bims-merabr 2026-02-22 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2026–02–22
ten papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

KCTD15 Enhances Stem Cell-Like Properties and Promotes Triple-Negative Breast Cancer Progression Through KLF4/β-Catenin Signaling.
Glycogen synthase 1 promotes breast cancer progression by promoting IκBα ubiquitination and degradation independent of its canonical enzyme function.
NRG4 suppresses breast cancer metastasis via ERBB4-YAP1-mediated down-regulation of MMPs.
Microbe-associated molecular patterns differentially mediate carcinogenic alterations of the breast tissue in the context of obesity.
MiR-200c restoration inhibits FOXP3 and metastatic spread in breast cancer: evidence from in vitro and in vivo models.
The role of growth hormone in metastasis and angiogenesis of breast cancer.
β-Catenin-Facilitated Glycolytic Reprogramming Fuels TNBC Progression: Therapeutic Blockade with XAV939.
GPX4 Inhibitor Resistance and Metastatic Features in Triple-Negative Breast Cancer.
Cancer-associated fibroblasts as a critical driver in tumor metastasis: The mechanisms and future perspectives.
Role and underlying mechanisms of miR‑200 family in breast cancer (Review).

FASEB J. 2026 Feb 28. 40(4): e71563

KCTD15 Enhances Stem Cell-Like Properties and Promotes Triple-Negative Breast Cancer Progression Through KLF4/β-Catenin Signaling.

Liang Yao, Wei Sun, Jun Xing, Jing Feng.

  Triple-negative breast cancer (TNBC) remains an aggressive malignancy with limited therapeutic options and poor prognosis, underscoring the critical need for novel therapeutic targets. This investigation elucidates the functional role of the potassium channel tetramerization domain 15 (KCTD15) in TNBC progression, providing mechanistic insights into its potential as a therapeutic target for this challenging disease. KCTD15 exhibited high expression in TNBC tissues, correlating with advanced grade and unfavorable prognosis. Functionally, KCTD15 knockdown in TNBC cell lines (BT-549/MDA-MB-231) markedly suppressed cellular proliferation, migration, and cancer stem cell properties, while concomitantly enhancing apoptosis. Mechanistically, KCTD15 directly interacted with KLF4, facilitating its nuclear translocation and subsequent activation of the β-catenin signaling cascade. Notably, KLF4 knockdown abrogated KCTD15-mediated stemness maintenance and β-catenin pathway activation. In vivo, KCTD15 silencing reduced xenograft tumor growth and downregulated Ki67, KLF4, and β-catenin protein expression in tumor tissues, confirming its oncogenic role through the KLF4/β-catenin axis. Our findings establish KCTD15 as a pivotal regulator of TNBC stemness through modulation of the KLF4/β-catenin signaling axis. These results provide a robust preclinical rationale for developing therapeutic strategies targeting this molecular axis in TNBC management.

Keywords:  KCTD15; KLF4; stem cell‐like properties; triple‐negative breast cancer; β‐catenin signaling

DOI:  https://doi.org/10.1096/fj.202503381R
Cell Commun Signal. 2026 Feb 18.

Glycogen synthase 1 promotes breast cancer progression by promoting IκBα ubiquitination and degradation independent of its canonical enzyme function.

Shixuan Zhuo, Zinan Wang, Yu Zhang, Yan Chen.

  Breast cancer remains a global health challenge, with triple-negative breast cancer (TNBC) posing a particular therapeutic difficulty. Glycogen synthase 1 (GYS1), a key glycogen metabolic enzyme, is upregulated in various cancers under hypoxic stress and is associated with therapy resistance, but its functional role in BRCAs remains incompletely defined. Here, we identify a non-canonical, glycogen-independent mechanism by which GYS1 promotes breast cancer progression. We demonstrate that Gys1 knockout suppresses proliferation and migration of breast cancer cells in vitro and inhibits tumor growth in vivo. Crucially, neither ablation of other glycogen synthesis enzymes nor pharmacological inhibition of GYS1 recapitulates these effects, uncoupling the oncogenic role of GYS1 from its metabolic function. Mechanistically, GYS1 activates the canonical NF-κB pathway by promoting the ubiquitination and degradation of IκBα. GYS1 stabilizes the interaction between IκBα and its E3 ubiquitin ligase BTRC, facilitating IκBα proteasomal degradation and enabling nuclear translocation of NF-κB. Our findings establish GYS1 as a novel scaffold protein and an upstream regulator of NF-κB signaling independent of its enzymatic function, nominating it as a promising therapeutic target for breast cancer particularly for TNBC subtype that lacks effective treatment.

Keywords:  Breast cancer; GYS1; Glycogen; IκBα; NF-κB; Tumorigenesis; Ubiquitination

DOI:  https://doi.org/10.1186/s12964-026-02728-z
Genes Dis. 2026 May;13(3): 101691

NRG4 suppresses breast cancer metastasis via ERBB4-YAP1-mediated down-regulation of MMPs.

Saijun Wang, Mingwei Guo, Lingyun Xu, Jiaming Xue, Shuai Chen, Ke Xu, Yan Zhou, Aihua Gu, Wei Gao, Jianwei Zhou, Yi Zhang, Liming Tang, Dongmei Wang.

  Obesity exacerbates breast cancer metastasis, yet the underlying mechanisms remain incompletely understood. Here, we identify neuregulin 4 (NRG4), a ligand of Erb-B2 receptor tyrosine kinase 4 (ERBB4), as a key regulator of metastasis, through the ERBB4-YAP1 signaling axis. Using MMTV-PyMT and 4T1 breast cancer models, we demonstrate that obesity accelerates metastasis, while NRG4, secreted by inguinal white adipose tissue (iWAT), inhibits cancer cell migration and epithelial-mesenchymal transition (EMT). Mechanistically, NRG4 activates ERBB4, producing a cleaved pERBB4 fragment that interacts with phosphorylated YAP1 (pYAP1), restricting its nuclear translocation. RNA sequencing revealed that NRG4 suppressed the transcription of Mmp9 and Mmp12, which encode matrix metalloproteinases critical for extracellular matrix remodeling and invasion. Co- immunoprecipitation and promoter assay confirmed that YAP1 bound to TEAD1 and activated MMP9/MMP12 transcription in the absence of NRG4. Importantly, recombinant NRG4 (rNRG4) reduced the growth and invasiveness of breast cancer organoids. These findings establish NRG4 as a metastasis suppressor in obesity-associated breast cancer by inhibiting the ERBB4-YAP1 pathway and down-regulating matrix metalloproteinases. Our study highlights the therapeutic potential of targeting NRG4-ERBB4 signaling to mitigate obesity-driven breast cancer progression.

Keywords:  Breast cancer; Epithelial–mesenchymal transition; Matrix metalloproteinase alterations; Neuregulin 4; YAP

DOI:  https://doi.org/10.1016/j.gendis.2025.101691
Neoplasia. 2026 Feb 17. pii: S1476-5586(26)00013-8. [Epub ahead of print]73 101284

Microbe-associated molecular patterns differentially mediate carcinogenic alterations of the breast tissue in the context of obesity.

Mohamed Gaber, Lauren M Moulden, Adam S Wilson, Valerie Payne, Julia Holmes, Kayla Neary, Abigail Peoples, Mary L Duet, Adam J Katz, Pierre-Alexandre Vidi, Katherine L Cook.

  Obesity is a risk factor for breast cancer. Obesity alters the microbiome and microbiome perturbations are reported in breast cancer patients. Yet, the impact of obesity-mediated microbial shifts on breast cancer risk remains unclear. Here, we investigate the effect of microbial-associated molecular pattern (MAMP) signaling on genome instability and inflammation. We show in human samples that obesity chronically elevates breast tissue levels of two MAMPs: lipopolysaccharide (LPS) and flagellin. In contrast, obesity was not associated with chronic elevations in lipoteichoic acid (LTA). Injections of LPS and flagellin in mouse mammary glands (MG) were sufficient to induce DNA damage and inflammation. Moreover, DNA damage was reduced in MG of animals on a high-fat diet by knockdown of toll-like receptors for LPS and flagellin (TLR4 and TLR5), but not TLR2 (LTA receptor). Experiments with breast acini cultures demonstrated LPS and flagellin (but not LTA) induce DNA double-strand breaks via TLR and reactive oxygen species (ROS) generation. Similarly, LPS and flagellin mediated nuclear factor-kappa B (NF-κB) pathway activation and increased expression of inflammatory cytokines. Analyses of non-cancerous breast tissue microbiome revealed an enrichment of Proteobacteria in obese women. Proteobacteria often contain LPS and many of these bacteria are flagellated. Tissue-resident Proteobacteria abundance correlated with breast tissue DNA damage. Our findings show that LPS and flagellin are systemic and local mediators of obesity-induced microbiome alterations, predisposing the breast to pre-malignant changes. These results underscore the importance of considering the tissue-resident microbiome as a biomarker of risk to improve primary prevention of breast cancer. Significance: Obesity differentially modulates non-cancerous breast tissue microbial-associated molecular pattern signaling, enriching LPS and flagellin, to promote oxidative stress and DNA damage.

Keywords:  Breast Cancer; DNA damage; Flagellin; Inflammation; Lipopolysaccharide; Lipoteichoic Acid; Microbiome; Obesity; Prevention; Proteobacteria; Reactive Oxygen Species (ROS)

DOI:  https://doi.org/10.1016/j.neo.2026.101284
BMC Cancer. 2026 Feb 14.

MiR-200c restoration inhibits FOXP3 and metastatic spread in breast cancer: evidence from in vitro and in vivo models.

Nashwa El-Khazragy, Ahmed Alsolami, Ahmed M Aref, Marwa N M Hassan, Mohamed S Othman.

   BACKGROUND: Metastatic breast cancer remains a leading cause of cancer-related mortality in women, often driven by molecular pathways that promote invasion and immune evasion. MicroRNA-200c (miR-200c) is a known tumor suppressor that inhibits epithelial-mesenchymal transition (EMT), while FOXP3, a transcription factor typically associated with regulatory T cells, is aberrantly expressed in breast cancer cells and may contribute to tumor progression. This study investigates whether targeting the miR-200c/FOXP3 axis can suppress metastasis in breast cancer.
METHODS: Metastatic (MDA-MB-361, MDA-MB-468) and non-metastatic (MCF-7) breast cancer cell lines were transfected with miR-200c mimic or inhibitor. Cell proliferation, apoptosis, and invasion were assessed using MTT, Annexin V/PI staining, and transwell assays. FOXP3 mRNA and protein levels were quantified using qRT-PCR and immunohistochemistry. A metastatic mouse model was established via intracardiac injection of tumor cells, followed by treatment with miR-200c mimic, inhibitor, or Cisplatin.
RESULTS: MiR-200c overexpression significantly suppressed proliferation and invasion and enhanced apoptosis in metastatic cells. FOXP3 mRNA and protein expression were downregulated in mimic-treated cells and tissues, while miR-200c inhibition led to increased FOXP3 expression. In vivo, miR-200c mimic treatment reduced tumor burden and metastatic infiltration in the brain and lungs. A strong inverse correlation between miR-200c and FOXP3 was observed (r = - 0.82, p < 0.01).
CONCLUSION: MiR-200c restoration inhibits FOXP3 and suppresses metastatic progression in breast cancer. Targeting the miR-200c/FOXP3 axis presents a novel and promising therapeutic approach for advanced breast cancer.

Keywords:  Breast cancer; Cell invasion; FOXP3 transcription factor; Gene expression regulation; MicroRNA-200; Neoplasm metastasis; Neoplastic

DOI:  https://doi.org/10.1186/s12885-026-15574-6
Biosci Rep. 2026 Feb 18. pii: BSR20253516. [Epub ahead of print]46(2):

The role of growth hormone in metastasis and angiogenesis of breast cancer.

Tamanna Alam, Mingyang Hu, Rivka L Isaacson.

  Breast cancer is a complex disease which has many factors affecting its progression and metastasis. Although steroid hormones, especially oestrogen, are most commonly associated with breast cancer, growth hormone (GH) also plays a substantial role in its development and spread via the activation of downstream signalling pathways and the regulation of growth factors such as insulin-like growth factor-1 (IGF-1) and the vascular endothelial growth factor (VEGF). Breast cancer patients usually have elevated levels of GH and IGF-1 in their circulation. Growth hormone receptor (GHR) signalling enhances migratory ability of tumour cells and excess IGF-1 production promotes angiogenesis. Gaining a full understanding of the mechanisms behind GH and breast cancer will allow researchers to develop more therapeutics to treat this devastating disease.

Keywords:  angiogenesis; breast cancers; growth hormones; insulin-like growth factor; metastasis

DOI:  https://doi.org/10.1042/BSR20253516
Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338261425407

β-Catenin-Facilitated Glycolytic Reprogramming Fuels TNBC Progression: Therapeutic Blockade with XAV939.

Sheikh Mohammad Umar, Shruti Kahol, Sandeep R Mathur, Ajay Gogia, S V S Deo, Shivam Pandey, Chandra Prakash Prasad.

  IntroductionGlycolytic phenotype positively supports cancer cell migration and metastasis in various cancers including Triple negative breast cancers (TNBCs). In-depth understanding of molecular pathways associated with increased aerobic glycolysis in TNBCs could provide key insights into the drivers of TNBC progression.Methodsβ-catenin and glycolytic proteins (PFKP, LDHA, MCT1) were assessed by Immunohistochemistry (IHC) in TNBC patients (n = 98), with prognostic value evaluated by Kaplan-Meier and Cox regression. In vitro, the β-catenin inhibitor ie, XAV939 was tested for suppressing β-catenin-driven aerobic glycolysis in TNBC models using MTT for proliferation, Western blotting for protein expression, and wound healing, droplet invasion, and colony formation assays for physiological changes.Resultsβ-catenin and glycolytic markers (PFKP, LDHA, MCT1) were overexpressed in >50% of TNBCs. Kaplan-Meier and Cox regression analyses showed that combined expression of β-catenin with glycolytic markers correlated with reduced survival. In vitro, XAV939 suppressed β-catenin-driven aerobic glycolysis in TNBC cells, downregulating β-catenin and glycolytic proteins, reducing glycolytic activity, and impairing aggressive phenotypes (proliferation, migration, invasion, clonogenicity).ConclusionOverall, our results highlight the crucial role of β-catenin in controlling aerobic glycolysis via regulation of key glycolytic proteins, thereby positively driving the progression and metastasis of TNBCs. Additionally, our data strongly establish that XAV939 effectively inhibits glycolytic phenotype, thereby suggesting its therapeutic potential in TNBC patients.

Keywords:  XAV939; aerobic glycolysis; migration; triple negative breast cancer; β-catenin

DOI:  https://doi.org/10.1177/15330338261425407
Adv Sci (Weinh). 2026 Feb 17. e23198

GPX4 Inhibitor Resistance and Metastatic Features in Triple-Negative Breast Cancer.

Marie Sabatier, Mayher Kaur, Milena Chaufan, Felix-Levin Hormann, Luiza Martins Nascentes Melo, Mario Palma, Jordan Torpey, Yanshan Liang, Alanis Carmona, Cameron Fraser, Midori Flores, Krystina J Szylo, Mahsa Yavari, Sheng Hui, Alpaslan Tasdogan, Sven Heiles, Jessalyn M Ubellacker.

  Leveraging ferroptosis as a cancer therapy has faced challenges due to the limited bioavailability and systemic toxicities of small-molecule ferroptosis modulators. Small molecule inhibitors such as RSL3 and ML210 trigger ferroptosis by targeting glutathione peroxidase 4 (GPX4), a key enzyme that neutralizes lipid peroxides. While many studies have focused on targeting primary tumors, much less is known about the extent to which GPX4-inhibitor resistance may contribute to metastasis. To address this, we cultured triple-negative breast cancer cell lines with GPX4 inhibitors to generate cell lines (M231, 4T1) that were resistant to GPX4 inhibitors (GPX4i). Tumors derived from GPX4i-resistant cells compared to parental cells had unique metabolic and lipidomic profiles, were associated with a shift toward an epithelial-like state (decreased vimentin, increased EpCAM expression), formed decreased spontaneous metastases from primary tumors, but had no differences in overall metastatic burden upon intravenous injection. Collectively, these data demonstrate that long-term maintenance with GPX4-inhibitors in vitro leads to altered metastatic profiles in vivo.

Keywords:  ferroptosis; lipid peroxidation; metastases; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202523198
iScience. 2026 Feb 20. 29(2): 114788

Cancer-associated fibroblasts as a critical driver in tumor metastasis: The mechanisms and future perspectives.

Lingyu Ding, Zhen Li, Jing Yue, Liqing Qiu, Zhifeng Tian, Hongfang Zhang.

  Tumor metastasis represents a lethal event for patients due to the lack of effective treatments. Compared with primary tumors, the components of the tumor microenvironment (TME) of metastatic tumors are different. Tumor cells alone are unable to metastasize. Cancer-associated fibroblasts (CAFs), as one major component of TME, drive tumor metastasis. In metastatic lesions, the proportion of CAFs is significantly higher and is spatially close to tumor cells with high metastatic potential. CAFs themselves are resistant to chemoradiotherapy and have strong invasive ability based on their major role in degrading the extracellular matrix (ECM). Furthermore, CAFs determined the organs to which tumor cells metastasize. By interaction with tumor cells, CAFs were activated, transdifferentiated, and in turn enhanced the invasive ability of tumor cells. Tumor cells also promoted the infiltration of CAFs in tumor tissues, allowing them to establish a pre-metastatic microenvironment. In this review, we have deeply analyzed the association of CAFs and tumor metastasis from the perspectives of exosomes, metabolic reprogramming, suppression of anti-tumor immunity, and epigenetic modification. We also discussed the future perspectives of CAFs-based anti-metastasis strategies. This information may deepen our understanding of CAFs-initiated tumor metastasis and shed novel insight into the development of anti-metastasis therapies.

Keywords:  Cancer; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2026.114788
Int J Oncol. 2026 Apr;pii: 43. [Epub ahead of print]68(4):

Role and underlying mechanisms of miR‑200 family in breast cancer (Review).

Jiaqi Liu, Hua Du, Yingxu Shi.

  Βreast cancer (BC) is the most common malignant tumor among women. Its significant heterogeneity and complex molecular mechanisms pose major clinical challenges, including limited therapeutic efficacy and drug resistance. Recently, microRNAs (miRs) have been recognized as key post‑transcriptional regulators involved in tumorigenesis and tumor progression through multiple pathways. Among these, the miR‑200 family (miR‑200a, miR‑200b, miR‑200c, miR‑429 and miR‑141) has attracted considerable attention due to its pivotal role in BC. The present review systematically summarizes the genomic characteristics, expression regulation mechanisms and biological functions of the miR‑200 family in BC. Special emphasis is given to their roles in epithelial‑mesenchymal transition, cell proliferation, apoptosis, maintenance of stemness, and remodeling of the tumor microenvironment. Furthermore, members of the miR‑200 family have potential as diagnostic and prognostic biomarkers and are closely linked to chemotherapy resistance. The present review aims to provide novel insights and a theoretical foundation for the diagnosis, treatment, and deeper investigation of BC by comprehensively examining the functional mechanisms of the miR‑200.

Keywords:  breast cancer; drug resistance; epithelial-mesenchymal transition; microRNA‑200 family; molecular markers

DOI:  https://doi.org/10.3892/ijo.2026.5856