least partly dependent on transferrin receptor (TFRC). Conversely, silencing LINC01929 led to reduced TFRC expression and induced ferroptosis in BC cells. Clinical data further confirmed that elevated TFRC levels correlate with aggressive tumor features and unfavorable outcomes. These findings suggest that targeting LINC01929 to regulate TFRC-mediated ferroptosis could represent a promising therapeutic strategy for BC, positioning both LINC01929 and TFRC as potential biomarkers and therapeutic targets.
BACKGROUND
Breast cancer remains a leading cause of cancer-related mortality worldwide, with triple-negative breast cancer (TNBC) representing a particularly aggressive subtype lacking targeted therapies. Inducing copper-mediated cell death stands as a significant therapeutic approach for tumors; however, research into non-coding RNA regulation of copper-mediated cell death in TNBC remains relatively scarce. This study analyses transcriptomic data from TNBC patients to identify long non-coding RNAs (lncRNAs) associated with copper-mediated cell death, aiming to uncover potential therapeutic targets.
METHODS
Bioinformatics analysis of transcriptomic data from breast cancer patients in the TCGA databases identified a key gene associated with copper-mediated cell death. The role of this gene in breast cancer tumor growth was then investigated at molecular, cellular, and animal model levels.
RESULT
This study finds long non-coding RNA LINC02207 is significantly downregulated in TNBC tissues and low expression correlates with poorer survival. It localizes in nucleus, acts as tumor suppressor by inhibiting cell proliferation, positively regulates cuproptosis and enhances sensitivity to Elesclomol. Knockdown impairs cuproptosis by modulating key genes. Mechanistically, NFAT5 is its nuclear binding partner. LINC02207 may regulate copper-dependent apoptosis by influencing the nuclear localisation of NFAT5, thereby influencing cancer progression. In vivo models confirm its overexpression suppresses tumor growth by promoting cuproptosis.
CONCLUSION
These findings reveal a critical tumor-suppressive role of LINC02207 mediated through NFAT5-dependent regulation of cuproptosis and suggest that LINC02207 may serve as a promising therapeutic target in breast cancer.
Jicheng Chen, Xinghang Fu, Xiaotang Gao et al.· Biochimica et Biophysica Act...· 0 citations
Brain metastasis in breast cancer patients represents an advanced and often fatal stage of disease, with survival typically less than one year following diagnosis. Despite therapeutic progress in primary tumors, effective treatments for breast cancer brain metastasis (BCBM) remain limited, highlighting the need for new mechanistic insights and therapeutic strategies. Our lab has recently found that SLC7A11 levels are significantly enriched in BCBM patient samples and are required for BCBM growth in vivo. SLC7A11, is a cystine/glutamate antiporter and is critical for glutathione (GSH) synthesis and protection against ferroptosis, a form of iron-dependent cell death. While it's function in ferroptosis resistance is well established, it's broader role in BCBM progression remains incompletely defined. Proteomic analyses of breast cancer cells overexpressing SLC7A11 revealed upregulation of extracellular matrix (ECM) and integrin-associated proteins, prompting investigation into regulation of ECM signaling pathways. In this study, we demonstrate that SLC7A11 overexpression significantly increases integrin [alpha]3, [alpha]6, and [beta]1 protein levels and focal adhesion kinase (FAK) activity, as evidenced by increased phosphorylation at tyrosine 397. Consistent with this data, using clonogenic survival assays, SLC7A11 overexpressing breast cancer cells showed resistance to FAK inhibitor induced cell death. In order to evaluate therapeutic potential of FAK inhibitors, we utilized an ex vivo brain slice model of BCBM. Treatment with clinically relevant FAK inhibitors including, PND-1186 and Defactinib resulted in significant tumor regression compared to controls. These findings indicate that FAK signaling contributes to BCBM tumor maintenance and that it's inhibition can effectively suppress tumor growth. Collectively, our results identify SLC7A11 as a non-canonical regulator of ECM/integrin-mediated FAK survival signaling in brain metastatic breast cancer cells. Targeting this axis may represent a promising strategy to enhance therapeutic vulnerability and improve outcomes in patients with breast cancer brain metastasis.
Kevin Michael Hughley, Mauricio J. Reginato· 0 citations
BACKGROUND
Breast cancer (BC) remains a significant global health threat with complex pathogenesis often linked to chemotherapy resistance and inflammatory microenvironments. Histidine triad nucleotide-binding protein 2 (HINT2) is a mitochondrial protein involved in metabolism and immunity, but its specific role in BC and potential as a therapeutic target require further elucidation.
OBJECTIVES
This study aimed to identify novel therapeutic targets for BC and evaluate the anti-tumor efficacy and molecular mechanisms of Albiflorin (Al), a natural monoterpene glycoside.
METHODS
Proteomic profiling was performed on BC xenografts in nude mice to identify differentially expressed proteins. In-vivo and in-vitro models (MDA-MB-231 cells) were established to assess the effects of Al (20 mg/kg or 20 µM) on tumor growth, apoptosis and cytokine production. Molecular docking and co-immunoprecipitation (Co-IP) were used to investigate the interactions among HINT2, NLRP3 and Al.
RESULTS
HINT2 was significantly upregulated in BC tissues and identified as a primary pro-tumorigenic factor. Co-IP confirmed an endogenous interaction between HINT2 and NLRP3. Al exhibited strong binding affinity to HINT2 (-7.36 kcal/mol) and significantly suppressed tumor volume and weight. Furthermore, Al treatment downregulated the HINT2/NLRP3 axis, reduced inflammatory cytokines (IL-1β, IL-6, TNF-α) and promoted apoptosis by modulating Caspase-3, Bax and Bcl-2 levels.
CONCLUSION
Albiflorin suppresses BC progression by inhibiting the HINT2/NLRP3 signaling pathway, suggesting HINT2 is a viable biomarker and Al a promising therapeutic agent for BC treatment.
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.
Zhi-Tao Zhang, Shaoyu Wang, Haifeng Sun et al.· Tissue & Cell· 0 citations
Breast cancer (BRCA) remains a leading cause of cancer-related mortality worldwide, necessitating the identification of novel biomarkers and therapeutic targets to overcome challenges such as treatment resistance and metastasis. In this study, we systematically characterized the multi-omic landscape of G1 to S phase transition protein 1 (GSPT1) in BRCA. Integrative bioinformatic analysis of public datasets revealed that GSPT1 mRNA and protein levels are significantly upregulated in BRCA across all clinical stages and molecular subtypes. To validate these findings, we performed immunohistochemical (IHC) staining on representative patient-derived tissue samples, which, complemented by transcriptomic analysis of diverse cell lines, confirmed this upregulation. High GSPT1 expression and its prevalent genomic alterations identified in public cohorts-particularly gene amplification observed in approximately 14% of cases-were strongly correlated with poor clinical outcomes, including diminished overall survival (OS), relapse-free survival (RFS), and distant metastasis-free survival (DMFS). Functional enrichment analyses indicated that GSPT1 expression is strongly associated with pathways critical for tumorigenesis, such as the cell cycle, DNA replication, and mitotic spindle organization. Furthermore, dependency analysis via the DepMap database and our experimental validation demonstrated that BRCA cells are highly dependent on GSPT1 for survival. Collectively, our findings further substantiate GSPT1 as a robust prognostic biomarker and provide translational evidence supporting its feasibility as a molecular glue-targetable vulnerability for precision oncology in BRCA.
