bims-merabr 2026-06-28 papers

Cell Death Discov. 2026 Jun 26.

TFCP2L1 suppresses breast cancer progression by promoting ferroptosis through direct and PI3K/AKT-mediated inhibition of GPX4.

Xiaoxiao Wang, Wei Lu, Yandi Cui, Keqiang He, Yuanzhi Bie, Shou-Dong Ye, Xiangfen Li.

Breast cancer is the most prevalent type of malignant tumor among women. Here, we identified transcription factor CP2-like 1 (TFCP2L1) as a suppressor of breast cancer cells. Patients with breast cancer have poorer prognoses when TFCP2L1 is expressed at low levels. Consistently, the expression of TFCP2L1 is greater in normal breast tissues and cells than in breast cancer tissues and cell lines. Gain- and loss-of-function experiments and xenograft tumor assays revealed that overexpression of TFCP2L1 significantly inhibited the proliferation and migration of breast cancer cells. Conversely, the knockdown of TFCP2L1 promoted the growth and migration of breast cancer cells. Mechanistically, TFCP2L1 suppresses breast cancer progression by inhibiting the expression of glutathione peroxidase 4 (GPX4), a key positive regulator of ferroptosis. Therefore, the addition of a ferroptosis inhibitor, Ferrostatin-1, can mediate the function of TFCP2L1 in breast cancer cells. On the other hand, high-throughput transcriptome sequencing revealed that TFCP2L1 negatively regulates the activity of the PI3K/AKT signaling pathway. The administration of SC79, an AKT activator, partially reversed the negative effects of TFCP2L1 on GPX4 transcription. Together, these findings indicate that TFCP2L1 functions partially by directly and indirectly regulating GPX4-mediated ferroptosis and may serve as a potential therapeutic target for breast cancer.

DOI: https://doi.org/10.1038/s41420-026-03231-7

Breast Cancer Res. 2026 Jun 25.

Targeting PFKFB3 to enhance CDK4/6 inhibitor response in ER+ breast cancer.

Sucheta Telang, Brian F Clem, Ariamna A Herrera Miret, Leanne Price, Susan M Dougherty, Anna Schmitz, Xinmin Yin, Xipeng Ma, Xiang Zhang, Jason Chesney, Yoannis Imbert-Fernandez.

BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are widely used in the treatment of estrogen receptor-positive (ER⁺) breast cancer; however, the metabolic adaptations induced by CDK4/6 inhibition remain incompletely defined. In ER⁺ breast cancer, estrogen signaling plays a central role in coordinating cell cycle progression and metabolic programs that support tumor growth. Glycolytic flux is regulated at the level of phosphofructokinase-1 (PFK1) through the inducible enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which is transcriptionally regulated by estrogen receptor signaling and has been shown to promote glycolysis and proliferation in ER⁺ breast cancer cells. Yet, how CDK4/6 inhibition intersects with estrogen-regulated glycolytic control to rewire glucose utilization in ER⁺ breast cancer has not been explored.
METHODS: Glucose metabolism was assessed using extracellular flux analysis, untargeted metabolomics, and stable isotope tracing with uniformly labeled 13C-glucose in ER+ breast cancer cell lines. In vivo metabolic tracing was performed following bolus administration of [U-13C]-glucose. The effects of pharmacologic PFKFB3 inhibition, alone and in combination with CDK4/6 inhibitors, were evaluated in vitro and in patient-derived xenograft (PDX) models. Statistical analyses were performed using appropriate tests with correction for multiple comparisons where applicable.
RESULTS: CDK4/6 inhibition increased glycolytic flux, as evidenced by elevated basal and compensatory glycolysis, accumulation of early glycolytic intermediates, and increased 13C labeling of fructose 1,6-bisphosphate. PFKFB3 deficiency significantly attenuated the CDK4/6 inhibitor-induced increase in glycolytic flux. Despite increased glycolysis, stable isotope tracing revealed markedly reduced incorporation of glucose-derived carbon into nucleotide biosynthesis and lipid-associated metabolites, consistent with reduced anabolic demand during G1 cell cycle arrest. In vivo glucose tracing demonstrated a dissociation between increased glycolytic flux and downstream biosynthetic utilization. Pharmacologic inhibition of PFKFB3 imposed additional constraints on glucose utilization and significantly enhanced the antitumor efficacy of CDK4/6 inhibition in PDX models.
CONCLUSIONS: CDK4/6 inhibition rewires glucose metabolism in ER+ breast cancer by increasing glycolytic flux while limiting downstream glucose utilization, resulting in heightened reliance on regulated glycolytic control to maintain metabolic homeostasis during cell cycle arrest. Disruption of this adaptive metabolic state through PFKFB3 inhibition enhances the antitumor effects of CDK4/6 inhibition and supports the therapeutic potential of targeting glycolytic regulation in combination with CDK4/6 inhibitor-directed therapies.

Keywords: Breast cancer; CDK4/6 inhibitor; Estrogen receptor; Glucose metabolism; PFKFB3

DOI: https://doi.org/10.1186/s13058-026-02336-2

Int J Biol Sci. 2026 ;22(11): 6218-6236

Cancer-associated adipocytes confer CDK4/6 inhibitor resistance in ER+ breast cancer through an IL-6/STAT3/SREBF2 axis coupled with cholesterol metabolism and cell cycle reprogramming.

Renhong Huang, Yiwei Tong, Xi Sun, Haoyu Wang, Zheng Wang, Yujie Tang, Kunwei Shen, Xiaosong Chen.

Cancer-associated adipocytes (CAAs) within the tumor microenvironment (TME) critically regulate oncogenic progression. However, the mechanistic basis underlying CAAs-mediated CDK4/6 inhibitor (CDK4/6i) resistance in estrogen receptor-positive (ER+) breast cancer remains elusive. In this study, we revealed that CAAs supernatant demonstrated enhanced capacity to induce CDK4/6i resistance in ER+ breast cancer cells compared to NAs-derived conditioned medium. Through integrated RNA sequencing and cytokine microarray screening, we identified marked upregulation of IL-6 in both CAAs and their conditioned media. Mechanistically, CAAs-derived IL-6 activates the JAK-STAT3 axis, leading to transcriptional upregulation of SREBF2, which directly drives CDK4/6i resistance through HMGCR-mediated lipid metabolism and CDKN2C-mediated cell cycle progression (IL-6-STAT3-SREBF2-HMGCR/CDKN2C axis). Reciprocally, breast cancer cell-secreted exosomal miR-1246 promotes the transformation of normal adipocytes (NAs) to CAAs via PAX5-dependent regulation, and CAAs highly express UCHL1, which stabilizes KLF5 through K48-linked deubiquitination to activate NF-κB signaling, thereby augmenting IL-6 production (exosomal miR-1246-PAX5 and UCHL1-KLF5-NF-κB loop). Pharmacologic inhibition of HMGCR with simvastatin, alone or combined with IL-6 blockade, restored CDK4/6i sensitivity in vitro and in vivo, highlighting a clinically accessible strategy to overcome adipocyte-mediated resistance. Collectively, our findings establish that CAAs confer CDK4/6i resistance in ER+ breast cancer through the IL-6-driven SREBF2 activation axis, sustained by a reciprocal exosomal miR-1246/UCHL1-mediated feedback loop.

DOI: https://doi.org/10.7150/ijbs.130653

Oncol Res. 2026 ;34(7): 24

PARK2-Mediated PGK1 Degradation Suppresses Partial Epithelial-Mesenchymal Transition and Metastasis in Triple-Negative Breast Cancer.

Zhengzheng Li, Haitong Xie, Yujuan Chen, Qiuyan Li, Xing Yuan, Xinyue Dai, Jie Chen.

Objectives: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies. Phosphoglycerate kinase 1 (PGK1) drives TNBC progression, but mechanisms governing its protein stability remain unclear. This study aims to identify the E3 ubiquitin ligase responsible for PGK1 degradation and evaluate its therapeutic potential against metastasis. Methods: Clinical datasets and 50 human TNBC tissues were analyzed via multiplex immunohistochemistry. Co-immunoprecipitation, ubiquitination linkage assays, and structural modeling were utilized for in vitro mechanistic studies in TNBC cells. Additionally, functional impacts on epithelial-mesenchymal transition (EMT) and metastasis were evaluated using transwell assays and an in vivo mouse lung metastasis model. Results: Parkinson disease protein 2 (PARK2) is a novel E3 ubiquitin ligase that mediates proteasomal degradation of PGK1 in TNBC cells. Elevated PGK1 expression and reduced PARK2 expression in TNBC, with high PGK1 levels correlating with unfavorable overall survival (HR: 2.138, 95%CI:1.001 to 4.569, p = 0.049). PARK2 physically binds PGK1 via its RING2 domain and promotes K48-linked polyubiquitination, leading to proteasomal degradation. A significant negative correlation between PARK2 and PGK1 at the protein levels were confirmed in 50 TNBC tumor tissues (Spearman's rho = -0.58, p < 0.001). Functionally, PARK2 overexpression reduced mesenchymal markers (Vimentin, Snail1, Slug) and suppressed migration and invasion of TNBC cells, effects that were reversed by PGK1 overexpression. PARK2 significantly inhibited PGK1-mediated lung metastasis in in vivo tail vein injection models Conclusion: These findings establish the PARK2-PGK1 axis as a critical regulator of partial epithelial-mesenchymal transition and metastasis in TNBC, suggesting that strategies to enhance PARK2 expression or activity may represent promising therapeutic approaches for this aggressive breast cancer subtype.

Keywords: Parkinson disease protein 2 (PARK2); Triple-negative breast cancer (TNBC); epithelial-to-mesenchymal transition; metastasis; phosphoglycerate kinase 1 (PGK1); proteasomal degradation

DOI: https://doi.org/10.32604/or.2026.081209

J Proteome Res. 2026 Jun 24.

Hypoxia Remodels the Extracellular Vesicle Proteome to Drive Metastasis in Breast Cancer via Metabolic-Epigenetic Coupling.

Vaidehi Bhavsar, Ashish Sahu, Akhil Karandikar, Ravindra Taware.

This study investigates how hypoxia remodels the extracellular vesicle (EV) proteome to promote metastasis in breast cancer (BC) cells. EVs from hypoxic MCF-7 and MDA-MB-231 cells were characterized and shown to enhance epithelial-mesenchymal transition (EMT), migration, invasion, and clonogenicity in recipient cells. Quantitative proteomics identified over 1250 EV proteins, with 78 commonly regulated by hypoxia across both cell lines. Pathway analysis revealed hypoxia-induced EV enrichment of ribosomal, chromatin remodeling, mitochondrial, and one-carbon metabolism proteins, alongside depletion of immune-modulatory factors. Interestingly, key one-carbon metabolism enzymes (SMS, CAD, and AHCYL1) were consistently upregulated in hypoxic EVs shed by both the cell lines. Notably, AHCYL1, a regulator of the methylation cycle enzyme AHCY, is significantly upregulated under hypoxic conditions. Our findings demonstrate that hypoxic EVs promote an increase in histone H3K9 trimethylation levels in recipient cells. This epigenetic shift downregulated epithelial and metastasis-suppressor genes (CDH1, EpCAM, and DKK1) while sustaining expression of EMT transcription factors (ZEB1 and SNAIL), thereby stabilizing EMT and enhancing invasiveness. Collectively, we describe a hypoxia-driven EV proteome that links metabolic reprogramming to epigenetic enforcement of metastatic traits in BC.

Keywords: extracellular vesicles; hypoxia; label-free proteomic analysis; metastasis; proteomes

DOI: https://doi.org/10.1021/acs.jproteome.6c00146

Int J Breast Cancer. 2026 ;2026 2364200

The Role of Angiogenesis in Breast Cancer and Obesity: Unravelling the Connection.

Yolo O K Sikuza, Charlise Basson, Nanette Oberholzer, Melvin A Ambele.

Breast cancer remains one of the leading causes of cancer-related mortality amongst women worldwide, with rising incidence rates paralleling the global obesity epidemic. Obesity has been increasingly recognised as a risk factor for breast cancer, yet the molecular mechanisms underlying the association remain poorly understood. This review explores the role of angiogenesis as the central mechanism linking obesity to breast cancer progression. Angiogenesis is essential for both adipose tissue expansion and tumour growth. It is dysregulated in obesity and breast cancer, resulting in the formation of abnormal vasculature that perpetuates hypoxia and malignancy. Obesity contributes to this process through hypertrophic adipose tissue, altered adipokine profiles and elevated expression of proangiogenic factors, such as VEGF. These changes create a tumour microenvironment conducive to cancer progression, treatment resistance and poor clinical outcomes. Emerging evidence also implicates endothelial cells, pericytes and lipid metabolism in this interaction, suggesting novel therapeutic targets.

Keywords: VEGF; angiogenesis; breast cancer; endothelial cells; hypoxia; obesity

DOI: https://doi.org/10.1155/ijbc/2364200

Biomolecules. 2026 Jun 11. pii: 856. [Epub ahead of print]16(6):

Small Molecule Liver X Receptor Modulator GAC0001E5 Targets Mechanisms of Endocrine Resistance in Estrogen Receptor-Positive Breast Cancer Cells.

Shinjini Basu, Asitha Premaratne, Scott Widmann, Esther A Olaleye, Chin-Yo Lin.

Endocrine therapy is an effective and common treatment strategy for estrogen receptor (ER)-positive breast cancers. However, the development of endocrine resistance, through genetic mutations and epigenetic alterations, in about 40% of treated patients remains a significant therapeutic challenge. Liver X receptors (LXRs) are nuclear receptors that regulate lipid metabolism and cholesterol homeostasis and have been implicated in metabolic reprogramming in breast cancers and other malignancies. We previously identified a novel LXR ligand GAC0001E5 (1E5), with potent antiproliferative activity across breast cancer subtypes. Here, we investigate its mechanisms of action in responsive (MCF-7) and endocrine-resistant (MCF-7-TamR) ER-positive breast cancer cells. Treatment with 1E5 resulted in the downregulation of LXR and its target genes, and significantly reduced ERα expression and the expression of ER-responsive genes. Aberrant expression of androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2), both implicated in endocrine resistance, were downregulated following 1E5 treatment. siRNA-mediated knockdown of LXR expression only partially recapitulated the actions of 1E5, suggesting the involvement of LXR-dependent and independent mechanisms. Collectively, these findings reveal potential crosstalk between LXR and the genetic and epigenetic regulation of pathways involved in endocrine response and alternative signaling mechanisms, highlighting potential targets in endocrine-resistant breast cancer.

Keywords: breast cancer; endocrine resistance; estrogen receptor; liver X receptor

DOI: https://doi.org/10.3390/biom16060856