bims-merabr 2025-10-26 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–10–26
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Deubiquitinating enzyme USP42 promotes breast cancer progression by inhibiting JNK/p38-mediated apoptosis.
TM9SF1 drives the lipophagic flux via AMPK-ULK1 signaling to sustain metabolic fitness in HER2-positive breast cancer.
Inhibiting NEDD4 in triple-negative breast cancer cells reprograms tumor immune microenvironment via the β-TrCP/YAP/ECM axis.
FTO promotes the progression of triple-negative breast cancer by regulating the m6A methylation of NFKBIE.
CCN3/IMP3/HIF1α positive feedback loop enhances malignant progression of triple-negative breast cancer.
The role of fibroblast growth factors in cell and cancer metabolism.
Impact of obesity on breast cancer recurrence by menopausal status and subtype: a retrospective cohort study.
Dual metabolic targeting liposomes potentiate triple-negative breast cancer radiosensitivity via glucose and glutathione starvation.

Sci Rep. 2025 Oct 21. 15(1): 36751

Deubiquitinating enzyme USP42 promotes breast cancer progression by inhibiting JNK/p38-mediated apoptosis.

Chongwu He, Jing Chen, Ruibo Tian, Liu Yang, Wenrui He, Longbo He, Jiawei Xu, Jianglong Li, Gongxian Wang, Changan Jiang, Qiang Liu, Xianghua Wan, Tenghua Yu.

This study investigated the role of ubiquitin specific peptidase 42 (USP42) in breast cancer proliferation, focusing on its modulation of apoptosis via the JNK/p38 signaling pathway. USP42 expression levels in breast cancer cell lines were assessed using western blotting and RT-qPCR. In vitro, cell proliferation was evaluated using CCK-8 assay and clonogenic assay assessed, while apoptosis was measured by flow cytometry evaluated. Western blotting was used to analyze the expression of apoptosis-related proteins and those associated with the JNK/p38 pathway. The effect of USP42 knockdown on breast cancer cell proliferation was examined in vivo using a xenograft nude mice model. USP42 protein levels were significantly higher in breast cancer tissues than in normal breast tissues. Moreover, USP42 expression was positively correlated with the advanced T stage, N stage, and pathological stage. USP42 knockdown in MCF7 and MDA-MB-231 cells resulted in decreased proliferation and increased apoptosis rates. USP42 silencing upregulated caspase-3 and Bax expression, while downregulating Bcl-2. Phosphorylation of JNK and p38 increased significantly following USP42 silencing. Treatment with SP600125 (JNK inhibitor) or SB203580 (p38 MAPK inhibitor) effectively recused JNK and p38 activation. Both inhibitors also reduced the apoptotic cell population, which was upregulated by USP42 silencing. These findings highlight USP42 promotes breast cancer progression by reducing JNK and p38 activation and inhibiting apoptosis, suggesting its potential as a therapeutic target in breast cancer treatment.

DOI: https://doi.org/10.1038/s41598-025-20573-x
Cell Death Dis. 2025 Oct 24. 16(1): 755

TM9SF1 drives the lipophagic flux via AMPK-ULK1 signaling to sustain metabolic fitness in HER2-positive breast cancer.

Xiaofen Li, Xiaoqin Yu, Kaiyan Huang, Xin Yu, Shiping Luo, Xiewei Huang, Chuangui Song.

Therapeutic resistance and recurrence in human epidermal growth factor receptor 2-positive breast cancer (HER2 + BC) remain critical challenges that portend poor patient outcomes. Dysregulated autophagy and lipid metabolism contribute to tumor progression, yet the crosstalk between these pathways is poorly understood. This study investigates the role of transmembrane 9 superfamily member 1 (TM9SF1) in lipophagy and lipid metabolic reprogramming in HER2 + BC under metabolic stress. Clinically, TM9SF1 was significantly upregulated in HER2 + BC tissues and correlated with poor prognosis. Functionally, its expression correlated with markers of enhanced autophagy and lysosomal lipid catabolism, and it promoted tumor cell proliferation in vitro and in vivo. Conversely, TM9SF1 knockdown suppressed lipophagy under both basal and starvation conditions, inhibiting lipid droplet (LD) hydrolysis and the conversion of triglycerides to free fatty acids. This suppression was phenotypically characterized by LD accumulation, reduced autophagosomes and lipophagosomes, and altered enzymatic and lipidomic profiles. Mechanistically, TM9SF1 sustained lipophagy by promoting the phosphorylation of AMP-activated protein kinase at Thr172 and UNC-51-like kinase 1 at Ser555. Consequently, TM9SF1 was pivotal for lipid metabolic reprogramming, maintaining energy homeostasis and enhancing adaptation to nutrient deprivation through lipophagy. Overall, our findings identify TM9SF1 as a key HER2 + BC-associated regulator that drives lipophagy via the AMP-activated protein kinase-UNC-51-like kinase 1 pathway, facilitating LD turnover and free fatty acids utilization to sustain energy homeostasis in HER2 + BC. This work establishes a critical link between malignant phenotypes and metabolic resilience. Targeting this regulatory network represents a promising strategy to dismantle the metabolic scaffolds underlying HER2 + BC aggressiveness and therapeutic resistance.

DOI: https://doi.org/10.1038/s41419-025-08093-y
Cell Rep Med. 2025 Oct 21. pii: S2666-3791(25)00493-8. [Epub ahead of print]6(10): 102420

Inhibiting NEDD4 in triple-negative breast cancer cells reprograms tumor immune microenvironment via the β-TrCP/YAP/ECM axis.

Nan Su, Wenhua Lian, Baoding Zhang, Yuan Tian, Linying Li, Yiyu Chen, Xiang Zhi, Taoling Zeng, Qiao Wu, Lanfen Chen, Dawang Zhou, Hong-Rui Wang, Shih-Chin Cheng, Li Li, Xianming Deng.

  Tumor immune microenvironment greatly influences triple-negative breast cancer (TNBC) progression. Identifying targets to convert "cold" tumors into "hot" tumors holds promise for improving treatment outcomes. Here, we show that high expression of NEDD4, an HECT-type E3 ubiquitin ligase, correlates with poor prognosis and reduced CD8+ T cell infiltration in TNBC patients. NEDD4 depletion in TNBC cells significantly inhibits tumor growth through enhancing CD8+ T cell-mediated cytotoxicity in immunocompetent hosts. Mechanistically, NEDD4 depletion stabilizes β-TrCP, leading to YAP ubiquitination and degradation. Downregulated YAP reprograms the immunosuppressive tumor extracellular matrix (ECM) to increase CD8+ T cell infiltration. Furthermore, a small-molecule inhibitor of NEDD4, XMU-MP-10, exhibits significant in vivo efficacy in inhibiting TNBC tumor growth by enhancing CD8+ T cell infiltration in mouse models. Collectively, our findings suggest that the genetic depletion or pharmacological inhibition of NEDD4 enhances antitumor immune responses via the β-TrCP/YAP/ECM cascades, offering a promising therapeutic strategy for TNBC treatment.

Keywords:  E3 ubiquitin ligase; antitumor immunity; triple-negative breast cancer; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2025.102420
Clin Exp Med. 2025 Oct 25. 25(1): 320

FTO promotes the progression of triple-negative breast cancer by regulating the m6A methylation of NFKBIE.

Jiayu Zhang, Xianpeng Meng, Bozhi Zhao, Hongyu Wang, Qunyu Hu, Songhe Wang, Linlin Zhou, Yinghui Zhang, Dongwei Zhang.

  Epigenetic research, particularly involving m6A RNA methylation-a dynamic and reversible posttranscriptional modification-has increasingly demonstrated its critical involvement in cancer pathogenesis. Although the m6A demethylase FTO is implicated in breast cancer (BC), its specific regulatory mechanisms against triple-negative breast cancer (TNBC) has not been clearly defined. Quantitative PCR (qPCR) was used to compare m6A regulatory enzyme expression in TNBC patient tissues with that in normal breast tissues, identifying FTO as the most differentially expressed enzyme. Two randomly selected TNBC/normal tissue pairs were subjected to methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Integrated analysis utilizing the SRAMP and RMBase databases predicted potential FTO target genes. Transcriptome sequencing of FTO-overexpressing TNBC cell lines identified downstream pathways. Dual-luciferase reporter assays and MeRIP-qPCR validated the functional role of FTO and its target, NFKBIE, and their regulatory interaction in TNBC. Compared with normal samples, clinical samples from TNBC patients presented significantly decreased FTO expression (p < 0.05) and correspondingly elevated global m6A levels. MeRIP-Seq confirmed substantial differences in m6A methylation (R = 0.23, p < 0.05). Bioinformatics and transcriptome analyses identified NFKBIE as the primary FTO target. Dual-luciferase assays demonstrated that FTO overexpression specifically modulated wild-type (WT), but not mutant (MT), NFKBIE promoter activity (p < 0.05). MeRIP-qPCR verified the FTO-mediated reduction in m6A methylation at three specific NFKBIE sites (p < 0.05). Functional assays (CCK-8, Transwell invasion/migration, and scratch wound healing) indicated that FTO overexpression significantly enhanced TNBC cell proliferation and motility; these oncogenic phenotypes were partially rescued by concurrent NFKBIE overexpression. FTO regulates NFKBIE expression via m6A-dependent demethylation, establishing a pivotal FTO-NFKBIE regulatory axis that drives TNBC progression. FTO overexpression promotes TNBC cell proliferation, migration, and invasion, effects that are partially reversible through NFKBIE restoration.

Keywords:   FTO ; NFKBIE ; BC; N6-methyladenosine

DOI:  https://doi.org/10.1007/s10238-025-01872-z
Cell Signal. 2025 Oct 16. pii: S0898-6568(25)00594-7. [Epub ahead of print] 112179

CCN3/IMP3/HIF1α positive feedback loop enhances malignant progression of triple-negative breast cancer.

Seogho Son, Seohee Jo, Hogeun Lim, Min-Gyeong Kang, Joo-Hyung Lee, Chang-Jun Lee, Kyung-Min Lee, Incheol Shin.

  Cancer cells are often exposed to a hypoxic environment due to indiscriminate proliferation and incomplete vasculature formation. Hypoxia-inducible factor-1 (HIF-1), which is induced by a hypoxic environment, promotes tumor malignancy by regulating cancer cell metabolism, metastasis, angiogenesis, and cancer stem cell formation. Previous studies have demonstrated increased activation of HIF-1-induced signaling pathways in triple-negative breast cancer (TNBC). Therefore, a hypoxic environment or hypoxia-induced genes are considered as attractive therapeutic targets for TNBC. We have previously identified CCN3 as a novel player in the cancer progression of TNBC. In this study, using public databases and cell lines with altered CCN3 expression, we found that CCN3 expression and hypoxia gene expression signatures were positively correlated, and that HIF1α and HIF1α target gene expression were regulated by CCN3. Furthermore, the induction of HIF1α by CCN3 was regulated at the post-transcriptional level, mainly by IMP3-mediated modulation of mRNA stability and translation of HIF1α. Additionally, we found that HIF1α directly regulates expression of CCN3 by binding to the promoter region of CCN3. This CCN3-HIF1α positive feedback loop may play an important role in HIF1α-induced tumorigenesis in TNBC and be involved in the metastasis of TNBC cells.

Keywords:  Breast cancer; CCN3; HIF1α; IMP3; TNBC

DOI:  https://doi.org/10.1016/j.cellsig.2025.112179
FEBS Lett. 2025 Oct 23.

The role of fibroblast growth factors in cell and cancer metabolism.

Jessica Price, Chiara Francavilla.

  The fibroblast growth factor (FGF) family and the FGF receptors are ubiquitously expressed and regulate a plethora of cell signaling cascades during development, tissue and cell homeostasis, and metabolism. Dysregulated FGF signaling is associated with cancer and several genetic and metabolic disorders. As FGF signaling regulates all the key metabolic processes to maintain whole-body homeostasis, there is an increasing focus on engineering FGFs as potential treatments for dysregulated metabolism. Within cancer, reprogramming of energy metabolism is a crucial step leading to tumorigenesis, metastasis formation, and resistance to therapy. FGF signaling dysregulation in cancer enables uncontrolled proliferation and survival and promotes therapy resistance and metastasis. However, the role of FGF signaling within cancer metabolism is not well understood. A better understanding of how FGF signaling affects the rewiring of cancer metabolism as well as tumorigenesis would provide novel avenues for discovering potential drug targets and biomarkers. Here, we discuss the role of paracrine, endocrine, and intracellular FGFs within metabolism as well as the current understanding of how FGF signaling contributes to rewired cancer metabolism.

Keywords:  FGF; cancer; cell signaling; fibroblast growth factor receptor; homeostasis; metabolism; metastasis; receptor tyrosine kinase; therapy resistance

DOI:  https://doi.org/10.1002/1873-3468.70199
Breast Cancer Res Treat. 2025 Oct 21.

Impact of obesity on breast cancer recurrence by menopausal status and subtype: a retrospective cohort study.

K-H Yoon, Y Yoon, S Jeong, J Kang, J H Oh, H W Koh, H-C Shin, E-K Kim.

   PURPOSE: To evaluate the effect of body mass index (BMI) on oncologic outcomes in patients with breast cancer stratified by menopausal status and histological subtype. Although studies have focused on the relationship between obesity and breast cancer risk, the association between BMI and breast cancer recurrence after surgery remains controversial.
METHODS: This retrospective study included patients who underwent curative surgery for breast cancer between June 2003 and November 2017. Normal weight and overweight groups were defined based on the World Health Organization classification. The primary outcome was recurrence-free survival, evaluated at 1, 5, and 10 years after curative surgery. Patients were stratified by BMI category, histological subtype, and menopausal status. The main measures included tumor characteristics, recurrence events, and survival outcomes across groups.
RESULTS: Among 4506 patients included in the analysis, 3384 (75.1%) had luminal-type breast cancer. The overweight group (n = 1259) was associated with older age (normal weight (NW): 50.2 ±10.9 vs. overweight (OW): 56.5 ± 1.9, P < 0.001) and higher T stage (≥ T2: NW: 1226 (37.7%) vs. OW: 577 (45.8%), P < 0.001). In patients with luminal-type breast cancer, 10-year recurrence-free survival was significantly worse in the overweight group (NW 89.3% vs. OW 85.7%, P = 0.018). Subgroup analysis showed that premenopausal patients with luminal-type breast cancer who were overweight had an increased risk of recurrence (P = 0.003).
CONCLUSIONS: Obesity is a significant, potentially modifiable risk factor for recurrence in premenopausal females with luminal-type breast cancer.

Keywords:  Body mass index; Breast cancer; Histological subtype; Menopause

DOI:  https://doi.org/10.1007/s10549-025-07823-2
Nanomedicine. 2025 Oct 19. pii: S1549-9634(25)00071-1. [Epub ahead of print] 102870

Dual metabolic targeting liposomes potentiate triple-negative breast cancer radiosensitivity via glucose and glutathione starvation.

Henan Zhang, Yanbin Liu, Xuezhi Gao, Guoli Ji, Yanzhen Zheng, Fei Luo, Xing Qi, Shasha Zhao, Shanghui Guan, Cong Wang, Ming Lu.

  Triple-negative breast cancer (TNBC) frequently develops resistance to radiotherapy, while its metabolic reliance on glucose and glutamine presents new therapeutic targets for radiotherapy sensitization. This study developed a targeted nanoliposome (G/B-Lip-R) co-delivering glucose oxidase (GOD) and buthionine sulfoximine (BSO) to enhance radiotherapy through dual metabolic intervention. GOD catalyzes glucose oxidation to generate hydrogen peroxide (H2O2) while depleting tumor energy supplies, whereas BSO inhibits glutathione (GSH) synthesis to disrupt redox homeostasis. Their synergistic action significantly elevates intracellular reactive oxygen species (ROS) levels, thereby potentiating radiosensitivity. Both in vitro and in vivo studies demonstrated that G/B-Lip-R effectively targets tumors and significantly improves radiotherapy outcomes. This work innovatively combines nanocarriers with dual metabolic pathway modulation, offering a novel strategy to overcome TNBC radioresistance with important clinical translation potential.

Keywords:  Cancer therapy; Glutathione depletion; Nanomaterials; Radiotherapy sensitization; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.nano.2025.102870