Triple‐negative breast cancer (TNBC) is the most aggressive subtypes of breast cancer, which has few effective targeted therapies. Various sources of evidence confirm that microRNAs (miRNAs) contribute to the progression and metastasis of human breast cancer. However, the molecular mechanisms underlying the changes in miRNAs expression and the regulation of miRNAs functions have not been well clarified. In this study, we found that the expression of miR‐30b‐5p was upregulated in breast cancer tissues and breast cancer cell lines, compared to paracancer tissues and normal breast cell lines. Moreover, induced overexpression of miR‐30b‐5p promoted the MDA‐MB‐231 and HCC 1937 cell growth, migration, and invasion and reduced the cellular apoptosis. Further studies confirmed that miR‐30b‐5p could directly target ASPP2 and then activate the AKT signaling pathway. Our results suggested that miR‐30b‐5p could act as a tumor promoter in TNBC. The newly identified miR‐30b‐5p/ASPP2/AKT axis represents a novel therapeutic strategy for treating TNBC.

Background: Cancer metabolism and specifically lipid metabolism play an important role in breast cancer (BC) progression and metastasis. However, the role of lipid metabolism-associated genes (LMGs) in the prognosis of breast cancer remains unknown. Methods: The expression profiles and clinical follow-up information of 1053 BC were downloaded from The Cancer Genome Atlas (TCGA), and metabolic genes were downloaded from the Gene Set Enrichment Analysis (GSEA) dataset. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed on the differentially expressed metabolism-related genes. Then, the formula of the metabolism-related risk model was composed, and the risk score of each patient was calculated. The breast cancer patients were divided into high-risk and low-risk groups with a cutoff of the median expression value of the risk score, and the prognostic analysis was also used to analyze the survival time between these two groups. Finally, we analyzed the expression, interaction and correlation among the lipid metabolism-associated genes risk model. Results: The results from the prognostic analysis indicated that the survival was significantly poorer in the high-risk group than in the low-risk group in TCGA, and single-sample gene set enrichment analysis (ssGSEA) shows it is plausible that lipid metabolism is highly correlated with tumor immunity. Conclusion: Lipid metabolism-associated genes may become a new prognostic indicator predicting the survival of BC patients. The prognostic genes (n = 16) may help provide new strategies for tumor therapy.

Circular RNAs (circRNAs), a novel group of non-coding RNAs, have been involved in the occurrence and development of different malignancies.However, the potential functional role of circRNAs in triple-negative breast cancer (TNBC) remains largely unknown,In this study, we aimed to investigate the regulatory functions and underlying mechanism of a conserved circRNA, circGNAI2, in TNBC. In this study, we demonstrated that circGNAI2 was aberrantly downregulated in TNBC cells and was negatively associated with poor prognosis. Functional experiments showed that circGNAI2 significantly suppressed TNBC cell proliferation and migration in vivo and in vitro. Mechanistically, we found that circGNAI2 upregulated VGLL4 and inhibited the phosphorylation STAT3 by sponging miR-454-3p. Moreover, EIF4A3 has binding sites in the upstream region of the GNAI2 pre-mRNA, and we confirmed that circGNAI2 was downregulated by EIF4A3 in TNBC cells. Overall, our study indicates that EIF4A3-regulated circGNAI2 suppresses TNBC progression possibly by regulating the miR-454-3p/VGLL4/STAT3 pathway, providing pivotal potential therapeutic targets for the treatment of TNBC.

Introduction: Advanced breast cancer remains a major therapeutic challenge with high mortality rates. While leucine-rich repeat (LRR) proteins play roles in various cancers including breast cancer, their specific functions are still underexplored. This study aimed to address this research gap by focusing on the leucine-rich repeat neuronal (LRRN) family, with the goal of clarifying their expression, clinical value, and prognostic significance in breast cancer—particularly LRRN1 in advanced cases. Methods: To investigate the expression of LRRN family members in breast cancer, this study utilized public databases including TCGA-BRCA, GEO, and UALCAN. It further analyzed the clinical value of these LRRN family members and specifically identified the prognostic significance of LRRN1 in advanced breast cancer cases. Functional assays (assessing proliferative, migratory, and invasive capabilities of cancer cells) were conducted to evaluate LRRN1’s biological effects. Additionally, WGCNA, GO analysis, KEGG analysis, and western blotting were employed to verify the molecular pathways impacted by LRRN1. Results: LRRN1 was found to be significantly downregulated in advanced breast cancer tissues compared to normal tissues (p < 0.001). Moreover, high LRRN1 expression correlated with better disease-free survival (DFS) in advanced breast cancer patients (HR=0.755, 95% CI: 0.617–0.923, p < 0.01). Functional assays revealed that LRRN1 suppresses cancer cell metastasis (without affecting cancer cell proliferation) (p<0.01). Results from WGCNA, GO, KEGG analyses, and western blot confirmed that LRRN1 impacts the Wnt signaling pathway (p<0.05). Additionally, LRRN1 may activate γδ T cells and resting dendritic cells, regulate the M1/M2 macrophage balance in the tumor microenvironment (p<0.001), and mediate the efficacy of certain tyrosine kinase inhibitors (TKIs) (p<0.001). Discussion: Overall, LRRN1 emerges as a promising prognostic indicator and functional mediator in advanced breast cancer. It potentially exerts its effects by influencing the Wnt signaling pathway and regulating immunotherapy responses. However, the specific mechanisms underlying LRRN1’s actions, as well as its potential clinical applications, still require further exploration to fully translate these findings into clinical practice for advanced breast cancer treatment.

Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) is frequently observed in various cancers and promotes tumorigenesis by activating the PI3K-AKT pathway. However, the effectiveness of therapies targeting this pathway is limited by complex signaling crosstalk and compensatory mechanisms. Here, we employed quantitative proteomic and phosphoproteomic analyses using MCF10A PTEN KO models to comprehensively map the signaling alterations induced by PTEN loss. Our analyses revealed that PTEN deficiency not only activates canonical PI3K-AKT signaling but also induces widespread changes in cytoskeleton organization, cell cycle regulation, and central carbon metabolism. PTEN loss also substantially elevates the activity of a variety of tyrosine kinases, including Src kinase and EphA2, a receptor tyrosine kinase implicated in cancer progression. Mechanistic studies demonstrated that Src activation, rather than the canonical AKT signaling pathway, drives the upregulation of the receptor tyrosine kinase EphA2. The activation of the noncanonical tyrosine kinase signaling renders AKT inhibition alone insufficient in PTEN-deficient cancers. Importantly, combined treatment with the Food and Drug Administration-approved AKT inhibitor capivasertib and the Src inhibitor dasatinib synergistically induced apoptosis and suppressed the tumor cell growth in various PTEN-deficient cell lines as well as in 3D cultures of endometrial cancer patient-derived xenograft models. Our study reveals that PTEN loss drives oncogenic signaling via dual activation of PI3K-AKT and tyrosine kinase pathways. Specifically, Src-mediated upregulation of EphA2 in PTEN-deficient cells highlights a therapeutic vulnerability that can be exploited by combined AKT and Src inhibition. This approach addresses the resistance associated with AKT inhibition alone and enhances therapeutic efficacy in PTEN-deficient cancers, supporting its potential application in targeted combination therapies.

Prior research suggests miR‑572 may suppress breast cancer (BC), but its precise role and mechanism in disease progression, particularly in triple