bims-merabr 2026-07-26 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2026–07–26
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

ZBTB11 Promotes Breast Cancer Progression by Activating FBXO28-Mediated MST1 Degradation and Suppressing Hippo Signaling.
Expression Profiling of SWI/SNF Complex Subunits in Triple-Negative Breast Cancer Using Tissue Microarray and Immunohistochemistry.
IFITM3 promotes triple-negative breast cancer progression by regulating β-catenin localization.
EDNRA Forms a Positive Feedback Loop with the Hippo/YAP Axis to Drive Triple-Negative Breast Cancer Progression.
ADSL drives fumarate mediated scrib-rictor complex formation to promote metastasis dissemination in triple-negative breast cancer.
TACC3, correlated with immune cell infiltrates, is a novel prognostic biomarker in BRCA.
Navigating the Metabolic-Genomic Paradigm: Mitochondrial Reprogramming as a Driver of Cancer Plasticity.
Hypoxia-induced mechanism of TNBC promoting tumour cell proliferation through exosomal miRNA.

Adv Sci (Weinh). 2026 Jul 20. e76618

ZBTB11 Promotes Breast Cancer Progression by Activating FBXO28-Mediated MST1 Degradation and Suppressing Hippo Signaling.

An Xu, Xiang-Nan Xu, Xiao Huang, Zhou Luo, Chun-Lian Li, Yang Du, Cheng Yan, Xiao-Jie Yu, Jian-Wen Wang, Long-Di Yao, De-Yuan Fu.

  Epithelial-mesenchymal transition (EMT) is a key driver of breast cancer progression, yet the upstream transcriptional and ubiquitin-mediated mechanisms that modulate Hippo signaling remain incompletely defined. In this study, we identify a regulatory axis in which the transcription factor ZBTB11 promotes breast cancer aggressiveness by enhancing the expression of the F-box protein FBXO28. ZBTB11 directly binds to the FBXO28 promoter and increases its transcription, leading to elevated FBXO28 protein levels. We show that FBXO28 functions as an E3 ubiquitin ligase that targets the core Hippo kinase MST1 for K48-linked ubiquitination and proteasomal degradation. Reduction of MST1 diminishes Hippo pathway activity, resulting in decreased phosphorylation and enhanced nuclear accumulation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which subsequently activates EMT-related gene expression. Functionally, disruption of the ZBTB11-FBXO28-MST1 axis suppresses EMT, migration, invasion, and tumor growth in vitro and in vivo, whereas reintroduction of FBXO28 or depletion of MST1 reverses these effects. Together, our findings reveal a previously unrecognized transcription-ubiquitination cascade that modulates Hippo signaling and contributes to breast cancer progression, highlighting this axis as a candidate therapeutic vulnerability that warrants further validation for limiting metastasis.

Keywords:  Hippo signaling; breast cancer; epithelial‐mesenchymal transition; ubiquitin‐proteasome system

DOI:  https://doi.org/10.1002/advs.76618
Breast Cancer (Dove Med Press). 2026 ;18 606605

Expression Profiling of SWI/SNF Complex Subunits in Triple-Negative Breast Cancer Using Tissue Microarray and Immunohistochemistry.

Shang Wang, Chen Gao, Qi Wang, Jing Xu.

   Introduction: The SWI/SNF (SWItch/Sucrose Non - Fermentable) complex is a multi - subunit, ATPase - dependent chromatin - remodeling complex involved in regulating key cellular processes. Tumors with SWI/SNF loss tend to be poorly differentiated and aggressive. Triple - negative breast cancer (TNBC) typically has a high histological grade and a poor prognosis. Given the limited reports on the SWI/SNF complex in breast cancer, we focused on its role in TNBC.
Methods: Using tissue microarray and immunohistochemistry (IHC), we evaluated the expression of four important subunits of the SWI/SNF complex (SMARCB1, SMARCA2, ARID1A, and SMARCA4) in 104 TNBC tissues, which included 96 cases of conventional TNBC and 8 cases of low - grade TNBC. Additionally, we evaluated the endogenous expression of the four subunits in five breast cancer cell lines by real - time quantitative PCR (RT - qPCR). These cell lines consisted of two TNBC cell lines (MDA - MB - 231, MDA - MB - 468) and three non - TNBC cell lines (MCF - 7, T47D, and MDA - MB - 453).
Results: The IHC results indicated that the deletion rate of SMARCA2 was the highest in TNBC compared with other subunits (91/104, 87.5%) (p < 0.0001), and SMARCA4 had the highest retention rate (98/104, 94.2%). Whether low - grade TNBC was excluded or not, there was no significant difference between the deletion rate and various clinicopathological parameters. Consistently, we found that SMARCA2 exhibited the lowest expression level across all five cell lines (p < 0.01). SMARCA4 showed the highest expression in all cell lines except MDA - MB - 453, in which ARID1A expression was the highest.
Conclusion: These results indicate that TNBC is characterized by a high proportion of SMARCA2 deletion and positive expression of SMARCA4, which are significant molecular features. The roles and potential mechanisms of these two factors in TNBC require further investigation.

Keywords:  SMARCA2; SMARCA4; SWI-SNF complex; chromatin remodelling; immunohistochemistry; triple-negative breast cancer

DOI:  https://doi.org/10.2147/BCTT.S606605
Biochem Biophys Res Commun. 2026 Jul 23. pii: S0006-291X(26)01099-5. [Epub ahead of print]831 154335

IFITM3 promotes triple-negative breast cancer progression by regulating β-catenin localization.

Heeyeon Kim, Youngim Yu, Yuseon Park, Haein Kim, Mirae Yeo, Ji-Yeun Hur, Eunhee Kim.

  Interferon-induced transmembrane protein 3 (IFITM3) is best known as an antiviral protein, but accumulating evidence supports pro-tumorigenic functions across several cancers. Here, we examined IFITM3 in triple-negative breast cancer (TNBC). IFITM3 depletion suppressed MDA-MB-231 cell proliferation, migration, sphere formation, and xenograft tumor growth, whereas IFITM3 overexpression enhanced these phenotypes. IFITM3 depletion restored E-cadherin expression and increased membrane-associated E-cadherin-β-catenin complexes. These changes were accompanied by reduced nuclear active β-catenin and decreased Wnt/β-catenin transcriptional activity in cultured cells. Altered β-catenin localization was also observed in xenograft tumors. Conversely, IFITM3 overexpression enhanced WNT3a-responsive transcription and nuclear accumulation of active β-catenin. IFITM3 expression was elevated in breast tumors and was associated with shorter overall survival in a selected lymph-node-negative TNBC cohort. Together, these findings identify IFITM3 as a regulator of β-catenin localization and Wnt signaling that promotes epithelial-mesenchymal transition (EMT) and stem-like properties in TNBC cells.

Keywords:  E-cadherin; Epithelial-mesenchymal transition; IFITM3; Triple-negative breast cancer; Wnt signaling; β-catenin

DOI:  https://doi.org/10.1016/j.bbrc.2026.154335
Adv Sci (Weinh). 2026 Jul 24. e76784

EDNRA Forms a Positive Feedback Loop with the Hippo/YAP Axis to Drive Triple-Negative Breast Cancer Progression.

Zehao Hong, Boyang Li, Jiahui Xu, Ruonan Lin, Jinghao Pan, Chenlu Fang, Boxiang Zhang, Lucy Yue Lau, Richard J Aldridge, Elizabeth A Whitmore, Yi Chen.

  Sustained Hippo/Yes-associated protein (YAP) activation drives triple-negative breast cancer (TNBC), but druggable upstream regulators remain unclear. We investigated G protein-coupled receptors (GPCRs) as membrane inputs for YAP activation. TCGA-based Hippo/YAP signature analysis, marketed-drug GPCR annotation, and siRNA screening using connective tissue growth factor (CTGF) identified endothelin receptor type A (EDNRA). EDNRA function was tested by knockdown, overexpression, endothelin-1 (ET-1) stimulation, and atrasentan blockade in TNBC cells and xenografts. YAP regulation was examined by immunoblotting, RT-qPCR, TEAD reporter assays, subcellular localization, docking, co-immunoprecipitation, mutagenesis, ChIP-qPCR, and CRISPRi. EDNRA correlated with Hippo/YAP signatures, adverse clinical features, and poor outcome. EDNRA depletion or atrasentan suppressed proliferation, migration, stem-like populations, and xenograft growth, whereas EDNRA overexpression or ET-1 had opposite effects. Mechanistically, EDNRA reduced YAP Ser127 phosphorylation, promoted nuclear YAP accumulation, and enhanced TEAD transcription through Gαq/11-Rho/ROCK-LATS signaling. Mutating predicted EDNRA-Gαq/11 interface residues impaired YAP activation and tumor-promoting activity. Reciprocally, YAP/TEAD4 enhanced EDNRA transcription through an enhancer-associated region. Atrasentan also sensitized TNBC cells to paclitaxel and produced positive zero interaction potency (ZIP) synergy scores. EDNRA establishes a druggable positive feedback loop with Hippo/YAP signaling and represents a potential therapeutic vulnerability in YAP-driven TNBC.

Keywords:  EDNRA; G protein‐coupled receptor; Hippo/YAP signaling; positive feedback loop; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/advs.76784
Mol Cancer. 2026 Jul 20.

ADSL drives fumarate mediated scrib-rictor complex formation to promote metastasis dissemination in triple-negative breast cancer.

Yidan Fan, Xiaofang He, Wei Deng, Jianxiang Sun, Jinkun Qin, Yutian Zou, Xudong Zhu, Xiaoming Xie, Hailin Tang, Ping Yu, Weiyu Bao, Feng Ye.

   BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by aggressive metastatic behavior and limited therapeutic options. Although metabolic reprogramming is increasingly recognized as a hallmark of TNBC, the mechanisms by which specific metabolic enzymes and intermediates drive metastasis remain poorly defined.
METHODS: We performed untargeted metabolomic profiling on TNBC tumors and matched normal tissues to identify dysregulated metabolic pathways. Functional assays, chemoproteomic succination profiling, molecular interaction analyses, and in vivo cancer metastasis models were used to define the mechanistic and biological consequences of altered metabolism. In vitro experiments validated the effects of N-acetylcysteine (NAC) in TNBC cell lines.
RESULTS: Metabolomic analyses revealed aberrant activation of the alanine-aspartate-glutamate axis and upregulation of adenylosuccinate lyase (ADSL) in TNBC. ADSL promoted tumor cell proliferation and metastasis by generating fumarate, which accumulated primarily through covalent protein succination. Chemoproteomic profiling identified the cell polarity regulator SCRIB as a critical fumarate target. Fumarate-mediated succination of SCRIB impaired its membrane localization, promoted epithelial-mesenchymal transition, and facilitated aberrant interaction with the mTORC2 component RICTOR, leading to activation of AKT/mTOR signaling. Genetic disruption of SCRIB succination abrogated these effects. Importantly, pharmacological perturbation of fumarate using NAC reduced SCRIB succination and attenuated the malignant phenotypes of TNBC cells in vitro.
CONCLUSIONS: These findings identify an ADSL-fumarate-SCRIB signaling axis that links metabolic reprogramming to the loss of cell polarity and activation of pro-metastatic signaling in TNBC. Targeting fumarate-mediated protein succination represents a previously unrecognized and experimental vulnerability in TNBC.

Keywords:  Adenylosuccinate lyase; Fumarate; Metastasis; SCRIB; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s12943-026-02742-2
Medicine (Baltimore). 2026 Jul 24. 105(30): e49943

TACC3, correlated with immune cell infiltrates, is a novel prognostic biomarker in BRCA.

Zhishuang Li, Xingchen Zhou, Xiangxiang Wu, Hui Li, Chengjun Zhou.

  Transforming acidic coiled-coil-containing protein 3 (TACC3) plays a crucial oncogenic role in various carcinomas and may act as a novel prognostic factor. However, its prognostic significance and underlying mechanisms in breast cancer (BRCA) remain unclear and require further investigation. This research included 181 breast cancer tissues, and the expression levels of TACC3 were analyzed by immunohistochemistry staining and grading. The mRNA expression of TACC3 in pan-cancer was analyzed with The Cancer Genome Atlas data platform. Receiver operating characteristic curve analysis assessed TACC3's feasibility as a biomarker, using the area under the curve score. Cox regression analysis evaluated TACC3's prognostic value in BRCA patients. Gene ontology enrichment analysis and gene set enrichment analysis (GSEA) were employed to explore TACC3's potential biological functions. Additionally, single-sample GSEA (ssGSEA) assessed the relationship between TACC3 expression and tumor-infiltrating immune cells in BRCA. High TACC3 expression was prevalent in BRCA tissues and correlated with T-stage and histological type. The Kaplan-Meier survival analysis showed that high TACC3 expression was associated with poor overall survival and disease-free survival. Receiver operating characteristic curve analysis indicated that TACC3 may act as a prognostic biomarker. ssGSEA analysis revealed a positive correlation between elevated TACC3 expression and various tumor-infiltrating immune cells in the tumor microenvironment, including B cells, cytotoxic cells, mast cells, dendritic cells, T cells, and so on. TACC3 plays a significant role in regulating the tumor immune response, presenting a promising molecular target that could provide new insights into treatment strategies for BRCA.

Keywords:  TACC3; bioinformatics; biomarker; breast cancer; prognosis

DOI:  https://doi.org/10.1097/MD.0000000000049943
Oncol Res. 2026 ;34(8): 5

Navigating the Metabolic-Genomic Paradigm: Mitochondrial Reprogramming as a Driver of Cancer Plasticity.

Yen-Dun Tony Tzeng, Chen-Yueh Wen, Su-Boon Yong, Zhi-Hong Wen, An-Jen Chiang, Chia-Jung Li.

  Breast cancer (BC) management has transitioned from histological classification to molecular subtyping, yet therapeutic resistance and intratumor heterogeneity remain critical clinical challenges. This review examines the emerging paradigm shift toward integrating mitochondrial metabolism into the precision medicine framework. We detail the complex mitonuclear crosstalk where nuclear genetic alterations, such as Breast Cancer 1 (BRCA1) deficiency and TP53 mutations, fundamentally reprogram mitochondrial bioenergetics. Specifically, the loss of BRCA1 function triggers a systemic NAD+ depletion trap through PARP1 hyperactivation, while oncogenic drivers like MYC coordinate with PGC1α to enhance mitochondrial biogenesis for metastatic survival. We evaluate the diagnostic potential of mitochondrial DNA heteroplasmy and machine learning derived metabolic gene signatures as high performance biomarkers for patient stratification and the detection of minimal residual disease via liquid biopsy. Furthermore, we analyze current clinical efforts to target mitochondrial vulnerabilities, including respiratory chain inhibitors like metformin and BH3 mimetics, while highlighting the significant challenges posed by metabolic plasticity and nutrient competition in the tumor microenvironment. The analysis of clinical trial data, such as the MA.32 study, suggests that metabolic interventions require precise patient selection based on specific metabolic phenotypes rather than broad application. Looking forward, the integration of genome scale metabolic models and artificial intelligence (AI) offers a transformative pathway to simulate patient specific metabolic fluxes and identify novel synthetic lethal targets. By bridging the gap between nuclear genomic drivers and dynamic mitochondrial adaptations, this review aims to provide a preliminary framework for the exploration of metabolic-genomic precision oncology in BC.

Keywords:  Breast cancer (BC); artificial intelligence (AI); metabolic reprogramming; precision medicine; therapeutic resistance

DOI:  https://doi.org/10.32604/or.2026.078924
Mamm Genome. 2026 Jul 18. pii: 90. [Epub ahead of print]37(1):

Hypoxia-induced mechanism of TNBC promoting tumour cell proliferation through exosomal miRNA.

Xiangxin Zheng, Peng Yang, Sai Zhou, Xiaochao Zhu, Xiaoqing Guan, Guoqin Jiang.

Triple-negative breast cancer (TNBC), characterized by the absence of ER, PR, and HER2 expression, is associated with aggressive clinical behavior and limited treatment options. Hypoxia in the tumor microenvironment (TME) may influence intercellular communication through exosomes. In this study, we investigated whether hypoxia-derived exosomes regulate malignant phenotypes of TNBC cells through exosomal miRNAs. Exosomes derived from hypoxic TNBC cells increased proliferation, migration, and invasion of recipient TNBC cells compared with normoxia-derived exosomes. Small RNA sequencing and RT-qPCR validation showed enrichment of miR-4791 in hypoxia-derived exosomes. Functional assays indicated that miR-4791 overexpression promoted TNBC cell proliferation, whereas miR-4791 inhibition reduced proliferative capacity. Mechanistically, miR-4791 directly targeted the 3'UTR of CTCFL and was associated with reduced PTEN expression. Rescue experiments suggested that restoration of CTCFL or PTEN partially attenuated miR-4791-associated malignant phenotypes in vitro and in vivo. Analysis of GSE19536 showed higher miR-4791 expression in breast cancer tissues than in normal tissues; however, the number of normal samples was limited. Survival analysis using GSE19783 indicated that higher miR-4791 expression was associated with poorer survival, although the prognostic ROC performance was weak-to-modest. Overall, these findings suggest that hypoxia-derived exosomal miR-4791 may contribute to TNBC progression, at least in part, through a CTCFL/PTEN-related mechanism.

DOI: https://doi.org/10.1007/s00335-026-10260-1