bims-merabr 2026-08-02 papers

Front Biosci (Landmark Ed). 2026 Jul 24. 31(7): 52064

GPR19 Drives Cell Cycle Progression via ERK-Dependent FOXM1 Activation in p53-Mutant Breast Cancer.

Jihan Qiu, Cheng Tian, Hanzhi Li, Sumei Gao, Chengcheng Yang, Qiuyan Luo, Yang Liu, Kuan He, Kang Li, Yang Peng, Haochen Yu, Lingfeng Tang, Shengchun Liu.

BACKGROUND: G protein-coupled receptor 19 (GPR19) is an orphan G protein-coupled receptor with emerging relevance in cancer; however, its role in breast cancer remains poorly understood. Given the high frequency of tumor protein p53 (TP53) alterations in aggressive breast cancer, particularly triple-negative breast cancer (TNBC), we investigated the clinical significance, biological function, and molecular mechanism of GPR19 in TP53-mutant breast cancer.
METHODS: Public datasets (Gene Expression Omnibus and The Cancer Genome Atlas) were analyzed to assess GPR19 expression in relation to TP53 status, molecular subtype, and prognosis. Expression was validated in breast cancer cell lines, paired clinical tissues, and tissue microarrays by quantitative PCR, Western blotting, immunofluorescence, and immunohistochemistry. Stable GPR19 knockdown models in MDA-MB-231 and BT-549 cells were used to evaluate proliferation, cell cycle distribution, and apoptosis. RNA sequencing, rescue experiments with the extracellular signal-regulated kinase (ERK) activator Ro 67-7476, and a nude mouse xenograft model were employed to investigate the underlying mechanism.
RESULTS: GPR19 was significantly upregulated in TP53-mutant breast cancer, primary tumors, and especially TNBC, and its high expression was associated with poor survival. Functionally, GPR19 depletion markedly suppressed cell proliferation, colony formation, and DNA synthesis, while inducing G2/M arrest and apoptosis in TP53-mutant breast cancer cells. Mechanistically, GPR19 knockdown reduced ERK phosphorylation and downregulated forkhead box protein M1 (FOXM1) and its downstream G2/M regulators cyclin B1 (CCNB1) and polo-like kinase 1 (PLK1), whereas total ERK levels remained largely unchanged. Pharmacological activation of ERK partially restored FOXM1 expression, alleviated cell cycle disturbance and apoptosis, and reversed the growth-inhibitory effects of GPR19 depletion. In vivo, GPR19 knockdown suppressed xenograft growth, reduced Ki-67 staining, increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) positivity, and inhibited the ERK-FOXM1-CCNB1/PLK1 signaling cascade, all of which were partially rescued by ERK activation.
CONCLUSIONS: GPR19 functions as a novel oncogenic driver and clinically relevant biomarker in breast cancer, particularly in TP53-mutant and TNBC subsets. By activating the ERK-FOXM1 axis, GPR19 sustains cell cycle progression and suppresses apoptosis, highlighting this pathway as a potential therapeutic vulnerability in aggressive breast cancer.

Keywords: G protein-coupled receptor 19; breast neoplasms; cell cycle checkpoints; forkhead box M1; p53 mutation

DOI: https://doi.org/10.31083/FBL52064

Immunology. 2026 Jul 29.

HMGB1-Induced Metabolic Rewiring of Macrophages via RAGE/MAPK Fosters Endocrine Resistance in Breast Cancer.

Donglin Liu, Shengnan Sun, Junning Peng, Shuling Shi, Yuwei Deng, Qingyuan Zhang.

Endocrine resistance remains a critical challenge in hormone receptor-positive (HR+) breast cancer. The impact of the immune microenvironment on endocrine therapy efficacy is increasingly recognised, but its mechanisms are not fully understood. Here, we investigated that nuclear HMGB1 expression in tumour cells was closely associated with endocrine therapy resistance in HR+ breast cancer using tumour genomic databases. Specially, tumours with high HMGB1 expression induced M2-like macrophage polarisation, which was related to HMGB1 paracrine signalling. Mechanistically, HMGB1 bound to the RAGE receptor on macrophages, activating the downstream MAPK signalling pathway and was closely linked to the activation of fatty acid metabolism pathways. Macrophages co-cultured with high-HMGB1 tumour cells exhibited metabolic characteristics associated with carcinogenesis, a loss of glycolytic intermediates and a shift toward a pro-tumourigenic metabolic state compared to those co-cultured with low-HMGB1 cells. Co-culture with M2-like macrophages significantly activated growth signalling pathways like NF-κB in the high-HMGB1 tumour cells. Taken together, high expression of HMGB1 in tumour cells promotes fatty acid metabolic remodelling and functional polarisation in macrophages, contributing to endocrine therapy resistance in HR+ breast cancer. HMGB1 acts as a candidate for immune mediator and paved a way to develop potential target drug.

Keywords: HMGB1; RAGE/MAPK signalling; endocrine resistance; hormone receptor‐positive breast cancer; macrophage polarisation; metabolic remodelling

DOI: https://doi.org/10.1111/imm.70182

Neuro Oncol. 2026 Jul 29. pii: noag173. [Epub ahead of print]

Estradiol Reprograms Microglia to Create an Immune‑Suppressed Niche Permissive to Breast Cancer Brain Metastasis.

Karen L F Alvarez-Eraso, María J Contreras-Zárate, Andrew Goodspeed, James Costello, Jenny A Jaramillo-Gómez, Stella Koliavas, R Alejandro Marquez-Ortiz, Morgan S Fox, Vesna Tesic, Qian Fang, D Ryan Ormond, Peter Kabos, Mercedes Rincon, Diana M Cittelly.

BACKGROUND: Young age is an independent risk factor for the development of breast cancer brain metastases (BM). Prior work showed that 17β-estradiol (E2), the predominant premenopausal hormone, promotes BM of tumors intrinsically unresponsive to E2, in part through modulating estrogen receptor-alpha expressing (ERα⁺) glial cells. However, how E2 reshapes the brain tumor microenvironment (TME), particularly microglia‑mediated immunity, and its impact to BM progression remains unclear.
METHODS: scRNA sequencing and multiparametric flow cytometry were used to define the impact of E2 and E2-suppression on brain immune-cell populations across different stages of BM progression using spontaneous and experimental models of BM. Depletion of microglia and T-cell co-cultures were used to study microglia's role in E2-induced BM. The effects of E2-suppression alone or in combination with whole brain radiotherapy were tested in preclinical models mimicking late-stage BM.
RESULTS: E2 repressed immune surveillance and immune activation programs in microglia from early to late stages of brain metastatic progression, suppressing recruitment of effector immune cells to BM. Estrogen suppression, in turn reactivated anti-tumoral signaling in microglia and increased recruitment of effector immune cells to the brain. Microglia from E2-treated BM-bearing mice showed a reduced capacity to promote T-cell expansion, effector potential, and CD8⁺T cell-mediated tumor cell killing. Conversely, E2-suppression reactivated an effective anti-tumoral response and synergized with RT to significantly decrease BM progression.
CONCLUSION: These findings reveal a previously unrecognized mechanism by which E2 accelerates BC‑BM progression through microglial immunosuppression and support evaluation of endocrine therapies as adjunct treatments for ER⁻ breast cancer brain metastases.

Keywords: Brain metastasis; estrogen; metastatic triple-negative breast cancer; microglia; tumor microenvironment

DOI: https://doi.org/10.1093/neuonc/noag173

Cancer Sci. 2026 Jul 30.

Adipocyte-Derived Palmitic Acid Promotes Breast Cancer Malignancy via ZDHHC15-Mediated S-Palmitoylation of PPARγ.

Geon Ho Moon, Min Young Lee, Jiwon Koh, Ki Yong Hong, Junji Fukuda, Sung Joon Kim, Yang-Sook Chun.

Peroxisome proliferator-activated receptor gamma (PPARγ), a well-characterized regulator of adipogenesis, also functions as a tumor suppressor in breast cancer. However, the PPARγ agonist rosiglitazone has shown limited clinical efficacy, highlighting the importance of understanding PPARγ regulation within the tumor microenvironment. Here, we demonstrate that adipocyte-derived palmitic acid promotes PPARγ S-palmitoylation via zinc finger DHHC-domain containing protein 15 (ZDHHC15), as confirmed by acyl-biotin exchange (ABE) assay. Immunoblot, RT-qPCR, and immunoprecipitation further revealed that this modification leads to ubiquitin-mediated proteasomal degradation of PPARγ. Functional studies using adipocyte-conditioned media and an oxygen-permeable 3D spheroid culture system showed that PPARγ palmitoylation promotes breast cancer malignancy and confers resistance to rosiglitazone. Notably, the palmitoylation inhibitor 2-bromopalmitate (2-BP) stabilizes PPARγ, suppressing breast cancer malignancy. Furthermore, 2-BP synergistically enhances the therapeutic efficacy of rosiglitazone, suggesting that targeting PPARγ S-palmitoylation represents a promising therapeutic strategy in breast cancer.

Keywords: PPARγ; ZDHHC15; adipocytes; breast cancer; palmitoylation

DOI: https://doi.org/10.1111/cas.70487

Curr Obes Rep. 2026 Aug 01. pii: 68. [Epub ahead of print]15(1):

Adipose Tissue Browning in MASLD and Its Molecular Mechanisms and Metabolic Crosstalk.

Jonathan Jaime G Guerrero, Mark Angelo S Del Rosario, Paolo C Encarnacion, Chen-Sung Lin, Lu-Te Chuang, Kin Israel Notarte, Jiayan Zhou, Chih-Hao Wang, Ching-Wen Chang, Wan-Chun Li.

PURPOSE OF REVIEW: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent complication of obesity and metabolic dysregulation, with limited therapies targeting upstream drivers of disease. Adipose tissue has emerged as a central regulator of systemic metabolic homeostasis, where dysfunction contributes to excess free fatty acid flux, chronic inflammation, and hepatic steatosis. In this context, adipose tissue browning-the induction of thermogenically active beige adipocytes within white adipose depots-has gained attention as a potential therapeutic mechanism.
RECENT FINDINGS: Recent advances highlight that adipose browning modulates multiple pathways relevant to MASLD. These include enhanced mitochondrial β-oxidation and energy expenditure, leading to reduced lipid delivery to the liver, as well as endocrine signaling mediated by batokines such as fibroblast growth factor 21 (FGF21), irisin, and neuregulin 4 (Nrg4). Collectively, these pathways influence hepatic lipid metabolism, insulin sensitivity, and inflammatory and fibrotic processes. The preclinical studies consistently demonstrate metabolic and hepatoprotective benefits of browning; however, translational evidence in humans remains limited and heterogeneous. Factors such as reduced thermogenic capacity in obesity, inter-individual variability, and challenges in sustaining browning activation constrain clinical applicability. Overall, adipose tissue browning represents a promising component of a systems-based approach to MASLD. Future work should focus on integrating mechanistic insights with clinical investigation to clarify its therapeutic potential and to identify strategies that enable durable and patient-specific metabolic benefits.

Keywords: Adipose tissue; Beige adipocytes; Browning; Liver metabolism; MASLD

DOI: https://doi.org/10.1007/s13679-026-00746-z

Breast Cancer (Dove Med Press). 2026 ;18 591634

Lipid Metabolic Reprogramming in Breast Cancer: Mechanisms and Emerging Therapeutic Strategies.

Xuliren Wang, Yuanyuan Zhao, Siqi Peng, Xuelong Wang, Qingzhong Wang, Shuang Hao.

Breast cancer remains the most commonly diagnosed malignancy among women worldwide, with a steadily increasing incidence. Lipid metabolic reprogramming is increasingly recognized as both a hallmark and a fundamental driver of breast cancer progression. Breast cancer cells exhibit enhanced lipid uptake, de novo fatty acid synthesis, fatty acid oxidation, and lipid storage, which collectively support membrane biosynthesis, energy production, and oncogenic signaling. In addition to cancer cell-intrinsic effects, lipid metabolic alterations reshape the tumor microenvironment by modulating immune responses, stromal activation, and angiogenesis. Key metabolic enzymes, including FASN, ACC, ACLY, SCD, and FABP4, play central roles in these processes and represent promising therapeutic targets. Emerging evidence from preclinical and clinical studies highlights the therapeutic potential of targeting lipid metabolism, particularly in aggressive subtypes such as triple-negative breast cancer. Despite these advances, challenges such as therapeutic resistance, metabolic compensation, and lack of predictive biomarkers remain major barriers to clinical translation. Overall, targeting lipid metabolic vulnerabilities offers a promising strategy for precision therapy in breast cancer.

Keywords: FABP4; FASN; breast cancer; fatty acid metabolism; lipid metabolism; metabolic reprogramming; spatial metabolomics; targeted therapy; triple-negative breast cancer; tumor microenvironment

DOI: https://doi.org/10.2147/BCTT.S591634