bims-merabr 2025-04-06 papers

Growth Factors. 2025 Apr 03. 1-11

Expression of DDX49 in breast cancer and its mechanism regulating the proliferation and metastasis of breast cancer cells.

Yuanbin Wang, Lijun Yang, Xiangli Li, Qing Yang, Ruimin Ma, Zhihao Wu.

DEAD-box RNA helicase (DDX) is linked to the invasion, drug resistance, proliferation, and epithelial-mesenchymal transition of tumour cells. This study examined the potential mechanisms of DDX49 in breast cancer. The expression of DDX49 in breast cancer tissues and cells was evaluated. The effects of DDX49 on proliferation, invasion, migration and apoptosis of breast cancer cells were evaluated. The expression of proteins associated with the JAK/STAT pathway was examined. A xenograft tumour model was established. DDX49 expression is elevated in breast cancer tissues and cell lines. shDDX49 suppressed the ability of breast cancer cells to proliferate, invade, and migrate, but promoted apoptosis. Conversely, overexpression of DDX49 exerted an opposite effect. The activation of the JAK-STAT signalling pathway is inhibited by the shDDX49. shDDX49 efficiently inhibits tumour growth in mice with breast cancer. shDDX49 may hinder the growth and spread of breast cancer cells by inhibiting the JAK-STAT pathway.

Keywords: Breast cancer; DDX49; JAK-STAT signalling pathway; apoptosis; proliferation

DOI: https://doi.org/10.1080/08977194.2025.2484007

Sci Rep. 2025 Apr 01. 15(1): 11040

The regulatory effect of CoL10A1 to the intracranial vascular invasion and cell proliferation in breast cancer via EMT pathway.

Xiaoyin Wang, Shunchang Ma, Shaomin Li, Wang Jia, Dainan Zhang.

With advances in breast cancer (BC) treatment technology, although it could prolong the BC patients' survival, brain metastasis (BM) is increasing gradually. Patients with brain metastasis of breast cancer (BMBC) could have the decline of survival rate and quality of life. Investigate the regulatory role of Collagen Type X Alpha 1 Chain (CoL10A1) in BMBC process was the aim of this study. CoL10A1 expression was analyzed from TCGA database and clinical tissues, and then detected the regulation of CoL10A1 on BC cells proliferation, migration, and invasion in BC cell lines and mouse models. Our findings indicated that BMBC tissues have significant levels of CoL10A1 expression. BC cells proliferation, migration and invasion may be inhibited by knocking down Co10A1 in vitro and in vivo. In addition, we found that knocking down CoL10A1 could reduce the penetration of 468 cells into hCMEC/D3 cells. Knocking down CoL10A1 regulated the epithelial-mesenchymal transition (EMT) pathway related proteins expression. CoL10A1 could regulate BC cells proliferation, migration and invasion, affect the penetration into hCMEC/D3 cells in vitro, and inhibit the intracranial vascular invasion in mouse models. These results suggested that CoL10A1 may be a new target for treating human BMBC.

Keywords: Breast cancer; Breast metastasis; CoL10A1; Epithelial–mesenchymal transition; Invasion

DOI: https://doi.org/10.1038/s41598-025-87475-w

Cell Rep. 2025 Apr 01. pii: S2211-1247(25)00258-X. [Epub ahead of print]44(4): 115487

Hypoxia-induced PRMT1 methylates HIF2β to promote breast tumorigenesis via enhancing glycolytic gene transcription.

Wen-Juan Li, Yan-Chao Chen, Yi-An Lin, Yi-Qin Zou, Guo-Sheng Hu, Jing-Jing Yang, Xin-Yu Nie, Mei-Yan Li, Yi-Ran Wang, Yao-Hui He, Yan Zhao, Yu-Hua Tan, Xianming Deng, Wei-Ling He, Yan Cheng, Fang-Meng Fu, Wen Liu.

Hypoxia-induced metabolic reprogramming is closely linked to breast cancer progression. Through transcriptomic analysis, we identified PRMT1 as a direct target of hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions in breast cancer cells. In turn, PRMT1 enhances the expression of HIF1α-driven glycolytic genes. Mechanistically, PRMT1 methylates HIF2β at arginine 42, facilitating the formation, chromatin binding, and the transcriptional activity of the HIF1α/HIF2β heterodimer. Genetic and pharmacological inhibition of PRMT1 suppresses HIF2β methylation, HIF1α/HIF2β heterodimer formation, chromatin binding, glycolytic gene expression, lactate production, and the malignant behaviors of breast cancer cells. Moreover, combination treatment with iPRMT1, a PRMT1 inhibitor, and menadione, an HIF1α/P300 interaction inhibitor, demonstrates synergistic effects in suppressing breast tumor growth. Clinically, PRMT1 and PRMT1-mediated HIF2β methylation were significantly elevated in breast tumors compared with adjacent normal tissues. In conclusion, our findings reveal the critical role of PRMT1-mediated arginine methylation in glycolytic gene expression, metabolic reprogramming, and breast tumor growth.

Keywords: CP: Cancer; CP: Metabolism; HIF2β; arginine methylation; breast cancer; glycolytic gene expression; hypoxia; lactate production; menadione

DOI: https://doi.org/10.1016/j.celrep.2025.115487

Mol Biol Rep. 2025 Apr 01. 52(1): 351

miR-526b enhances glucose metabolism in breast cancer cells, an effect reversed by targeting the COX-2/EP4 pathway.

Braydon D Nault, Mousumi Majumder.

INTRODUCTION: Cancer cells reprogram metabolic pathways to meet energy demands and sustain rapid growth, a hallmark of malignancy. Identifying molecular signatures underlying these changes can aid in early detection and inform targeted therapies. miR-526b has been shown to promote migration, invasion, angiogenesis, and metastasis, yet its role in dysregulated glucose metabolism remains underexplored.
METHODS: We used MCF7 (Luminal A) and SKBR3 (HER2-Enriched) breast cancer cell lines, which exhibit distinct metabolic characteristics, to study miR-526b's impact on metabolic marker expression, ATP production, oxygen consumption rate, and extracellular acidification. Cells were treated with glycolysis inhibitor 2 Deoxy-D-Glucose (2DG) or ox-phos inhibitor Oligomycin (OM) to measure dependence on glycolysis or oxidative phosphorylation. Stable transfection was used to overexpress miR-526b in MCF7 and SKBR3 cell lines, and miRNA inhibitors were used to inhibit miR-526b in MCF7-COX2 cells, comparing its effects across subtypes. Targeted inhibition of EP4 with a specific antagonist (EP4A) RQ-15986 (CJ-042794) was done in aggressive MCF7-COX2 cells to test the involvement of COX-2/EP4.
RESULTS: SKBR3 exhibits an enhanced glycolytic phenotype, while MCF7 demonstrates increased ox-phos metabolism. Overexpression of miR-526b amplified these inherent metabolic properties, increasing ATP production and proliferation in both cell lines. miR-526b enhanced ox-phos activity in MCF7, reducing sensitivity to glycolysis inhibition, whereas it amplified glycolytic metabolism in SKBR3, reducing sensitivity to ox-phos inhibition. Overexpression of COX-2 in MCF7 replicated the metabolic effects of miR-526b. Inhibition of miR-526b in MCF7-COX2 cells enhances HK2 and GLUT1 expression, but did not significantly alter cell proliferation or cell viability. Targeting the COX-2/EP4 axis with a selective EP4A reversed the transcriptomic changes induced by miR-526b, but did not reduce the increased proliferation observed in MCF7-COX2.
CONCLUSION: miR-526b enhances inherent metabolic characteristics of breast cancer cell lines, increasing ATP production, proliferation, and resistance to metabolic inhibitors. Targeting the COX-2/EP4 axis mitigated some of the effects induced by miR-526b, but it did not normalize cell behavior, highlights the complex regulation of glucose metabolism in breast cancer and underscores the need for combination therapy strategies.

Keywords: Breast cancer; COX-2; EP4; Glucose; Glycolysis; Metabolism; Oxidative phosphorylation; miR-526b

DOI: https://doi.org/10.1007/s11033-025-10430-5

bioRxiv. 2025 Mar 19. pii: 2025.03.18.643983. [Epub ahead of print]

Sp1 mechanotransduction regulates breast cancer cell invasion in response to multiple tumor-mimicking extracellular matrix cues.

Abhishek Sharma, Rowan F Steger, Jen M Li, Jane A Baude, Kellie A Heom, Siddharth S Dey, Ryan S Stowers.

Breast cancer progression is marked by extracellular matrix (ECM) remodeling, including increased stiffness, faster stress relaxation, and elevated collagen levels. In vitro experiments have revealed a role for each of these factors to individually promote malignant behavior, but their combined effects remain unclear. To address this, we developed alginate-collagen hydrogels with independently tunable stiffness, stress relaxation, and collagen density. We show that these combined tumor-mimicking ECM cues reinforced invasive morphologies and promoted spheroid invasion in breast cancer and mammary epithelial cells. High stiffness and low collagen density in slow-relaxing matrices led to the greatest cell migration speed and displacement. RNA-seq revealed Sp1 target gene enrichment in response to both individual and combined ECM cues, with a greater enrichment observed under multiple cues. Notably, high expression of Sp1 target genes upregulated by fast stress relaxation correlated with poor patient survival. Mechanistically, we found that phosphorylated-Sp1 (T453) was increasingly located in the nucleus in stiff and/or fast relaxing matrices, which was regulated by PI3K and ERK1/2 signaling, as well as actomyosin contractility. This study emphasizes how multiple ECM cues in complex microenvironments reinforce malignant traits and supports an emerging role for Sp1 as a mechanoresponsive transcription factor.

DOI: https://doi.org/10.1101/2025.03.18.643983