bims-merabr 2026-07-19 papers

Cell Biochem Funct. 2026 Jul;44(7): e70263

Mechanistic Links Between Obesity and Breast Cancer Progression: Cellular Crosstalk, Metabolic Reprogramming and Microenvironmental Drivers.

Charlise Basson, Michael S Pepper, Anna M Joubert, Melvin A Ambele.

Obesity is increasingly recognised as an important factor contributing to cancer progression, particularly in breast cancer. However, the cellular and molecular mechanisms underlying obesity-driven breast cancer remain unclear. Several theories have been proposed to explain the complex interactions between adipose tissue and cancer, incorporating both local and distant crosstalk. This review describes existing theories on the cellular and molecular mechanisms linking obesity and breast cancer progression with a focus on inflammation, oxidative stress, metabolic reprogramming, the tumour microenvironment and crosstalk between adipose tissue and tumours. The nature of these interactions appears to be influenced by the specific characteristics of adipose tissue, including its type and anatomical location, which play distinct roles in modulating breast cancer risk and outcomes. Understanding the cellular and molecular mechanisms that underlie obesity-driven breast cancer progression may pave the way for the development of targeted therapies.

Keywords: adipokines; adipose tissue; breast cancer; cancer metabolism; obesity; oxidative stress; tumour microenvironment

DOI: https://doi.org/10.1002/cbf.70263

Biochem Pharmacol. 2026 Jul 15. pii: S0006-2952(26)00599-X. [Epub ahead of print] 118260

EFO2 promotes triple-negative breast cancer progression and reduces CD8+ T cell-mediated killing by acetylating USF1 to enhance SLC2A1-mediated glycolysis.

Lin Jia, Liru Li, Junning Peng, Zhenyu Liu, Jiaxin Gong, Yuwei Deng, Jianli Ma, Qingyuan Zhang.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by significant intratumoral heterogeneity and poor prognosis. Our study identified Establishment Factor-Like Protein 2 (EFO2) as a key oncogenic driver of TNBC progression. Using GEO datasets, we identified differentially expressed genes in TNBC. Functional roles of EFO2 were assessed via knockdown in human (MDA-MB-231, HCC1937) and mouse (4 T1, EMT6) TNBC cells, examining proliferation, glycolysis, and co-culture with CD8⁺ T cells. In vivo tumor growth was evaluated. Molecular mechanisms were investigated through co-immunoprecipitation, mutagenesis, luciferase reporter, and ChIP-qPCR assays. We observed that EFO2 was highly expressed in TNBC tissues, and this high expression correlated with shorter patient survival. Functional experiments showed that EFO2 knockdown suppressed tumor growth and proliferation both in vitro and in vivo. Furthermore, EFO2 knockdown inhibited glycolysis, as evidenced by decreased glucose uptake, ATP production, and lactate production. Moreover, EFO2 deficiency enhanced CD8⁺ T cell-mediated cytotoxicity against TNBC cells. Mechanistically, we demonstrated that EFO2 promoted the acetylation of Upstream Transcription Factor 1 (USF1), thereby enhancing transcriptional upregulation of the SLC2A1 promoter, a key glucose transporter. This EFO2/USF1/SLC2A1 signaling axis accelerated glycolysis in TNBC cells, which concurrently sustained tumor proliferation and impaired CD8⁺ T cell effector function, reducing TNBC cell susceptibility to T cell-mediated killing. Our findings identify a novel EFO2/USF1/SLC2A1 signaling axis that modulates glycolytic metabolism and CD8⁺T cell cytotoxicity, positioning EFO2 as a promising therapeutic target for TNBC treatment.

Keywords: CD8⁺ T cell; EFO2; Glycolysis; Triple-negative breast cancer; USF1

DOI: https://doi.org/10.1016/j.bcp.2026.118260

PLoS One. 2026 ;21(7): e0353376

TBX20 promotes doxorubicin resistance in breast cancer cells through enhanced ABCC1 expression and inhibition of mitophagy.

Shuai Nie, Dejian Liu, Jun Hu, Yu Gan, Liangliang Mi.

This study aimed to investigate the role and mechanism of T-box transcription factor 20 (TBX20) in doxorubicin resistance in breast cancer cells. RNA-seq data from breast cancer samples in the TCGA database were analyzed. Lentiviral vectors were used to establish TBX20 overexpression and silencing models in MCF-7 and MDA-MB-231 cells. Gene and protein expression were detected by qPCR and Western blot, respectively. Cell viability and the half-maximal inhibitory concentration of doxorubicin were measured using the CCK-8 assay. Apoptosis, migration, and invasion were analyzed by flow cytometry, wound healing assay, and Transwell assay. Mitophagy levels were assessed via immunofluorescence staining and western blotting. ChIP and dual-luciferase reporter assays were performed to validate the transcriptional regulation of ABCC1 by TBX20. Results showed that TCGA data analysis revealed a high expression of TBX20 in breast cancer tissues, which was positively correlated with ABCC1 expression. In MCF-7 and MDA-MB-231 cells, TBX20 overexpression significantly enhanced cell proliferation, migration, invasion, and resistance to doxorubicin, while suppressing the expression of mitophagy-related proteins LC3-II/LC3-I, PINK1, and BNIP3. ChIP and dual-luciferase reporter assays confirmed that TBX20 directly binds to and activates the ABCC1 promoter. Silencing of ABCC1 or restoration of mitophagy by CCCP reversed TBX20 overexpression‑induced doxorubicin resistance. TBX20 enhances the resistance of breast cancer cells to doxorubicin by transcriptionally upregulating ABCC1 and is correlated with the suppression of mitophagy.

DOI: https://doi.org/10.1371/journal.pone.0353376

Transl Cancer Res. 2026 Jun 30. 15(6): 449

METTL16-mediated upregulation of LINC00665 inhibits the apoptosis of breast cancer via regulating miR-28-5p/GLG1 axis.

Ya Zhou, Jie Ren, Xiaojuan Cai, Shiyu Lu, Hanbing Gu, Weizhe Xu, Xun Zhu.

Background: Long non-coding RNAs (lncRNAs) are intensively involved in the progression of breast cancer. This study aimed to investigate the potential of LINC00665 in breast cancer.
Methods: RNA expression was determined by quantitative reverse transcriptase polymerase chain reaction. The binding sites between miR-28-5p and LINC00665/golgi glycoprotein 1 (GLG1) was predicted by Starbase3. The bindings sites were confirmed by luciferase assay. N6-methyladenosine (m6A) modification of LINC00665 was determined by methylated RNA immunoprecipitation assay. Cell viability was determined by Cell Counting Kit-8 assay. Cell migration was detected by wound healing assay. Cell invasion was detected by transwell assay. Cell apoptosis was detected using flow cytometry.
Results: We found that methyltransferase-like 16 (METTL16)-mediated m6A modification drove the upregulation of LINC00665 in breast cancer. However, LINC00665 knockdown inhibited the proliferation, migration and invasion of breast cancer cells, as well as promoted cell apoptosis. Furthermore, LINC00665 sponged miR-28-5p to upregulate GLG1. GLG1 overexpression alleviated the effects of LINC00665 knockdown and mediated malignant behaviors of breast cancer cells.
Conclusions: Taken together, LINC00665 promotes the progression of breast cancer via regulating miR-28-5p/GLG1 axis.

Keywords: Breast cancer; LINC00665; apoptosis; metastasis

DOI: https://doi.org/10.21037/tcr-2025-1-2774

Cell Death Dis. 2026 Jul 11.

ENO2 sustains cancer stemness and metastatic competence through a phosphoenolpyruvate-dependent metabolic axis in triple-negative breast cancer.

Cing-Hong Wang, Ru-Tsun Mai, Ke Jia Khoo, Chi-Feng Hung, Cheng-Kuang Yang, Meng-Ju Wu, Chi-Hong Chao.

Enolase 2 (ENO2) is a neuron-specific glycolytic enzyme whose expression is elevated in aggressive breast cancers, yet its enzymatic and biological contributions to triple-negative breast cancer (TNBC) progression remain incompletely defined. Here, we demonstrate that ENO2 sustains cancer stem cell (CSC) properties and metastatic competence through a phosphoenolpyruvate (PEP)-dependent metabolic axis. Elevated ENO2 expression correlated with advanced tumor grade and poor clinical outcomes in TNBC cohorts, underscoring its clinical relevance. Genetic depletion of ENO2 impaired aerobic glycolysis and oxidative phosphorylation, reduced migration, invasion, and CSC frequency, and suppressed tumor growth and pulmonary metastasis in orthotopic models. Mechanistically, exogenous PEP or pyruvate restored CSC-associated traits and invasiveness in ENO2-deficient cells, supporting the functional involvement of ENO2-derived metabolites in CSC maintenance. Reconstitution with wild-type ENO2, but not a catalytically impaired mutant, restored CSC properties, invasiveness, and metastatic colonization, establishing that ENO2 catalytic activity is required for these malignant traits. Further analysis revealed that PKM2 perturbation preferentially attenuated PEP-mediated rescue while largely sparing pyruvate-mediated rescue, supporting a functional PEP-PKM2-pyruvate axis in CSC regulation. Consistently, PKM2 depletion partially blunted ENO2-mediated rescue; however, residual rescue despite PKM2 perturbation suggested additional PKM2-independent PEP-responsive mechanisms. Importantly, pharmacological inhibition of enolase with POMHEX phenocopied genetic ENO2 loss and suppressed CSC maintenance in vitro and tumor growth in vivo. Taken together, these findings identify the ENO2-driven PEP-dependent metabolic axis as a mechanistic link between metabolic reprogramming, cancer stemness, and metastasis, revealing a therapeutically actionable metabolic vulnerability in TNBC.

DOI: https://doi.org/10.1038/s41419-026-09106-0