bims-merabr 2025-09-28 papers

Cancer Res Treat. 2025 Sep 24.

LRRC15 Promotes the Development of Breast Cancer by Regulating Autophagy through the PI3K/AKT/mTOR Signaling Pathway.

Xinru Fan, Liu Gao, Zheng Zhang, Xu Jiang, Xiawei Wang, Jiayu Shi, Yu Ling, Rundong Yan, Jiani Shi, Li Yu.

Purpose: Leucine-rich repeats (LRR) play important roles in tumorigenesis and may serve as novel biomarkers for cancer therapy. The expression of leucine-rich repeat-containing protein 15 (LRRC15) is increased in several cancers. However, it is still unknown whether LRRC15 is involved in breast cancer and autophagy.
Materials and Methods: This study conducted bioinformatic analysis on LRRC15 expression and prognosis in breast cancer. Clinical samples were collected and subjected to immunohistochemistry and qRT-PCR to analyze LRRC15 expression in tissues and serum. Clonal formation, MTT, wound healing, and Transwell assays were used to examined breast cancer cell proliferation, migration, and invasion. Western blotting detected autophagy-related and PI3K/AKT/mTOR signaling pathway proteins.
Results: Patients with breast cancer having elevated expression of LRRC15 have a markedly worse prognosis compared with those having lower levels. Furthermore, LRRC15 expression was strongly correlated with tumor aggressiveness and poor differentiation in breast cancer cell lines. Functionally, LRRC15 drives cancer cell proliferation, migration, and invasion. LRRC15 inhibited autophagy in breast cancer cells, thus modulating their proliferative capacity. Mechanistically, LRRC15 exerted these effects by activating the PI3K/AKT/mTOR signaling cascade.
Conclusion: LRRC15 regulates autophagy-induced proliferation and other biological activities of breast cancer cells through the PI3K/AKT/mTOR signaling pathway.

Keywords: Autophagy; Breast neoplasms; Carcinogenesis; LRRC15

DOI: https://doi.org/10.4143/crt.2025.543

Acta Histochem. 2025 Sep 23. pii: S0065-1281(25)00064-9. [Epub ahead of print]127(4): 152292

Cancer-associated fibroblast-derived CCL5 enhanced aerobic glycolysis through upregulation of IP3R to promote breast cancer cell metastasis.

Mingxiang Zhang, Zhengzhi Zhu, Guang Yang, Yongyun Zhu.

BACKGROUND: This study aimed to investigate whether cancer-associated fibroblast (CAF)-derived chemokine C-C motif ligand 5 (CCL5) promotes breast cancer (BC) cell metastasis by enhancing aerobic glycolysis via upregulation of IP3R.
METHODS: Lentiviral vectors for CCL5 overexpression or knockdown were constructed, transfected into CAFs, and co-cultured with ZR-75-30 cells CCL5. Cell proliferation and apoptosis were assessed by CCK-8, cloning assay and flow cytometry. Cell migration and invasion were verified by scratch assay and Transwell assay. Co-IP verified the interactions between CCL5 and IP3R. The kit detects aerobic glycolysis-related indexes. western bloting detects CCL5, IP3R, glycolysis-related proteins, EMT-related proteins and metastasis-related proteins.
RESULTS: Knockdown of CCL5 in CAFs and co-culture with breast cancer cells resulted in decreased cell proliferation, migration, and invasionCCL5, increased apoptosis, and attenuated aerobic glycolysis. Co-immunoprecipitation (Co-IP) assays revealed direct protein-protein interactions between CCL5 and IP3RCCL5. IP3R overexpression following CCL5 knockdown rescued breast cancer cell proliferative viability CCL5, restoration of migration and invasion abilities, and enhanced aerobic glycolysis.
CONCLUSION: CAF-derived CCL5 enhanced aerobic glycolysis in breast cancer cells by up-regulating IP3R expression, which in turn promoted their metastasis.
DATA AVAILABILITY: The data used to support the findings of this study are available from the corresponding author upon request.

Keywords: Aerobic glycolysis; Breast Cancer; CAF-CCL5; IP3R

DOI: https://doi.org/10.1016/j.acthis.2025.152292

Stem Cell Res Ther. 2025 Sep 25. 16(1): 494

NCAPH-YAP1 interaction promotes breast cancer stemness and tumor progression.

Caixin Qiu, Yansha Wei, Jiehua Li.

RATIONALE: Breast cancer (BC) is the most prevalent malignant tumor in women globally. Despite improved cure rates and survival for early- to mid-stage patients, around 30% still progress to metastatic BC due to cancer stem cells (CSCs), which drive tumor recurrence, progression, metastasis, and drug resistance.
METHODS: This study used bioinformatics to analyze BC datasets from gene expression omnibus (GEO), cBioportal, and The Cancer Genome Atlas (TCGA), identifying NCAPH as a gene associated with breast cancer stem cells (BCSCs) characteristics. The mRNA stemness index algorithm was used to calculate tumor stemness scores. WGCNA, Lasso regression, and Kaplan-Meier analyses validated the link between NCAPH and BC prognosis. In vitro and in vivo experiments explored NCAPH's effects on BC cells. Transcriptomic sequencing and Gene set enrichment analysis (GSEA) analysis revealed Hippo-YAP1 pathways regulated by NCAPH. Co-immunoprecipitation and immunofluorescence co-localization experiments confirmed the interaction between NCAPH and YAP1, with functional rescue experiments using the YAP1 inhibitor Verteporfin.
RESULTS: Results showed NCAPH was overexpressed in BC, linked to advanced tumor stages and poor prognosis. It enhanced CSCs properties, accelerated cell cycle progression, and promoted proliferation, migration, and invasion in vitro and in vivo. GSEA analysis suggested NCAPH regulates YAP1 in the Hippo signaling pathway. NCAPH promotes LATS1 and YAP1 expression, dephosphorylation, and nuclear translocation, enhancing BCSC traits and malignant phenotypes. Notably, Verteporfin reversed NCAPH-driven BCSC traits and malignant phenotypes.
CONCLUSION: This study identifies NCAPH as a novel oncogenic factor in BC. NCAPH interacts with YAP1, promoting its nuclear translocation and enhancing BCSC traits and malignancy. Critically, YAP1 inhibition reverses NCAPH-driven effects, validating the NCAPH as a promising therapeutic target.

Keywords: Breast cancer; Cancer stem cell; NCAPH; YAP1

DOI: https://doi.org/10.1186/s13287-025-04648-0

Sci Rep. 2025 Sep 26. 15(1): 32986

Overexpression of alcohol dehydrogenase 1 A inhibits the progress of triple negative breast cancer via Wnt/β-catenin signaling.

Lihong Su, Chunlin Qiao, Jin Luo, Bianling Zhu, Yunxiao Liu.

The identification of novel therapeutic targets in triple negative breast cancer (TNBC) continues to be of paramount importance. In this context, ADH1A (Alcohol Dehydrogenase 1 A), a protein involved in tyrosine metabolism, was comprehensively examined to assess its expression and functional roles in TNBC. A combination of bioinformatics approaches and local tissue analyses was utilized to determine the expression levels of ADH1A in TNBC samples. Genetic manipulation techniques were employed to alter ADH1A expression, and the subsequent effects on TNBC cell behavior were systematically analyzed. This study is the first to report on the alterations of 14 genes related to tyrosine metabolism within the TCGA-TNBC cohorts. Notably, reduced expression of these enzymes is associated with poorer survival outcomes in patients with TNBC. An analysis of the TCGA database revealed reduced levels of ADH1A in human TNBC tissues. Furthermore, ADH1A protein expression was diminished in TNBC tissues of patients who received local treatment, in contrast to the elevated expression observed in adjacent normal tissues. In the MDA-MB-231 and SUM159PT cell lines, ADH1A knockdown significantly promoted cell proliferation, migration, and invasion. On the contrary, ADH1A overexpression inhibited cell proliferation, migration, and invasion, while inducing cell apoptosis. Mechanistically, the overexpression of ADH1A may attenuate the malignant characteristics of TNBC cells by inhibiting the Wnt/β-catenin signaling pathway. In conclusion, ADH1A may be a useful biomarker for TNBC prognosis. This study is the first to reveal that ADH1A inhibits the malignant progression of TNBC via the Wnt/β-catenin signaling pathway.

Keywords: Breast cancer; Migration; Prognosis; Proliferation; Tyrosine metabolism

DOI: https://doi.org/10.1038/s41598-025-17643-5

Cells. 2025 Sep 22. pii: 1482. [Epub ahead of print]14(18):

Targeting the CXCR4/CXCL12 Axis to Overcome Drug Resistance in Triple-Negative Breast Cancer.

Desh Deepak Singh, Dharmendra Kumar Yadav, Dongyun Shin.

Triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant forms. TNBC is an aggressive and therapeutically resistant subtype of breast cancer, marked by the absence of estrogen, progesterone, and HER2 receptors. The lack of defined molecular targets significantly limits treatment options and contributes to high recurrence rates. Among the key pathways involved in TNBC progression and resistance, the CXCR4/CXCL12 chemokine axis has emerged as a critical player. CXCR4, a G-protein-coupled receptor, binds specifically to its ligand CXCL12, promoting tumour cell proliferation, metastasis, immune evasion, and stromal remodelling. Its overexpression is frequently associated with poor prognosis, disease progression, and resistance to conventional therapies in TNBC. This review explores how the chemokine receptor type 4 (CXCR4/CXCL12) axis facilitates drug resistance through mechanisms such as epithelial-mesenchymal transition (EMT), cancer stemness, and microenvironmental interactions. Notably, CXCR4 antagonists like plerixafor, balixafortide, and POL5551 have shown encouraging preclinical and clinical results, particularly when combined with chemotherapy or immunotherapy. Additionally, innovative strategies, including radiopharmaceuticals, peptide inhibitors, and nanotechnology-based delivery platforms, offer expanded therapeutic avenues. Despite persistent challenges such as tumour heterogeneity and potential toxicity, growing clinical evidence supports the translational relevance of this axis. This manuscript provides an in-depth analysis of CXCR4/CXCL12-mediated drug resistance in TNBC and evaluates current and emerging therapeutic interventions.

Keywords: CXCL12; CXCR4; chemoresistance; drug resistance; targeted therapy; triple-negative breast cancer (TNBC)

DOI: https://doi.org/10.3390/cells14181482