bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–02–15
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. KDM5B cooperates with CRL4B complex to promote the tumorigenesis of ER+ breast cancer via regulating cholesterol metabolism.
  2. LDHB Deficiency in Fibroblasts Induces Lactate-Mediated Inflammatory Reprogramming that Promotes Breast Cancer Metastasis.
  3. The preliminary study on the effect of PSEN1 on the proliferation and invasion of breast cancer cells.
  4. Tamoxifen promotes metastasis of breast cancer via reshaping lipid-driven fibrotic microenvironments in the lung.
  5. Association of METTL14 expression with prognosis and immunotherapy in breast cancer.
  6. Dual Targeting of IDH2 and the Ubiquitin-Proteasome System Reveals a Functional Vulnerability in Breast Cancer Models.
  7. FGFR4 and HER2 co-expression is associated with the proinflammatory tumor microenvironment in HR + breast cancer.
  1. Cell Death Dis. 2026 Feb 07. 17(1): 207
    KDM5B cooperates with CRL4B complex to promote the tumorigenesis of ER+ breast cancer via regulating cholesterol metabolism.
    Yunkai Yang, Tianyang Gao, Baowen Yuan, Xinhui Hao, Miaomiao Huo, Ting Hu, Tianyu Ma, Min Zhang, Die Zhang, Xu Teng, Hefen Yu, Wei Huang, Jingyao Zhang, Yan Wang.
      Estrogen receptor-positive (ER+) breast cancer is the predominant subtype of breast cancer, and its development is closely linked to metabolic reprogramming, including alterations in cholesterol metabolism. Therefore, this study aimed to investigate the functional interplay between lysine demethylase 5B (KDM5B) and the Cullin-RING ligase 4B (CRL4B) complex in modulating cholesterol metabolism to promote ER+ breast cancer progression. Immunohistochemical assays and bioinformatic analysis of various cancer databases were performed to examine KDM5B expression levels in breast cancer. Additionally, KDM5B overexpression and knockdown were performed to investigate the role of KDM5B in breast cancer cell proliferation and progression. Notably, we identified physical and functional interactions between KDM5B and the CRL4B subunits, CUL4B and DDB1. Mechanistically, KDM5B recruits CRL4B to the promoters of INSIG1 and INSIG2, which are key regulators of cholesterol biosynthesis and uptake, and suppresses their expression by upregulating H2AK119ub1 and downregulating H3K4me3 histone marks, thereby promoting the proliferation, migration, and invasion of tumor cells. Functional assays revealed that disruption of the KDM5B-CRL4B axis impairs cholesterol homeostasis and inhibits tumor growth. KDM5B upregulation was significantly negatively correlated with the survival rates in various cancer types, including thyroid, lung, esophageal and colorectal cancers. Overall, these findings establish a novel regulatory axis in cholesterol metabolism, uncover potential therapeutic vulnerabilities in ER+ breast cancer, and suggest that targeting the KDM5B could provide a strategy to curb tumor progression.
    DOI:  https://doi.org/10.1038/s41419-026-08438-1
  2. Cancer Res. 2026 Feb 13.
    LDHB Deficiency in Fibroblasts Induces Lactate-Mediated Inflammatory Reprogramming that Promotes Breast Cancer Metastasis.
    Zhihong Luo, Kangdi Li, You Yu, Yi Liu, Hong Weng, Xian-Tao Zeng, Yi Zheng, Wenhua Li.
      Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and often undergo metabolic reprogramming. Metabolic shifts within CAFs can influence cancer cell behavior. In this study, we revealed that the loss of lactate dehydrogenase B (LDHB) in CAFs drives a metabolic shift that significantly enhances breast cancer metastasis. LDHB loss in CAFs drove a shift towards an inflammatory fibroblast phenotype. Mechanistically, LDHB deficiency led to lactate accumulation, which disrupted the interaction between dual specificity phosphatase 16 (DUSP16) and p38, causing sustained p38 activation. Persistent p38 signaling reprogrammed CAFs into an inflammatory phenotype characterized by abundant secretion of the chemokine CXCL8, which in turn enhanced metastasis of breast cancer cells. In summary, these findings identify LDHB as a key metabolic regulator in CAFs and provide insights into how metabolic reprogramming promotes the inflammatory, pro-metastatic phenotype of CAFs, highlighting activating LDHB as a potential strategy for limiting cancer metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2792
  3. Transl Breast Cancer Res. 2026 ;7 6
    The preliminary study on the effect of PSEN1 on the proliferation and invasion of breast cancer cells.
    Miao Yang, Jia-Qun Zou, Wei Yang.
       Background: Breast cancer is the most common form of cancer among women, and PSEN1 dysfunction is a primary contributor to the pathogenesis of Alzheimer's disease. However, the involvement of PSEN1 in breast cancer remains unclear. This study was conducted to explore the function and related mechanisms of PSEN1 in breast cancer cells.
    Methods: The correlation between two genes was determined utilizing the R2 platform, and the association between gene expression and prognosis was analyzed employing the Kaplan-Meier plotter. The expression of PSEN1 in breast cancer was assessed by in immunofluorescence. The Transwell assay was employed to detect the migration and invasion capabilities of cells. Colony formation and EdU staining were employed to evaluate the effects of PSEN1 on breast cancer cell proliferation.
    Results: We observed a positive correlation between the expression of PSEN1 and the prognosis of breast cancer patients. After manipulated the expression of PSEN1 in breast cancer cell lines Sum159 and BT549, we found that PSEN1 could inhibit cell proliferation and growth in breast cancer through colony formation assays and EdU staining. Meanwhile, we revealed that interference with the cell cycle by PSEN1 was associated with cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CKIs) in breast cancer samples. Furthermore, we observed that an increase in PSEN1 expression inhibited the invasive capabilities of breast cancer cells, while a decrease in PSEN1 expression enhanced invasion in both Sum159 and BT549 cell lines. Lastly, we discovered a negative correlation between PSEN1 and epithelial-to-mesenchymal transition (EMT) transcription factors as well as markers in breast cancer patients.
    Conclusions: Our study demonstrates that PSEN1 inhibits the invasion and proliferation of breast cancer cells, suggesting that PSEN1 could potentially serve as a prognostic biomarker and a novel therapeutic target for patients with breast cancer.
    Keywords:  Breast cancer; PSEN1; cell cycle; invasion; proliferation
    DOI:  https://doi.org/10.21037/tbcr-25-42
  4. Neoplasia. 2026 Feb 09. pii: S1476-5586(26)00015-1. [Epub ahead of print]73 101286
    Tamoxifen promotes metastasis of breast cancer via reshaping lipid-driven fibrotic microenvironments in the lung.
    Seung-Su Kim, Seungchan An, Sewon Hwang, Hae-Min Kwon, Ga Young Lim, Na-Lee Ka, Minsoo Noh, Mi-Ock Lee.
      Patients with estrogen receptor (ER)-positive breast cancer (BC) remain at risk of distant recurrence for up to 20 years after diagnosis, with an overall recurrence rate of approximately 30%. Although tamoxifen is a cornerstone of endocrine therapy, its long-term effects on metastatic niche formation remain poorly defined. Here, we investigated the impact of long-term tamoxifen treatment on metastatic niche formation. Using PyMT and 4T1 allograft mouse models, we found that tamoxifen increased lung metastasis, despite reduced or unchanged primary tumor size. Lungs from tamoxifen-treated mice exhibited fibrotic features, such as collagen deposition, increased airway wall thickness, and altered expression levels of fibrosis-associated proteins. These changes were accompanied by elevated neutral lipid levels and upregulation of lipid metabolism-related genes. Single-cell RNA sequencing (scRNA-seq) revealed an expansion of a macrophage subpopulation enriched for lipid metabolic gene signatures and exhibiting strong interaction with fibroblasts via TGFβ signaling. Immunofluorescence and flow cytometry further demonstrated an increased number of PRG4+ macrophages in the lungs of tamoxifen-treated mice. Importantly, inhibition of lipid accumulation with the fatty acid synthase inhibitor C75 reduced PRG4+ macrophage numbers, attenuated fibrosis, and suppressed lung metastasis. Together, these findings implicate long-term tamoxifen treatment as a potential risk factor for lung metastasis in ER-positive BC by disrupting the lung microenvironment, and suggest that targeting lipid metabolism may represent a therapeutic strategy to limit metastatic progression, particularly in the lung.
    Keywords:  Breast cancer metastasis; Lipid metabolism; Lung fibrosis; PRG4+ macrophage; Tamoxifen
    DOI:  https://doi.org/10.1016/j.neo.2026.101286
  5. Transl Cancer Res. 2026 Jan 31. 15(1): 45
    Association of METTL14 expression with prognosis and immunotherapy in breast cancer.
    Junbo Hu, Zhen Wang, Yanju Lu, Zhen Wei, Lindan Dong, Yuxia Li, Honglin Yan, Na Tang.
       Background: Methyltransferase-like 14 (METTL14) is recognized as a key factor in the advancement and progression of breast cancer (BC). While its involvement in this context is acknowledged, many aspects of METTL14's functions remain unclear. We aimed to explore the function and potential mechanism of METTL14 in BC.
    Methods: The level of METTL14 in BC cell lines and tissues was evaluated using quantitative real-time polymerase chain reaction, immunohistochemistry, and western blotting methods. The cell counting kit-8 (CCK-8) assay, wound healing assay, and transwell chamber assay were employed to investigate the biological functions of METTL14 in BC. The relationship between immune characteristics and METTL14 was analyzed using the Tumor Immune Estimation Resource (TIMER) and Tumor-Immune System Interaction Database (TISIDB). The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict immunotherapy response of BC patients. Multiplex immunofluorescence (mIF) was used to evaluate the expression of eight candidate markers of immune cell subsets and checkpoints in BC samples. Furthermore, a Kaplan-Meier survival analysis was performed to assess the prognostic significance of METTL14 in BC.
    Results: Our study revealed a significant downregulation of METTL14 in BC tissues. The reduced expression of METTL14 was found to be associated with tumor progression, unfavorable recurrence-free survival (RFS) outcomes, and advanced tumor stages. Furthermore, METTL14 expression exhibited a positive correlation with the abundance of CD8+ T cells, CD4+ T cells, macrophages, and mast cells, while a negative correlation was observed with the abundance of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, and follicular helper T cells, as determined through immune analysis. METTL14 downregulation is associated with an immunosuppressive tumor microenvironment (TME), potentially through the upregulation of certain immunosuppressive factors. Results from mIF confirmed that low METTL14 expression correlates with high programmed death-1 (PD-1) expression. The analysis using the TIDE algorithm indicated that METTL14 expression was primarily negatively associated with the response to immunotherapy.
    Conclusions: METTL14 demonstrates significant predictive value regarding prognosis in BC. The METTL14 has the potential to serve as a predictive biomarker and a promising target for immunotherapy.
    Keywords:  Breast cancer (BC); CD4+ T cells; immunotherapy; methyltransferase-like 14 (METTL14); tumor microenvironment (TME)
    DOI:  https://doi.org/10.21037/tcr-2025-1331
  6. Cancers (Basel). 2026 Jan 24. pii: 368. [Epub ahead of print]18(3):
    Dual Targeting of IDH2 and the Ubiquitin-Proteasome System Reveals a Functional Vulnerability in Breast Cancer Models.
    Nariman Gharari, Elisabetta Mereu, Beatrice Luciano, Bahareh Heidari, Sylvie Mader, Roberto Piva.
      Background/Objectives: Breast cancer cells rely on both mitochondrial metabolism and proteostatic mechanisms for cell fitness. The mitochondrial enzyme IDH2 supports redox balance and biosynthesis, while the ubiquitin-proteasome system (UPS) preserves protein quality. This study aimed to determine whether inhibiting IDH2 enhances sensitivity to proteasome-targeting agents across breast cancer subtypes. Methods: A panel of human and murine breast cancer cell lines was treated with the IDH2 inhibitor AGI-6780, alone or in combination with the proteasome inhibitor carfilzomib (CFZ) or the E1 ubiquitin-activating enzyme inhibitor TAK-243. Synergy was evaluated using Bliss scoring. Apoptosis, clonogenicity, and pathway modulation were assessed through Western blotting, colony-formation assays, and reverse-phase protein array (RPPA) profiling. Results: We observed that co-targeting IDH2 and the UPS produced strong synergistic cytotoxicity in multiple breast cancer models, including in triple-negative MDA-MB-231 and 4T1 cells (Bliss > 25). Combination treatments led to pronounced apoptosis, evidenced by cleaved PARP-1 and Caspase-3 cleavage, and a marked loss of clonogenic potential. RPPA analysis revealed significant alterations in key survival and stress-response pathways, including NF-κB, PI3K-p85, Src, and p38-MAPK. Conclusions: Inhibition of IDH2 markedly enhances the cytotoxic effects of proteasome-targeting by disrupting metabolic-proteostatic balance and promoting apoptotic cell death. These findings identify a growth-inhibitory effect that may be leveraged to improve functional dependency in breast cancer, particularly in triple-negative breast cancer, which currently lacks efficient drug treatments.
    Keywords:  IDH2 inhibition; breast cancer; combinatorial treatment; functional synergy; proteasome inhibitors
    DOI:  https://doi.org/10.3390/cancers18030368
  7. Breast Cancer. 2026 Feb 11.
    FGFR4 and HER2 co-expression is associated with the proinflammatory tumor microenvironment in HR + breast cancer.
    Yike Gao, Longyun Chen, Fei Yao, Jin Wang, Changbin Zhu, Shafei Wu, Zhiyong Liang.
       BACKGROUND: Dysregulated FGFR4 signaling has been associated with aggressive subtypes of breast cancers, characterized by HER2 enrichment or endocrine resistance. However, the biological functions of FGFR4 across breast cancer subtypes remain unclear. This study investigated the molecular characteristics of FGFR4-high tumors to inform potential therapeutic strategies.
    METHODS: This study analyzed clinicopathological characteristics and gene expression profile of 53 hormone receptor-positive (HR+) and 41 HR-negative (HR-) patients using the AmoyDx Master Panel. The results were validated using The Cancer Genome Atlas (TCGA) and single-cell RNA-seq datasets.
    RESULTS: The patients in the PUMCH cohort (n = 94) were stratified by HER2 and HR statuses and further stratified according to FGFR4 expression. FGFR4-high tumors showed no genomic differences but enriched immune activation pathways, specifically in HR+HER2-low/positive subgroups. HR+ tumors with co-expression of FGFR4 and HER2 exhibited increased immune infiltration (T cells, NK cells, M1 macrophages) and upregulated checkpoints (BTLA, CTLA4, HAVCR2, LAG3). Single-cell data confirmed elevated T-cell abundance in HR+HER2-high FGFR4-high cases. TCGA analysis linked high FGFR4 to prolonged disease-free survival (DFS) in HR+HER2-positive patients but reduced DFS in HR+HER2-zero patients.
    CONCLUSIONS: Co-expression of FGFR4 and HER2 is associated with a proinflammatory tumor microenvironment in HR+ breast cancer, suggesting immunotherapy potential. Further studies should explore therapeutic strategies to reshape the tumor immune microenvironment.
    Keywords:   FGFR4 ; Breast cancer; Hormone receptor; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12282-026-01833-8
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