bims-merabr 2025-08-17 papers

Sci Rep. 2025 Aug 13. 15(1): 29621

Substrate stiffness regulates triple-negative breast cancer signaling through CXCR4 receptor dynamics.

Kenneth K Y Ho, Johanna M Buschhaus, Anne Zhang, Alyssa C Cutter, Brock A Humphries, Gary D Luker.

Biophysical properties of the extracellular matrix (ECM), such as mechanical stiffness, directly regulate behaviors of cancer cells linked to cancer initiation and progression. Cells sense and respond to ECM stiffness in the context of dynamic changes in biochemical inputs, such as growth factors and chemokines. While commonly studied as isolated inputs, mechanisms by which combined effects of mechanical stiffness and biochemical factors affect functions of cancer cells remain poorly defined. Using a combination of elastically supportive surface (ESS) culture dishes with defined stiffnesses and single-cell imaging, we report here that culturing cells on a stiff (28 kPa) versus soft (1.5 kPa) substrate increases CXCR4 and EGFR expression and promotes greater ligand-dependent internalization of CXCR4. In addition to increased CXCR4 expression, a stiff ECM also increases basal activation of Akt and ERK as well as signaling through these kinases in response to CXCL12-α and EGF and promotes migration of triple negative breast cancer (TNBC) cells. These data implicate receptor dynamics as a key mediator of Akt and ERK signaling as a mechanism for adverse effects of enhanced ECM stiffness on disease progression in TNBC.

Keywords: Akt; CXCR4; ERK; Extracellular matrix; Signaling dynamics; Triple-negative breast cancer

DOI: https://doi.org/10.1038/s41598-025-14495-x

Breast Cancer Res. 2025 Aug 12. 27(1): 145

Exosome-delivered METTL14 drives hypoxia-induced proliferation, metastasis, and glycolysis of breast cancer cells through regulating TRIM16-mediated FGF7 ubiquitination.

Bo Huang, Yichao Zhang, Zhanjun Chen, Yuanyuan Yuan, Jianshan Lin.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and has a poor prognosis. Previous studies have indicated that Fibroblast Growth Factor 7 (FGF7) plays a vital role in the development and progression of breast cancer. However, the role and molecular mechanisms of FGF7 in TNBC remain largely unclear under hypoxia.
METHODS: FGF7 and Methyltransferase-like 14 (METTL14) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). FGF7, tripartite motif-containing protein 16 (TRIM16), METTL14, METTL3, YTHDF1, WTAP, FTO, CD63, CD81, and TSG101 protein levels were examined by western blot. Cell viability, proliferation, invasion, and migration were determined using MTT, EdU, transwell, and wound healing assays. Glucose consumption, lactate production, and ATP levels were assessed using relevant kits. After STRING database analysis, the interaction between TRIM16 and FGF7 was verified using a Co-immunoprecipitation (CoIP) assay. Interaction between METTL14 and TRIM16 was validated using methylated RNA immunoprecipitation (MeRIP), RIP, and dual-luciferase reporter assays. The biological role of hypoxia-induced exosomal METTL14 on breast cancer tumor growth was assessed using the xenograft tumor model in vivo.
RESULTS: FGF7 was highly expressed in TNBC patients and cell lines. Moreover, FGF7 expression was increased in the hypoxia group compared with the normoxia group. Functionally, FGF7 knockdown suppressed hypoxia-induced TNBC cell proliferation, metastasis, and glycolysis. Mechanistically, TRIM16 triggered the ubiquitination of FGF7 and promoted its degradation. METTL14 enhanced TRIM16 mRNA stability and expression by m6A methylation. Hypoxia-induced exosomal METTL14 knockdown repressed tumor growth in vivo.
CONCLUSION: Hypoxia-induced exosomal METTL14 supports the proliferation, metastasis, and glycolysis of TNBC cells through regulating TRIM16-mediated FGF7 ubiquitination, providing a promising therapeutic target for TNBC treatment.

Keywords: FGF7; Hypoxia; METTL14; Proliferation; TNBC; TRIM16

DOI: https://doi.org/10.1186/s13058-025-02099-2

Biochim Biophys Acta Mol Cell Res. 2025 Aug 10. pii: S0167-4889(25)00148-X. [Epub ahead of print]1872(8): 120043

ESCO2 drives breast cancer proliferation and metastasis through PI3K/AKT/mTOR phosphorylation: A potential therapeutic target.

Pingchuan Li, Lineng Wei, Meng Li, Huawei Yang.

Breast cancer remains a major global health threat to women, underscoring the urgent need for novel therapeutic targets. While ESCO2, an essential cell cycle regulator, has been implicated in cancer progression, its precise role and molecular mechanisms in breast cancer remain poorly understood. In this study, we first demonstrated significant upregulation of ESCO2 in breast cancer through analysis of TCGA and GEO datasets, which was further validated in clinical specimens and cell lines, with its expression correlating with advanced T-stage, aggressive molecular subtypes and poor prognosis. Functional studies in MDA-MB-231 and MDA-MB-468 cells revealed that ESCO2 overexpression promoted cell proliferation, migration and invasion, while its knockdown exerted opposite effects. Mechanistic investigations uncovered that ESCO2 depletion reduced phosphorylation of PI3K/AKT/mTOR pathway components, and co-immunoprecipitation assays confirmed direct interaction between ESCO2 and PI3K. Importantly, the tumor-suppressive effects of ESCO2 knockdown could be rescued by SC79-mediated AKT activation. In vivo experiments using xenograft mouse models consistently showed that ESCO2 silencing significantly inhibited tumor growth, increased apoptosis and necrosis, and reduced metastasis. Collectively, our findings establish ESCO2 as a novel oncogene driving breast cancer progression through PI3K/AKT/mTOR pathway activation, highlighting its potential as a promising therapeutic target for breast cancer intervention.

Keywords: Breast cancer; ESCO2; Metastasis; PI3K/AKT/mTOR; Proliferation

DOI: https://doi.org/10.1016/j.bbamcr.2025.120043

Breast Cancer Res. 2025 Aug 11. 27(1): 142

Non-enzymatic SETD1A activity drives breast cancer cell proliferation via cyclin K.

Kanako Hayashi, Takayuki Hoshii, Meng Ning, Makoto Matsumoto, Shintaro Izumi, Masaki Fukuyo, Bahityar Rahmutulla, Masahiko Tanabe, Atsushi Kaneda.

BACKGROUND: Breast cancer is the most common cancer in women worldwide. SETD1A, a histone H3 lysine-4 methyltransferase, is associated with poor prognosis in breast cancer. While both its enzymatic and non-enzymatic functions are implicated in cancer progression, the specific role of SETD1A in breast cancer remains unclear. This study aimed to elucidate the molecular mechanisms underlying SETD1A dependency in breast cancer.
METHODS: SETD1A-high breast cancer cell lines were identified using TCGA and DepMap databases, along with SETD1A knockdown experiments. A CRISPR knockout of SETD1A was performed in a doxycycline-inducible Cas9-expressing KPL-1 breast cancer cell line. RNA-seq, ChIP-seq, CRISPR-tiling screening, and rescue experiments with exogenous SETD1A mutants were performed to investigate the roles of SETD1A in breast cancer.
RESULTS: SETD1A is highly expressed in estrogen receptor-positive / human epidermal growth factor receptor 2-negative (ER+HER2-) breast cancer and is associated with shorter overall survival in luminal-type breast cancer patients. We found that SETD1A is required for cell cycle progression from G1 to S phase in KPL-1 breast cancer cells, but its catalytic domain is dispensable. SETD1A disruption reduces the expression of DNA repair-associated genes, including RPA3 and PRIM1. Exogenous expression of both genes restores defective cell proliferation following SETD1A knockout. The non-catalytic function of SETD1A in breast cancer cells depends on its cyclin K-associated FLOS domain. SETD1A disruption also leads to defective transcriptional elongation in downregulated genes. Treatment with the cyclin K degrader CR8 recapitulates the phenotypes observed in SETD1A knockout cells. Both SETD1A knockout and CR8 were also effective in triple negative breast cancer (TNBC) cells.
CONCLUSIONS: SETD1A promotes breast cancer cell replication through its non-enzymatic role via cyclin K, suggesting that the SETD1A-cyclin K axis could be a potential therapeutic target in breast cancer.

Keywords: Breast cancer; Epigenome; H3K4 methyltransferase; SETD1A; Transcription

DOI: https://doi.org/10.1186/s13058-025-02101-x

Sci Rep. 2025 Aug 10. 15(1): 29273

CAFs exosomal circFOXO1 promotes TNBC autophagy and radioresistance via miR-27a-3p/BNIP3 axis.

Xueqiong Xun, Huiyong Hu, Qing Liu, Ruijun Su, Jun Ai.

Cancer-associated fibroblasts (CAFs) are related to tumor treatment tolerance. Therefore, this study investigated the molecular mechanisms and tumor microenvironment-influencing factors of CAFs in promoting triple-negative breast cancer (TNBC) radiotherapy tolerance. Transwell assays were used to detect cell invasion capacity, and wound-healing assays were used to detect cell migration capacity. CCK-8 was used to assess cell proliferation, and flow cytometry was used to assess apoptosis. Western blotting was used to detect the expression levels of epithelial‒mesenchymal transition (EMT)-related and autophagy marker proteins. Transmission electron microscopy was performed to observe the number of autophagosomes. A nude mouse model of TNBC xenograft tumor was established, and the expression levels of circRNA-FOXO1, miR-27a-3p and BNIP3 in the tumor tissues of the nude mice were detected using RT‒qPCR. The results revealed that circRNA-FOXO1 was highly expressed in CAFs exosomes subjected to radiotherapy. The overexpression of circRNA-FOXO1 in TNBC cells promoted proliferation, migration and invasion; reduced the cell apoptosis rate; and promoted the occurrence of EMT and autophagy. However, the knockdown of circRNA-FOXO1 resulted in the opposite outcome. Transfection of the miR-27a-3p mimic reversed the promoting influence of FOXO1 on the malignant biological behavior of TNBC cells. BNIP3 overexpression effectively reversed the inhibitory influence of miR-27a-3p on the malignant biological behavior of TNBC cells. In addition, in vivo animal experiments have shown that CAFs exosomes or overexpression of FOXO1 can promote the growth of tumors in nude mice, while further treatment with the autophagy inhibitor 3-MA weakens the effects of exosome or FOXO1 overexpression to a certain extent. In conclusion, exosomal circRNA-FOXO1 in CAFs promotes TNBC cell autophagy and reduces radiosensitivity by regulating the miR-27a-3p/BNIP3 axis.

Keywords: Autophagy; Cancer-associated fibroblasts; Exosomes; FOXO1/miR-27a-3p/BNIP3; Triple-negative breast cancer

DOI: https://doi.org/10.1038/s41598-025-13876-6