bims-merabr 2026-09-27 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2026–09–27
ten papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

SIRT1 Promotes Breast Cancer Stem Cell-Associated Properties and Represents a Potential Therapeutic Target.
Breast cancer-associated fibroblast-derived exosomal miR-1290 promotes triple-negative breast cancer cell proliferation.
Metabolic Reprogramming Of Macrophages In Breast Cancer: Mechanisms And Therapeutic Implications.
Circulating microRNAs at the Interface of Obesity and Breast Cancer: From Molecular Machinery, Diagnostic Potential, and Therapeutic Perspectives.
Sulfated Hyaluronan Drives Cell Adaptation and Matrix Composition in Advanced 3D Breast Cancer Cell Models.
The mechanism of breast cancer stem cells and tumor microenvironment promoting radioresistance in breast cancer and its intervention strategies.
PRMT1 and YBX1 Cooperatively Transcriptionally Activate GPX4 to Inhibit Ferroptosis and Promote Breast Cancer Progression.
Altered Lipolytic Protein Expression in Tumor-Associated Adipose Tissue Correlates with Aggressive Breast Cancer Features.
Adipose tissue ceramides: emerging lipid components of extracellular vesicles and their influence on metabolic dysregulation.
Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.

Int J Mol Sci. 2026 Sep 15. pii: 8226. [Epub ahead of print]27(18):

SIRT1 Promotes Breast Cancer Stem Cell-Associated Properties and Represents a Potential Therapeutic Target.

Jianmin Ding, Baoxiang Guan, Xuejun Fan, Ningyan Zhang, Eva Sevick, Songlin Zhang.

  Breast cancer stem cells (BCSCs) drive tumor progression, metastasis, and therapeutic resistance. Sirtuin 1 (SIRT1) has been implicated in stem cell regulation, but its context-dependent role in BCSC maintenance and the underlying molecular mechanisms remain poorly defined. SIRT1 expression was evaluated in human breast cancer specimens. Pharmacologic and genetic SIRT1 inhibition was assessed in breast cancer cell lines and orthotopic xenograft models to determine effects on stemness, epithelial-mesenchymal transition (EMT), metastasis, and chemoresistance, with emphasis on Wnt/β catenin signaling. SIRT1 was overexpressed in breast cancer and correlated with higher tumor grades. SIRT1 inhibition reduced BCSC markers (CD44, ALDH1), stemness genes (NANOG, SOX-2), mammosphere formation, EMT, and invasion. In vivo, SIRT1 inhibition suppressed tumor growth, blocked lymphatic metastasis, and delayed cisplatin resistance. Mechanistically, these effects were mediated by downregulation of Disheveled 3 (DVL3) and attenuation of Wnt/β catenin signaling. SIRT1 is associated with the maintenance of BCSC-related properties, EMT, and activation of the Wnt/β-catenin pathway in breast cancer. Targeting SIRT1 may represent a potential therapeutic strategy to suppress tumor progression and improve treatment response.

Keywords:  DVL; SIRT1; SIRT1 inhibitor; TGF-β; Wnt/β-catenin pathway; breast cancer; breast cancer stem cell (BCSC); cancer stem cell (CSC); epithelial–mesenchymal transition (EMT)

DOI:  https://doi.org/10.3390/ijms27188226
Signal Transduct Target Ther. 2026 Sep 20. pii: 411. [Epub ahead of print]11(1):

Breast cancer-associated fibroblast-derived exosomal miR-1290 promotes triple-negative breast cancer cell proliferation.

Jinkwon Lee, Taesang Son, Gyeonghwa Kim, Hye Won Lee, In Hwan Tae, Yunsang Kang, Jeongmin Lee, Jinsan Kim, Su-Gi Lee, Tae-Hee Han, Hyun Seung Ban, Kunhyang Park, Cho-Rok Jung, Jung Hwa Lim, Mi-Young Son, Dae-Soo Kim, Keun Hur, Tae-Su Han, Hyun-Soo Cho.

Breast cancer is a major cause of cancer-associated mortality in females. Although therapeutic strategies targeting subtype-specific receptors have been developed for various breast cancer subtypes, effective targeted therapies for triple-negative breast cancer (TNBC) are lacking. Recently, the role of the tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), in the progression and metastasis of breast cancer, especially TNBC, has attracted increasing attention. However, the role of exosomes secreted by CAFs in TNBC cell proliferation is poorly understood. Thus, in this study, we analyzed exosomes derived from both CAFs and MDA-MB-231 cells and identified exosomal miR-1290 as a key component. When delivered to TNBC cells (BT-549 and Hs578T), exosomal miR-1290 directly suppressed the expression of the putative tumor suppressor TBC1D4, which was accompanied by reduced TSC1 expression and activation of the mTOR pathway. The promotion of TNBC cell growth by miR-1290 through direct targeting of TBC1D4 was validated using 2D culture models, 3D spheroid models, and in vivo xenograft models. Furthermore, we demonstrated that treatment with the mTOR inhibitor rapamycin and the FDA-approved rapamycin analog everolimus effectively suppressed miR-1290-induced TNBC cell proliferation, suggesting a potential therapeutic strategy for TNBC. Moreover, in patient cohorts, elevated levels of circulating miR-1290 significantly distinguished patients with breast cancer from healthy individuals and correlated with poor survival outcomes. Therefore, miR-1290 and its direct target TBC1D4 have potential value in both targeted treatment and diagnosis of TNBC.

DOI: https://doi.org/10.1038/s41392-026-02922-y
Cancer Treat Res Commun. 2026 Sep 19. pii: S2468-2942(26)00287-X. [Epub ahead of print]49 101376

Metabolic Reprogramming Of Macrophages In Breast Cancer: Mechanisms And Therapeutic Implications.

Jiaoyu Zhang, Rui Yang.

  As key immune cells in the tumor microenvironment (TME), macrophages polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes, with their functional states tightly linked to metabolic pathway dynamics. This review comprehensively examines macrophage metabolic reprogramming in glycolysis, lipid metabolism, glutamine metabolism, the pentose phosphate pathway (PPP), mitochondrial function, the tricarboxylic acid (TCA) cycle, and amino acid metabolism, while exploring their implications for breast cancer's immune microenvironment and therapeutic approaches. In M1 macrophages, glycolysis is significantly enhanced, promoting the inflammatory response through lactate accumulation and reactive oxygen species (ROS) production. Simultaneously, the TCA cycle is disrupted at the citrate and succinate nodes, leading to the accumulation of metabolic intermediates and further strengthening the pro-inflammatory phenotype. On the other hand, M2 macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). They regulate epigenetic modifications through metabolites such as alpha-ketoglutarate (α-KG) to maintain anti-inflammatory and tissue repair functions. Breast cancer cells reprogram macrophages via glutamine competition and exosome secretion, driving M2 polarization to support tumor progression. Different molecular subtypes exhibit distinct metabolic features: triple-negative breast cancer (TNBC) shows high glycolytic activity and glutamine addiction, whereas hormone receptor-positive breast cancer relies more on exogenous amino acid uptake. Targeting glycolysis or glutamine metabolism can revert tumor-associated macrophages (TAMs) to an anti-tumor M1-like state, boosting immunity. Although metabolic intervention strategies (such as inhibiting key enzymes hexokinase 2 (HK2), glutaminase (GLS), or fatty Acid Binding Protein 4 (FABP4)) show therapeutic potential, existing studies still have limitations: the compensatory effects between metabolic pathways, tumor heterogeneity, and insufficient clinical translation. Emerging strategies, including metabolic checkpoint targeting, CAR-macrophages (CAR-M), and biomimetic nanocarrier-based delivery systems, hold promise for overcoming these challenges. In summary, in-depth elucidation of the molecular mechanisms underlying macrophage metabolic reprogramming and their metabolic crosstalk with breast cancer cells will provide new insights and novel therapeutic targets for the precise immunometabolic therapy of breast cancer.

Keywords:  Breast cancer; Macrophage; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ctarc.2026.101376
Cancers (Basel). 2026 Sep 18. pii: 3035. [Epub ahead of print]18(18):

Circulating microRNAs at the Interface of Obesity and Breast Cancer: From Molecular Machinery, Diagnostic Potential, and Therapeutic Perspectives.

Georgina Victoria-Acosta, Stephanie I Núñez-Olvera, María Elizbeth Alvarez-Sánchez, Yarely M Salinas-Vera, Jonathan Puente-Rivera.

  Obesity influences breast cancer risk, progression, and therapeutic response through endocrine, inflammatory, metabolic, stromal, and vesicular mechanisms. Circulating and extracellular vesicle (EV)-associated microRNAs are attractive liquid biopsy candidates; however, in obesity-associated breast cancer, they should not be interpreted as tumor-only biomarkers. This narrative review analyzes circulating/EV-miRNAs as mixed host-tumor signals and separates association-based biomarker evidence from functional EV-mediated transfer. We performed a narrative and integrative review of studies on miRNA biogenesis, circulating miRNA transport, EV biology, adipose tissue dysfunction, adipose-tumor communication, biomarker development, therapy response, and methodological reporting standards. The current literature is read along two independent axes: human relevance and source attribution, from non-breast models to obesity-stratified human cohorts, and mechanistic causality, from association only to EV-level function, miRNA-level function, and causality with rescue; clinical validation is treated as a separate qualifier rather than as the top of a single scale. For example, EV-let-7a in overweight/obese breast cancer patients mainly supports an obesity-stratified biomarker candidate. Breast adipose tissue-derived EV cargoes enriched in miR-155-5p, miR-10a-3p, and miR-30a-3p provide stronger functional support for metabolic reprogramming, whereas EV-associated miR-221/222 has mediator-level evidence in endocrine resistance but is not obesity specific. Conclusions: The main contribution of this review is an operational interpretation framework in which circulating miRNAs are evaluated according to probable source, evidence level, and clinical purpose. Future studies should report EV workflow quality, sample type, hemolysis and platelet control, normalization strategy, external validation, tumor subtype, and obesity phenotyping beyond BMI, including waist circumference or waist-to-hip ratio, insulin resistance, diabetes, menopausal status, and inflammatory markers.

Keywords:  adipose tissue; breast cancer; circulating miRNAs; extracellular vesicles; liquid biopsy; microRNA therapeutics; obesity; therapy resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers18183035
Cells. 2026 Sep 17. pii: 1687. [Epub ahead of print]15(18):

Sulfated Hyaluronan Drives Cell Adaptation and Matrix Composition in Advanced 3D Breast Cancer Cell Models.

Christos Koutsakis, Katerina Mineschou, Konstantinos Spanopoulos, Sylvia Mangani, Marco Franchi, Evgenia Karousou, Zoi Piperigkou, Nikos K Karamanos.

  Hyaluronan (HA), a major extracellular matrix (ECM) glycosaminoglycan, plays a key role in breast cancer progression. Although native HA lacks sulfate groups, chemically modified sulfated hyaluronan (sHA) has demonstrated promising antitumor activity. Previous work from our group showed that sHA alters cellular functions and modulates ECM-related gene expression in triple-negative breast cancer (TNBC) cells. The aim of this study was to investigate the effects of low-molecular-weight HA (50 kDa) and its sulfated derivative of the same molecular weight, sHA, in MDA-MB-231 and MCF-7 breast cancer cells using advanced 3D cell culture models. Gene expression analyses focused on ECM components, including HA receptors and matrix metalloproteinases (MMPs) that were evaluated. The 3D cell morphology was examined using scanning electron microscopy (SEM). Spheroid growth and expression profiles linked to ECM remodeling and invasiveness were also assessed. Notably, sHA significantly inhibited 3D spheroid growth, reduced cell spreading in a cell line-dependent manner and influenced the expression of genes correlated with ECM remodeling and HA synthesis. These findings emphasize the importance of 3D models for studying ECM-driven breast cancer progression, further supporting sHA as a potential therapeutic modulator.

Keywords:  3D cell platforms; breast cancer; extracellular matrix; hyaluronan; spheroids; sulfated hyaluronan

DOI:  https://doi.org/10.3390/cells15181687
Front Immunol. 2026 ;17 1786163

The mechanism of breast cancer stem cells and tumor microenvironment promoting radioresistance in breast cancer and its intervention strategies.

Ying Zhao, Xiaohan Liu, Xin Bai, Jianming Tang.

   Background: Breast cancer (BC) is the most common malignant tumor among women worldwide. Radiotherapy (RT) is a primary treatment modality; however, local recurrence driven by radioresistance frequently undermines its efficacy.
Mechanisms: Growing evidence indicates that breast cancer stem cells (BCSCs) and the tumor microenvironment (TME) cooperatively regulate multiple signaling pathways, thereby reducing RT efficacy. BCSCs exhibit intrinsic radioresistance through enhanced DNA repair capacity (Section 2.2.1), maintenance of redox homeostasis via the NRF2-KEAP1 and HIF-1α axes (Section 2.2.2), dysregulated cell cycle checkpoints (Section 2.2.3), and epithelial-mesenchymal transition (EMT) (Section 2.2.4). Concurrently, TME components-particularly cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs)-construct a protective niche that sustains BCSCs, promotes immune evasion, and triggers post-RT recurrence.
Subtype-specific heterogeneity: The molecular subtyping of BC (Luminal A/B, HER2+, and triple-negative breast cancer (TNBC)) profoundly influences radiosensitivity and resistance mechanisms, necessitating subtype-specific therapeutic strategies (Section 2.1.2 and 3.1.1).
Intervention strategies and challenges: To overcome radioresistance, we discuss emerging combination approaches, including RT with immune checkpoint inhibitors (ICIs), BCSCs-directed agents, metabolic interventions, and nanodelivery systems. We critically appraise translational barriers, including the paucity of validated biomarkers, the plasticity of BCSCs, and the toxicity profiles of multimodal regimens.
Conclusion: By explicitly distinguishing preclinical from clinical evidence and identifying knowledge gaps between mechanistic insights and clinical application, this review provides a framework for rational trial design and precision RT in BC.

Keywords:  breast cancer; breast cancer stem cells; combination radiotherapy; immunotherapy; radioresistance; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1786163
Cancer Lett. 2026 Sep 22. pii: S0304-3835(26)00613-0. [Epub ahead of print] 218849

PRMT1 and YBX1 Cooperatively Transcriptionally Activate GPX4 to Inhibit Ferroptosis and Promote Breast Cancer Progression.

Yu Li, Baowen Yuan, Jiaxiang Liu, Xin Wang, Jingyao Zhang, Ting Hu, Tianyu Ma, Die Zhang, Yinuo Wang, Jingjing Zhang, Jiayi Gao, Tianyang Gao, Xinhui Hao, Chang Guo, Dong Yan, Wei Huang, Yan Wang.

  Ferroptosis, a regulated form of cell death driven by lipid peroxide accumulation, is crucial in tumor development and controlled by Glutathione Peroxidase 4 (GPX4). Targeting ferroptosis offers a promising cancer therapy approach but remains challenging. Here we show that Protein Arginine Methyltransferase 1 (PRMT1) is highly expressed in breast cancer and forms a transcriptional activation complex with Y-box binding protein 1 (YBX1). This complex binds the GPX4 promoter, suppressing ferroptosis and promoting breast cancer growth and metastasis. YBX1 recruits PRMT1 independently of its enzymatic activity, while PRMT1's methyltransferase function activates transcription via H4R3me2a modification. Combined treatment with MS023 (a type I PRMT inhibitor targeting PRMT1) and SU056 (a YBX1 inhibitor) synergistically decreases GPX4 expression, enhances ferroptosis, and suppresses tumor growth. These findings establish the PRMT1-YBX1-GPX4 axis as a previously unrecognized transcriptional regulatory module and a promising therapeutic target for breast cancer.

Keywords:  GPX4; PRMT1; YBX1; breast cancer; ferroptosis

DOI:  https://doi.org/10.1016/j.canlet.2026.218849
Cancers (Basel). 2026 Sep 16. pii: 3001. [Epub ahead of print]18(18):

Altered Lipolytic Protein Expression in Tumor-Associated Adipose Tissue Correlates with Aggressive Breast Cancer Features.

Priscila Pagnotta, Tomás González-Garello, Cecilia Lotufo, María Luján Crosbie, Natalia Santiso, Anabela Ursino, Celeste Frascarolli, Alicia Amato, Rubén Dreszman, Camila Ramos Quintana, Juan Carlos Calvo, Judith Toneatto.

   BACKGROUND: Adipose tissue (AT) has emerged as a metabolically active component of the breast tumor microenvironment that contributes to breast cancer (BC) progression. Adipocytes release adipokines and lipids that influence tumor growth; however, the specific lipolytic proteins involved in these interactions remain poorly characterized.
METHODS: In this study, we analyzed the expression of perilipin 1, adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL) by Western blot and immunofluorescence in adipose tissue explants from BC patients and healthy donors, evaluating their associations with clinicopathological features related to BC prognosis.
RESULTS: We found that perilipin 1 expression was increased in AT from patients with aggressive tumor characteristics, including advanced stage, premenopausal status, and obesity. In contrast, ATGL and HSL levels were reduced in specific patient subgroups, particularly in obese and postmenopausal patients and in tumor-adjacent AT from invasive lobular carcinoma.
CONCLUSIONS: Together, these findings indicate that the expression of proteins involved in the regulation of lipolysis is influenced by both tumor proximity and clinicopathological characteristics, suggesting alterations in the molecular machinery governing lipid droplet regulation and lipid mobilization within tumor-associated AT. The observed associations identify perilipin 1, ATGL, and HSL as potential candidate markers of tumor-associated AT alterations and provide further insight into tumor-adipocyte interactions in BC. Despite the exploratory nature of this study, the observed associations provide a basis for further investigation into their potential biological and clinical relevance in BC.

Keywords:  ATGL; HSL; clinicopathological characteristics; hormone receptor-positive (HR+) breast cancer; perilipin 1; tumor-associated adipose tissue

DOI:  https://doi.org/10.3390/cancers18183001
Front Endocrinol (Lausanne). 2026 ;17 1919367

Adipose tissue ceramides: emerging lipid components of extracellular vesicles and their influence on metabolic dysregulation.

Sharon Angelini, Juana Maria Sanz Molina, Fabiola Castaldo, Nenad Naumovski, Angelina Passaro, Domenico Sergi.

  Adipose tissue dysfunction is at the interphase between obesity and impaired metabolic health. Increased lipid spillover is a key mechanism by which adipose tissue dysfunction contributes to systemic metabolic dysregulation. This, in turn, leads to the accumulation of lipotoxic lipid species, such as ceramides, within metabolically active tissue not suited for lipid storage tissues thereby fueling insulin resistance. However, the buildup of ceramides also occurs in the adipose tissue of individuals with obesity where these sphingolipids may disrupt energy metabolism, insulin sensitivity and affect adipose tissue secretome, compromising systemic metabolic health. This review will provide an updated overview on the contribution of ceramides to adipose tissue dysfunction, with a particular focus on the onset of insulin resistance. Additionally, this manuscript will focus on the involvement of ceramides in modulating extracellular vesicle (EVs) secretion from the white adipose tissue and their role as bioactive components of EV lipidome able to discern individuals based on their metabolic status.

Keywords:  adipose tissue; ceramides; extracellular vesicles; insulin resistance; lipid metabolism; obesity

DOI:  https://doi.org/10.3389/fendo.2026.1919367
Nat Commun. 2026 Aug 21. pii: 10037. [Epub ahead of print]17(1):

Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.

Kristina Todorova, Stefano Sol, Fabiana Boncimino, Andrea Clocchiatti, Kazuki Takagaki, Enkhtuul Gantumur, Mihaela Ruseva, Meaghan Cadieux, Michelle Liu, Victor A Neel, Amy S Colwell, Christine G Lian, George F Murphy, Peter Carmeliet, Anna Mandinova.

Skin barrier function relies on the epidermis, whose integrity is maintained by basal stem cells that continuously renew and differentiate into a multilayered architecture. Disrupted epidermal differentiation underlies numerous hyperproliferative and inflammatory skin disorders. While transcriptional and epigenetic mechanisms are known to regulate late differentiation, the molecular events driving early commitment remain elusive. Here, we reveal that early mitochondrial reprogramming, characterized by the activation of oxidative phosphorylation, is a determinant of differentiation initiation. We identify fatty acid oxidation as the primary metabolic pathway fueling oxidative phosphorylation during this process. Pharmacological and genetic inhibition of fatty acid oxidation, in vitro and in vivo, disrupts differentiation and compromises stratification, causing defective responses to physical insults. Mechanistically, fatty acid oxidation enables ATP production in committed epidermal cells to support the differentiation process, linking lipid metabolism and epidermal homeostasis. These results uncover an unrecognized role for metabolic reprogramming in epidermal stem cell fate and highlight fatty acid oxidation as a promising therapeutic target for restoring differentiation defects in disease.

DOI: https://doi.org/10.1038/s41467-026-77023-z