bims-merabr 2026-11-08 papers

Cell Rep. 2026 Nov 02. pii: S2211-1247(26)00866-1. [Epub ahead of print] 117788

Circulating FABP4 promotes obesity-associated breast cancer lung metastasis through PIP2.

Shanshan Liu, Jiaqing Hao, Jianyu Yu, Xingshan Jiang, Liping Yu, Devin Reusch, Zhen Xu, Nicholas Schnicker, Anthony Avellino, Xiaochun Han, Jonathan Shilyansky, Zhaohua Wang, Guanpeng Li, Christopher Ahern, Edward R Sauter, Sonia L Sugg, Bing Li.

Obesity is a well-established risk factor for increased incidence and mortality in multiple cancers, including breast cancer. However, the key molecular mechanisms linking obesity to breast cancer progression remain incompletely understood. In this study, using several high-fat diet-induced obesity models, we demonstrate that obesity promotes breast cancer lung metastasis through elevated levels of adipocyte-derived circulating FABP4. Mechanistically, circulating FABP4 directly binds to a subset of breast cancer cells via the membrane lipid PIP2. This FABP4/PIP2 interaction activates PKC signaling and enhances mitochondrial ROS production, driving cancer cell migration. Genetic deletion of FABP4, either globally or specifically in adipocytes, markedly reduces obesity-associated metastasis. Moreover, therapeutic targeting of circulating FABP4 using a distinctive neutralizing monoclonal antibody significantly suppresses breast cancer metastasis in multiple preclinical models. Together, these findings identify the FABP4/PIP2 axis as a key mechanism underlying obesity-driven breast cancer and highlight it as a promising therapeutic target for treating metastatic breast cancer.

Keywords: CP: cancer; CP: metabolism; FABP4; PIP2; adipocyes; adipokine; breast cancer; humanized anti-FABP4 antibody; immunotherapy; metastasis; monoclonal antibody; obesity

DOI: https://doi.org/10.1016/j.celrep.2026.117788

Transl Breast Cancer Res. 2026 ;7 43

Hypoxia-stimulated breast cancer-associated fibroblasts activation regulates glucose metabolism and facilitates progression of breast cancer.

Shuaifeng Yu, Bing Han, Weizheng Li, Zan Li, Lu Bai, Xian Li, Wenxiang Zhi.

Background: Cancer-associated fibroblasts (CAFs) are known to significantly contribute to the advancement and spread of triple-negative breast cancer (TNBC), which is recognized as the most aggressive subtype of breast cancer (BC) with a grim prognosis. Our previous studies revealed that hypoxia promotes glycolytic activity of CAFs in the tumor microenvironment. However, their role within the TNBC tumor microenvironment remains unknown. This study aims to explore the mechanism by which hypoxia drives normal fibroblast (NF) conversion to CAFs, seeking to uncover how this process enhances glucose metabolism and tumor progression in TNBC.
Methods: The proliferation of fibroblasts was evaluated by Trypan Blue cell counting assays after coculturing with MDA-MB-231 cells in hypoxic or normal conditions. Scratch and Transwell assays were performed to confirm the promotion of invasive and metastatic in TNBC. Converting NFs into CAFs was assessed by Western blots and immunofluorescence. Moreover, the impact of glucose metabolism in CAFs under hypoxia was investigated with or without glucose transporter type 1 (GLUT1) inhibitor both in vitro and in vivo (orthotopic xenografts). To explore potential therapeutic targets, we analyzed gene expression data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx) datasets, focusing on TNBC-related gene expression.
Results: TNBC cells promote fibroblast proliferation, migration, and invasion under hypoxia in Scratch and Transwell assays. Immunohistochemistry showed higher α-smooth muscle actin (α-SMA) levels in NFs cells when co-cultured with MDA-MB-231 cells under hypoxia. Western blotting revealed increased α-SMA, fibroblast activation protein (FAP), and GLUT1 expression in NF cells under hypoxia compared with that under normal. In vivo, hypoxic treatment led to increased tumor growth and higher levels of α-SMA, GLUT1, and the consumption of glucose and lactate. We report that glycolysis inhibition of GLUT1 with BAY-876 significantly suppressed TNBC cell growth under co-culture conditions of MDA-MB-231cells and NF cells. Analysis of TCGA and GTEx data identified 2,523 upregulated and 1,467 downregulated proteins in the TNBC stroma compared to normal tissue, with increased levels of hypoxia-inducible factor 1-alpha (HIF-1α), α-SMA, and GLUT1. Furthermore, elevated HIF-1α, α-SMA, and GLUT1 mRNA levels were associated with poorer disease-free survival in TNBC patients.
Conclusions: This study indicates that TNBC can stimulate NFs to become CAFs in low oxygen conditions, possibly through alternating glucose metabolism and promoting tumor growth.

Keywords: Hypoxia; cancer-associated fibroblasts (CAFs); glucose metabolism; normal fibroblasts (NFs); triple-negative breast cancer (TNBC)

DOI: https://doi.org/10.21037/tbcr-25-56

Oncogene. 2026 Nov 05.

RHBDL2 promotes cancer stemness and chemoresistance in triple-negative breast cancer through EGFR/PI3K/AKT/mTOR/c-Myc pathway.

Dan Wang, Xing Niu, Jingqi Tian, Ruibin Liu, Yuxuan Song, Dingye Zhang, Junze Dai, Shenglong Li, Xudong Zhu.

Chemoresistance remains a major challenge in the treatment of triple-negative breast cancer (TNBC). However, the mechanisms underlying chemoresistance remain poorly understood. In this study, we identified that higher levels of Rhomboid-Like 2 (RHBDL2) expression were associated with chemoresistance and poor prognosis in patients with TNBC. Notably, the knockdown of RHBDL2 suppressed cancer stemness and chemoresistance by inhibiting CD44+/CD24- breast cancer stem cells (BCSCs) in TNBC cells. RNA sequencing analysis revealed that the EGFR/PI3K/AKT/mTOR/c-MYC signaling pathway was involved in this process. Mechanistically, we observed that RHBDL2 activated the EGFR/PI3K/AKT/mTOR/c-MYC signaling pathway by binding to EGFR. Knockdown of RHBDL2 inhibited the expression of EGFR on the TNBC cell membrane, thereby deactivating the downstream signaling pathway, and ultimately inhibiting TNBC progression and chemoresistance. Remarkably, our in vivo experiments demonstrated that knockdown of RHBDL2 effectively inhibited tumor growth in xenograft tumor models. Collectively, our study uncovers the roles and mechanisms of RHBDL2 in TNBC chemoresistance and proposes targeting RHBDL2 as an innovative therapeutic strategy to overcome chemoresistance in TNBC.

DOI: https://doi.org/10.1038/s41388-026-04007-0

J Vis Exp. 2026 Nov 03.

Promotion of the Proliferation and Migration of Breast Cancer Cells by the Micro Ribonucleic Acid miR-425-5p via Dihydropyrimidinase-Like 2.

Liping Jing, Fang Wang, Zhiqiang Cui, Liyan Ren, Guoyong Qiao, Yan Luo, Xiaolin Hao, Jiao Zheng, Yanli Yi.

Breast cancer (BC) is the most common malignant tumor in women. MicroRNAs (miRNAs) are a class of noncoding single-stranded RNA molecules that are closely related to the development, progression, and metastasis of BC. The miRNA miR-425-5p is upregulated in a variety of cancers and can promote cancer progression. This study aimed to investigate the role of miR-425-5p in BC and its molecular mechanism. The expression of miR-425-5p in BC was analyzed using the Cancer Genome Atlas database and two Gene Expression Omnibus validation cohorts. Expression of miR-425-5p in paired BC and adjacent nontumor tissues from four patients with invasive ductal carcinoma and in normal breast epithelial and BC cell lines. Expression of miR-425-5p in BC tissues and cell lines was detected via quantitative real-time polymerase chain reaction. Protein expression was detected using a Western blot. Cell growth and proliferation were assessed via a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A transwell assay was used to detect the migration ability of BC cells. The effects of miR-425-5p and DPYSL2 were verified using patient-derived BC organoids established from the four tumor samples, as well as xenograft experiments in female nude mice randomly divided into three groups (five or eight mice per group). The experimental results showed that miR-425-5p expression levels were higher in tumor tissue than in normal tissue. The RT-qPCR results showed high expression of miR-425-5p in clinical samples and BC cell lines; miR-425-5p promoted the growth and migration of BC cells and targeted and degraded the DPYSL2 messenger RNA. The DPYSL2 protein content decreased upon miR-425-5p overexpression. The MTT and Transwell assay results indicated that miR-425-5p regulated BC progression via DPYSL2. Inhibition of miR-425-5p or overexpression of DPYSL2 inhibited BC growth in organoid and nude mouse xenograft experiments. In summary, miR-425-5p promoted BC development by targeting DPYSL2.

DOI: https://doi.org/10.3791/72049

Oncol Rev. 2026 ;20 1959034

Breast cancer adaptation to oxygen stress: mechanisms of tumor survival, progression, and therapeutic resistance.

Emmanuel Ifeanyi Obeagu, Izuchukwu Hilary Edeoga.

Breast cancer cells encounter heterogeneous oxygen conditions arising from abnormal vasculature, impaired perfusion, rapid proliferation, and fluctuating blood flow. Adaptation to oxygen stress is increasingly recognized as a major driver of tumor progression and therapeutic resistance. This review integrates current evidence on the mechanisms through which breast cancer cells adapt to oxygen stress and identifies opportunities for precision therapeutic intervention. Oxygen stress activates hypoxia-inducible factors and interconnected signaling networks that coordinate metabolic reprogramming, mitochondrial adaptation, reactive oxygen species generation, and redox homeostasis. These responses are reinforced by autophagy, unfolded protein response, epithelial-mesenchymal plasticity, cancer stemness, extracellular-matrix remodeling, angiogenesis, and immune suppression. Together, these mechanisms sustain cellular survival, facilitate invasion and metastasis, and promote resistance to chemotherapy, radiotherapy, endocrine therapy, HER2-directed treatment, and other targeted approaches. Oxygen-stress responses vary across breast cancer subtypes, emphasizing the need for biologically informed therapeutic strategies. Potential precision approaches include targeting hypoxia signaling, glycolytic and mitochondrial dependencies, lactate metabolism, antioxidant systems, autophagy, proteostasis, hypoxia-activated pathways, and hypoxia-associated immune suppression. Integrating molecular biomarkers, metabolic profiling, spatial technologies, and functional imaging may improve identification of tumors with actionable oxygen-stress dependencies. Oxygen-stress adaptation represents an interconnected survival network rather than a single hypoxia pathway. Therapeutically exploiting tumor-specific adaptive dependencies, while accounting for subtype and spatial heterogeneity, may provide new opportunities to overcome treatment resistance and improve precision management of breast cancer.

Keywords: angiogenesis; breast cancer; cell survival; hypoxia; metabolic reprogramming

DOI: https://doi.org/10.3389/or.2026.1959034

BMC Biol. 2026 Aug 08. pii: 227. [Epub ahead of print]24(1):

Transcriptomic insights into age-associated extracellular matrix promotion of breast cancer.

Lauren Hawthorne, Gokhan Bahcecioglu, Jun Yang, Emilija Aleksandrovic, Erin Howe, Siyuan Zhang, Pinar Zorlutuna.

BACKGROUND: Aging is a key risk factor for breast cancer; however, the independent effects of the aged extracellular matrix (ECM) remain understudied.
RESULTS: To address this, we developed a novel hybrid in vivo model that enables the independent investigation of age-related ECM influences on breast cancer development and progression. To examine the effects of genes known to be enriched in a cancerous and aged microenvironment, we first seeded normal or stable knockdown cells onto decellularized ECM (dECM) from aged murine mammary glands and implanted them into young Rag1-/- mice. We identified LOX as a principal driver of tumor progression, with knockdown reducing invasion, in vitro and in vivo, and stress-related pathways. To further isolate the independent influence of ECM aging on tumor growth, normal MCF10A cells were seeded atop young or aged matrices and implanted. Aged tumors exhibited significantly greater volume and a larger tumorigenic region when compared to young tumors, with single-cell RNA sequencing revealing enrichment of inflammatory and invasive genes.
CONCLUSIONS: Together, these findings identify LOX as a driver of tumor progression and a potential therapeutic target and demonstrate that the aged ECM alone is sufficient to promote breast cancer progression.

Keywords: Aging; Breast cancer; Cancer; Extracellular matrix (ECM)

DOI: https://doi.org/10.1186/s12915-026-02697-2