bims-merabr 2026-01-18 papers

Mol Biol Rep. 2026 Jan 10. 53(1): 270

The impact of the telomerase inhibitor on the Wnt signaling pathway in breast cancer and breast cancer stem cells.

Pinar Guler, Leila Sabour Takanlou, Maryam Sabour Takanlou, Arman Rostamlou, Cigir Biray Avci.

BACKGROUND: Breast cancer remains one of the leading causes of cancer-related mortality in women worldwide. Breast cancer stem cells (BCSCs) contribute to tumor initiation, metastasis, recurrence, and resistance to therapy. The Wnt signaling pathway is a major regulator of stemness properties and is associated with poor clinical outcomes. BIBR1532 is a selective telomerase inhibitor widely used in cancer research due to its ability to inhibit telomerase activity in tumor cells with minimal toxicity in normal tissues. This study aimed to investigate the effects of BIBR1532 on the Wnt signaling pathway in breast cancer cells and BCSCs.
METHODS: Cytotoxicity of BIBR1532 was evaluated in MCF-7 breast cancer cells, MCF10A normal breast epithelial cells, and BCSCs using a 48-hour treatment. IC₅₀ values were calculated, and apoptosis induction was assessed. Changes in the expression of Wnt pathway-related genes following BIBR1532 treatment were analyzed using RT-qPCR.
RESULTS: The IC₅₀ values of BIBR1532 at 48 h were 35.29 µM for MCF-7, 28.16 µM for MCF10A, and 30.42 µM for the BCSC line. BIBR1532 markedly induced apoptosis in MCF-7 and BCSCs, whereas minimal apoptotic changes were observed in MCF10A cells. RT-qPCR analysis revealed significant modulation of genes in the Wnt signaling pathway: several oncogenic components were downregulated, while multiple tumor-suppressive genes were upregulated. Additionally, expression changes in less-studied Wnt-related genes may provide new insights for future breast cancer research.
CONCLUSIONS: BIBR1532 exerts selective cytotoxic and pro-apoptotic effects on breast cancer cells and BCSCs and modulates key components of the Wnt signaling pathway. These findings suggest that telomerase inhibition may influence stemness-related signaling in breast cancer.

Keywords: Apoptosis; BIBR1532; Breast cancer; Cancer stem cells; Proliferation; Wnt signaling

DOI: https://doi.org/10.1007/s11033-025-11412-3

J Nutr Biochem. 2026 Jan 12. pii: S0955-2863(26)00005-7. [Epub ahead of print] 110263

Brown Adipocyte-Derived SAA3-CPT1A Axis Regulates Diet-Induced Thermogenesis and Protects Against Obesity.

Pei-Chi Chan, Chun-Han Jhuang, Hsin-Yi Chang, Po-Shiuan Hsieh.

Diet-induced thermogenesis (DIT), a critical component of energy expenditure driven by brown adipose tissue (BAT), is essential for maintaining metabolic health; however, its precise molecular regulation remains poorly understood. We investigated whether Serum Amyloid A3 (SAA3), a factor secreted by brown adipocytes, regulates DIT and protects against diet-induced obesity. Using two distinct mouse models: mice with brown adipocyte-specific Saa3 deletion and mice with lentiviral-mediated Saa3 overexpression in BAT, we examined energy expenditure (EE), substrate utilization, and thermogenic responses under chow or short-term high-fat diet (HFD) feeding. SAA3 expression in BAT was acutely induced by refeeding. Loss of SAA3 severely diminished postprandial DIT and total EE, leading to accelerated weight gain on an HFD. Mechanistically, Saa3 deletion compromised UCP1 induction, chiefly by impairing ATGL-driven lipolysis and, critically, by inhibiting Carnitine Palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). Conversely, SAA3 overexpression robustly enhanced DIT, stimulated lipolysis and FAO, and promoted mitochondrial oxidative phosphorylation. Studies in primary brown adipocytes confirmed that SAA3 deficiency reduced CPT1A expression, palmitate-stimulated lipolysis, and mitochondrial respiration. Together, these findings identify the SAA3-CPT1A axis as a novel, BAT-intrinsic mechanism that couples nutrient sensing to UCP1 function via enhanced FAO. By promoting lipid utilization and postprandial energy dissipation, SAA3 optimizes postprandial thermogenesis and defends against obesity, highlighting conserved SAA signaling as a potential nutritional and therapeutic target in metabolic disease.

Keywords: Carnitine palmitoyltransferase 1A; Serum Amyloid A-3; brown adipose tissue; diet-induced thermogenesis; fatty acid oxidation

DOI: https://doi.org/10.1016/j.jnutbio.2026.110263

bioRxiv. 2026 Jan 08. pii: 2026.01.07.698253. [Epub ahead of print]

Cell Communication Network factor 4 promotes tumor-induced immunosuppression in breast cancer.

David J Klinke, Atefeh Razazan, Anika C Pirkey, Wentao Deng.

Cell Communication Network factor 4 (CCN4/WISP1) is a matricellular protein secreted by cancer cells that is upregulated in essentially all invasive breast cancers and promotes immunosuppression in melanoma. Recent work suggests that limited anti-tumor immunity also associates with poor patient outcomes in patients with breast cancer. Motivated by increased CCN4 correlating with dampened anti-tumor immunity in primary breast cancer, we test for a direct causal link by knocking out CCN4 (CCN4 KO) in the Py230 and Py8119 mouse breast cancer models. Tumor growth is reduced when CCN4 KO breast cancer cells are implanted in immunocompetent but not in immunodeficient mice. Correspondingly in size-matched tumors, CD4+ and CD8+ T cells are significantly increased in CCN4 KO tumors while the myeloid compartment is shifted from polymorphonuclear- to monocytic-myeloid-derived suppressor cells (MDSC). This shift in the MDSC compartment is also associated with a significant reduction in splenomegaly. Among mechanisms linked to local immunosuppression, CCN4 knockout has a similar impact on the secretome of both breast cancer and melanoma cell lines. Overall, our results suggest that CCN4 promotes tumor-induced immunosuppression in the context of breast cancer and is a potential target for therapeutic combinations with immunotherapies.

DOI: https://doi.org/10.64898/2026.01.07.698253

Int Immunopharmacol. 2026 Jan 15. pii: S1567-5769(26)00044-5. [Epub ahead of print]172 116201

RAB10 mediates metabolic regulation of ferroptosis in breast Cancer and synergistically remodels the tumour immune microenvironment via macrophage M2 polarization.

Ruonan Li, Yuting Liu, Bo Pang, Xingyu Liu, Chengle Zhu, Guohui Tang, Ruorong Ran, Wenrui Wang, Changjie Chen, Qingling Yang.

This study aimed to investigate the multifaceted biological functions of RAB10 in the development and progression of breast cancer, with a specific focus on its role and molecular mechanisms in remodelling the tumour metabolic and immune microenvironments. Experimental results demonstrated that RAB10 promotes the expression of PPARγ and its downstream target gene DGAT1 via activation of the PI3K/AKT signalling pathway. This axis drives lipid metabolic reprogramming and inhibits ferroptosis, thereby enhancing breast cancer cells survival under stress. The functional state of RAB10 modulates the tumour microenvironment via tumour-derived exosomes. Upon uptake by macrophages, these exosomes transmit signals that promote M2 polarization and inhibit ferroptosis. Crucially, knocking down RAB10 inhibits PPARγ via the PI3K/AKT pathway, thereby blocking M2 polarization of tumour-associated macrophages and enhancing CD8+ T cell infiltration, thus reversing the immunosuppressive microenvironment. This study investigates the potential role of the RAB10/PI3K/AKT/PPARγ axis in remodelling the breast cancer microenvironment from the perspective of metabolic-immune crosstalk. These findings not only enhance the understanding of the interplay between metabolism and immune responses in the tumour microenvironment but also provide a potential theoretical foundation and novel research directions for combination treatment strategies targeting this pathway.

Keywords: Breast cancer; Ferroptosis; Immune microenvironment; Metabolism; RAB10

DOI: https://doi.org/10.1016/j.intimp.2026.116201

Am J Hum Genet. 2026 Jan 13. pii: S0002-9297(25)00479-3. [Epub ahead of print]

Genetic regulation of fatty acid content in adipose tissue.

Xinyu Yan, Amy L Roberts, Julia S El-Sayed Moustafa, Sergio Villicaña, Maryam Al-Hilal, Max Tomlinson, Cristina Menni, Thomas A B Sanders, Maxim B Freidin, Jordana T Bell, Kerrin S Small.

Fatty acids are important as structural components, energy sources, and signaling mediators. While studies have extensively explored genetic regulation of fatty acids in serum and other bodily fluids, their regulation within adipose tissue, a crucial regulator of cardiovascular and metabolic health, remains unclear. Here, we investigated the genetic regulation of 18 fatty acids in subcutaneous adipose tissue from 569 female twins from TwinsUK. Using twin models, the heritability of fatty acids ranged from 5% to 59%, indicating a substantial genetic regulation of fatty acid levels within adipose tissue, which was also tissue specific in many cases. Genome-wide association studies identified 10 significant loci, in SCD, ADAMTSL1, ZBTB41, SNTB1, EXOC6B, ACSL3, LINC02055, MKRN2/TSEN2, FADS1, and HAPLN across 13 fatty acids or fatty acid product-to-precursor ratios. Using adipose gene expression and methylation, which were concurrently measured in these samples, we detected five fatty acid-associated signals that colocalized with expression quantitative trait locus (eQTL) and methylation quantitative trait locus (meQTL) signals, highlighting fatty acids that are regulated by molecular processes within adipose tissue. We explored links between polygenic scores of common metabolic traits and adipose fatty acid levels and identified associations between polygenic scores of BMI, body-fat distribution, and triglycerides and several fatty acids, indicating these risk scores impact local adipose tissue content. Overall, our results identified local genetic regulation of fatty acids within adipose tissue and highlighted their links with renal and cardio-metabolic health.

Keywords: adipose tissue; fatty acid; genome-wide association study; polygenic score

DOI: https://doi.org/10.1016/j.ajhg.2025.12.008