bims-merabr 2026-04-05 papers

Endocr Relat Cancer. 2026 Apr 01. pii: ERC-25-0312. [Epub ahead of print]

Breast Cancer Metastasis in Obesity: Extracellular Vesicles as Drivers.

Isadora Ramos-Andrade, Carolinne Souza Amorim, Luiz Gabriel Xavier Botelho, Victor Aguiar Franco, Isabelle Karine da Costa Nunes, Luiz Guilherme Kraemer-Aguiar, Yasmin Forte, Georgia C Atella, João Alfredo Moraes, Christina Barja-Fidalgo, Mariana Renovato-Martins.

Obesity, a significant risk factor for breast cancer, contributes to tumor progression by releasing proinflammatory adipokines through extracellular vesicles (EVs) secreted by adipose tissue (AT). These EVs, which are small membrane vesicles, have the potential to modulate tumor cell behavior, yet the mechanisms underlying this communication remain largely unclear. This study investigates how EVs derived from obese AT influence malignancy-related processes in MCF-7 breast cancer cells. To assess the effects of obese AT-EVs on MCF-7 cells, EVs were isolated from the adipose tissue secretome obtained from obese and lean individuals (control group). MCF-7 cells were stimulated with these EVs, and subsequent analyses were performed to assess changes in cellular functions, epithelial marker expression, and signaling pathways. Obese AT-derived EVs exhibited significantly elevated levels of TGF-β, leading to activation of the TGF-β/SMAD signaling pathway. This activation resulted in reduced E-cadherin expression and enhanced migration and invasiveness of MCF-7 cells. Additionally, these EVs were enriched in fatty acids, which fueled the tumor cells via fatty acid oxidation (FAO), further contributing to their migratory capacity. This study identifies TGF-β signaling and fatty acid oxidation as central mechanisms by which obese adipose tissue-derived EVs promote a metastatic phenotype in breast cancer cells. These findings provide insight into the molecular crosstalk between obesity and breast cancer and highlight potential targets for therapeutic intervention.

Keywords: Obesity. Adipose tissue. Extracellular vesicles. Breast cancer

DOI: https://doi.org/10.1530/ERC-25-0312

iScience. 2026 Apr 17. 29(4): 115260

AK5 suppresses breast cancer progression and modulates anti-PD-L1 efficacy via the miR-182-5p/PD-L1 axis.

Guang-Shun Sun, Yi-Han Li, Li Li, Li-Li Fan, Hui Yang, Qun Lu, Zhao Liu, Shui Wang, Jin-Juan Peng.

Adenylate kinase 5 (AK5) is a poorly characterized metabolic enzyme with unknown roles in breast cancer. Single-cell transcriptomics revealed AK5 enrichment in malignant epithelial cells, and its low expression correlated with poor patient prognosis, suggesting tumor-suppressive functions. Functionally, AK5 overexpression inhibited, while its knockdown promoted, breast cancer cell proliferation, migration, and invasion. Mechanistically, AK5, dependent on its kinase activity, post-transcriptionally suppressed miR-182-5p maturation, thereby de-repressing -L1 expression. In vivo experiments have proved that AK5 overexpression attenuated tumor growth and synergized with anti-PD-L1 therapy. Our work defines AK5 as a novel tumor suppressor, unveils a kinase-dependent non-canonical role in regulating an immune checkpoint via miR-182-5p, and nominates it as a potential therapeutic target to sensitize tumors to immunotherapy.

Keywords: Cancer; Immune response; Therapy

DOI: https://doi.org/10.1016/j.isci.2026.115260

Exp Cell Res. 2026 Mar 27. pii: S0014-4827(26)00118-7. [Epub ahead of print]458(2): 115001

AGTPBP1 promotes breast cancer progression via the EVPL/ERK signaling axis.

Hudeer Song, Hongxia Li, Yanchao Bian, Jingyuan Song, Chenxi Yang, Houke Lu, Yuqi Zhang, Pengfei Li, Rui Xiao.

BACKGROUND: The role of ATP/GTP binding protein 1 (AGTPBP1), a cytosolic carboxypeptidase, in oncogenesis remains largely unexplored. Although we previously identified its tumor-promoting function in pancreatic cancer, its expression pattern, biological function, and underlying mechanisms in breast cancer remain elusive.
METHODS: AGTPBP1 expression and its clinical relevance in breast cancer were first assessed using public proteomic databases. Stable AGTPBP1 overexpression and knockdown models were established in the luminal A T47D and triple-negative MDA-MB-231 breast cancer cell lines to account for tumor heterogeneity. Malignant phenotypes were evaluated through a series of in vitro functional assays, including proliferation, colony formation, migration, and matrigel invasion assays. Mechanistic insights were gained by RNA-sequencing (with biological triplicates) and subsequent experimental validation, including rescue experiments.
RESULTS: AGTPBP1 was significantly upregulated in breast cancer tissues. Functional studies demonstrated that AGTPBP1 overexpression markedly enhanced cell proliferation, colony formation, migration and invasion, whereas its knockdown suppressed these malignant behaviors. Transcriptomic profiling revealed that AGTPBP1 was critically involved in cell adhesion and cell-cell junction pathways. We identified envoplakin (EVPL), a core desmosomal protein, as a key downstream effector, whose expression was negatively regulated by AGTPBP1. Mechanistically, AGTPBP1-mediated repression of EVPL led to the activation of the ERK signaling pathway, as evidenced by increased phosphorylation of ERK1/2. Rescue experiments confirmed that EVPL overexpression attenuated AGTPBP1-induced malignant phenotypes and ERK activation.
CONCLUSION: This study unveils a novel oncogenic role of AGTPBP1 in breast cancer. We delineate a previously unrecognized AGTPBP1/EVPL/ERK axis whereby AGTPBP1 drives tumor progression by simultaneously disrupting intercellular adhesion and activating pro-tumorigenic ERK signaling. Our findings propose AGTPBP1 as a potential therapeutic target for breast cancer intervention.

Keywords: AGTPBP1; Breast cancer; ERK; EVPL

DOI: https://doi.org/10.1016/j.yexcr.2026.115001

FASEB J. 2026 Apr 15. 40(7): e71746

Metabolic Response to CDK4/6 Inhibition in ER+ Breast Cancer Creates a Therapeutic Vulnerability in Drug-Tolerant Persister Cells.

Huijuan Yang, Steven Tau, Andrew D McCray, Alyssa M Roberts, Jonathan D Marotti, Kristen Muller, Yuzhou Huang, Md Al Mamun, Kazuhiro Aoki, Eugene Demidenko, Todd W Miller.

Although endocrine therapies prevent recurrence and progression of estrogen receptor alpha (ER)-positive breast cancer, approximately one-third of patients experience recurrent disease that is rarely cured in the advanced/metastatic setting. A subpopulation of endocrine-tolerant breast cancer cells persists as residual disease that confers risk for the eventual emergence of drug resistance. An analysis of persisters that continue to proliferate despite endocrine therapy revealed the activation of pathways related to metabolism and E2F transcription factor signaling. E2F signaling is driven by cyclin-dependent kinases 4 and 6 (CDK4/6), and CDK4/6 inhibitors (CDK4/6i) are used clinically to prevent and manage endocrine resistance. CDK4/6i slowed the cycling of endocrine-tolerant persisters. Analyzing metabolic alterations induced by CDK4/6i, we found that CDK4/6i-tolerant persisters had upregulation of mitochondrial content, mitochondrial membrane potential, respiration, and reactive oxygen species (ROS). Inhibition of mitochondrial complex I further increased ROS levels and enhanced growth inhibition in both endocrine-sensitive and -resistant cell lines and patient-derived xenografts. These findings collectively offer mitochondrial respiration as a therapeutic target in CDK4/6-tolerant persister breast cancer cells to help eradicate residual disease.

Keywords: CDK4/6; abemaciclib; breast cancer; drug resistance; drug‐tolerant persisters; metabolism; palbociclib

DOI: https://doi.org/10.1096/fj.202502515RR