bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–11–09
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. LSR overexpression induces chemoresistance in triple negative breast cancer cells through MDR1 upregulation and apoptosis attenuation.
  2. SERPINA1 gene regulates the tumorigenesis and progression of breast cancer through PI3K/AKT signaling pathway and tumor immune microenvironment.
  3. RANBP1 promotes immune evasion in triple-negative breast cancer by suppressing T cell infiltration via the miR-769-5p/PRUNE2 axis.
  4. Loss of Nuclear Profilin 1 Triggers Oncogenic Reprogramming of Mammary Epithelial Cells Through Dysregulated DNA Replication in Breast Cancer.
  5. LINC02159 modulated the glycolysis and proliferation of TNBC cell via targeting miR-1285-3p/G6PI axis.
  6. Serotonin promotes aggressive features in breast cancer cells by modulating proliferation and migration, hormone receptors and HER2 expression.
  7. Exosomal miR-155-5p Modulates Breast Cancer Proliferation and Metastasis Via NF-κB Activation.
  1. PLoS One. 2025 ;20(11): e0336124
    LSR overexpression induces chemoresistance in triple negative breast cancer cells through MDR1 upregulation and apoptosis attenuation.
    Ming Zhao, Zhikun Ma, Amanda B Parris, Xiaohe Yang.
      Chemoresistance in breast cancer therapy, especially for triple negative breast cancer (TNBC) remains a significant challenge. Recent studies showed that overexpression of lipolysis-stimulated lipoprotein receptor (LSR), known as a tricellular tight-junction protein, was detected in TNBC and MDR1 was among LSR upregulated genes in a screening assay but its functional impact has not been studied. This study aimed to characterize LSR overexpression-induced regulation of MDR1 in TNBC cells focusing on chemoresistance. LSR was overexpressed in MDA-MB-231 cells and knocked-out via CRISPR/Cas9 in MDA-MB-468 cells for functional studies. Chemoresistance of individual cell lines was evaluated with doxorubicin treatment, followed by cell proliferation, invasion, colony formation and apoptosis assays. Modulated protein and mRNA levels of specific genes were assessed with Western blotting and RT-qPCR. MDR1 inhibitor verapamil and MDR1-targeted siRNA were used to evaluate the functional impact of LSR-induced MDR1. Overexpression of LSR not only promotes cell proliferation and invasion in MDA-MB-231 cells, but also renders the cells resistant to doxorubicin. LSR induces MDR1 expression at both mRNA and protein levels. Moreover, inhibition of MDR1 with specific inhibitor verapamil or MDR1 knockdown reversed cellular resistance to doxorubicin in LSR-overexpressing MDA-MB-231 cells. In contrast, knockout of LSR expression in MDA-MB-468 cells, which express higher levels of LSR, significantly sensitized the cells to doxorubicin-induced growth inhibition and apoptosis. Our data demonstrated that LSR overexpression promotes TNBC cell proliferation and invasion, and upregulation of MDR1 in these cells renders them resistant to doxorubicin, suggesting that targeting LSR could be a useful strategy to overcome chemoresistance in TNBC.
    DOI:  https://doi.org/10.1371/journal.pone.0336124
  2. Sci Rep. 2025 Nov 06. 15(1): 38901
    SERPINA1 gene regulates the tumorigenesis and progression of breast cancer through PI3K/AKT signaling pathway and tumor immune microenvironment.
    Chuqi Lei, Wei Lu, Yuan Li, Huaiyu Yang, Ke Zhang, Nianchang Wang, Lixue Xuan, Changyuan Guo.
      This study aims to reveal the influence of SERPINA1 gene on the development, prognosis evaluation and immune environment changes of breast cancer. Cell lines with differential SERPINA1 expression were constructed. These models were used to explore its impact on the biological behavior of breast cancer cells. The expression of SERPINA1 in breast tumor tissues of patients undergoing surgery in our hospital was detected by immunohistochemistry to evaluate the regulatory effect of SERPINA1 gene on tumor microenvironment. The results found that the overexpression of SERPINA1 gene could significantly inhibit the proliferation and migration of breast cancer cells and promote apoptosis. Transcriptome sequencing analysis revealed that SERPINA1 may regulate the biological behavior of cells by affecting biological functional pathways such as adaptive immune response, natural killer cell-mediated cytotoxicity, and phosphatidylinositol signaling system1. Western blot analysis showed that SERPINA1 overexpression was accompanied by an increase in PTEN expression and a decrease in Akt and mTOR phosphorylation levels, suggesting a molecular mechanism by which SERPINA1 gene and PTEN cooperate to negatively regulate the passage of PI3K. In addition, the high expression of SERPINA1 is related to the recruitment of regulatory T cells (Treg) in breast cancer tissues, which may change the tumor microenvironment.
    Keywords:  Breast cancer; PI3K/AKT; SERPINA1 gene; Tumor immune microenvironment
    DOI:  https://doi.org/10.1038/s41598-025-22658-z
  3. Discov Oncol. 2025 Nov 04. 16(1): 2026
    RANBP1 promotes immune evasion in triple-negative breast cancer by suppressing T cell infiltration via the miR-769-5p/PRUNE2 axis.
    Pengxia Song, Xianglin Liu, Huiping Qiu, Yanhui Cao, Jie Liu, Xin Zheng, Shuihong Yao, Meng Cao.
       BACKGROUND: T cell dysfunction in the tumor microenvironment (TME) is a major obstacle to effective immunotherapy in triple-negative breast cancer (TNBC). The molecular mechanisms underlying T cell exclusion remain poorly understood.
    PURPOSE: This study identifies RANBP1 as an oncogenic factor in TNBC and investigates its role in modulating T cell infiltration and tumor progression.
    METHODS: Single-cell and bulk RNA sequencing were used to assess immune cell infiltration associated with RANBP1 expression. RANBP1 protein levels were evaluated in 87 TNBC tumor and adjacent normal tissues by immunohistochemistry. Kaplan-Meier analysis was used to assess overall survival. In vitro and in vivo assays were performed to explore the RANBP1/miR-769-5p/PRUNE2 pathway.
    RESULTS: scRNA-seq identified 10 cell types in the TNBC TME. High RANBP1 expression correlated with increased tumor cells, B cells, macrophages, and epithelial cells, and reduced T cells. Cell-cell communication was enhanced in the high-RANBP1 group. TCGA and GSE65194 data confirmed decreased CD4⁺ T cells and Tregs in high-RANBP1 tumors. RANBP1 was significantly upregulated in TNBC and associated with poor prognosis. Functional studies showed that RANBP1 promotes TNBC cell proliferation and migration. Mechanistically, RANBP1 upregulates oncogenic miR-769-5p, which suppresses PRUNE2, a tumor suppressor that normally inhibits TNBC progression.
    CONCLUSIONS: RANBP1 shapes an immunosuppressive microenvironment in TNBC by reducing T cell infiltration through the miR-769-5p/PRUNE2 axis. These findings reveal a novel immune escape mechanism and suggest that targeting RANBP1 may enhance immunotherapy efficacy in TNBC.
    Keywords:  Breast cancer (BC); Motility; PRUNE2; RANBP1; Tumorigenesis; miR-769-5p
    DOI:  https://doi.org/10.1007/s12672-025-03872-7
  4. J Breast Cancer. 2025 Oct;28(5): 333-346
    Loss of Nuclear Profilin 1 Triggers Oncogenic Reprogramming of Mammary Epithelial Cells Through Dysregulated DNA Replication in Breast Cancer.
    Zheng Zhao, Yingbin Huang, Junhao Mai, Fei Cao, Qi Fang, Di Wu, Ziqian Li, Xuekui Liu.
       PURPOSE: Profilin 1 (Pfn1) has been implicated in cytoskeletal regulation; however, its role in breast cancer progression and DNA replication remains unclear. This study investigated the functional significance of Pfn1 nuclear-cytoplasmic shuttling in breast cancer.
    METHODS: We analyzed Pfn1 expression and its correlation with DNA replication, repair, and oncogenic markers in breast cancer cell lines. Chromatin-bound and soluble Pfn1 levels were quantified by western blotting. The effects of nuclear (nuclear localization sequence-Pfn1) and cytoplasmic (nuclear export sequence-Pfn1) localization on cell growth, DNA replication, and stemness were assessed using colony formation, Alamar blue fluorescence, replication protein A 32-kDa foci staining, and DNA fiber assays. Mouse xenografts of breast cancer cells were used to determine the effect of Pfn1 localization on tumor growth in vivo. We identified the direct interactors of nuclear Pfn1 by immunoprecipitation, and their affinity was determined using bio-layer interferometry.
    RESULTS: Pfn1 expression was positively correlated with DNA replication, repair, p53, and MYC expression. Chromatin-bound Pfn1 was significantly degraded in breast cancer cell lines compared to that in non-cancerous MCF10a cells. Nuclear Pfn1 inhibited cell growth and DNA replication in SKBR3 cells, while cytoplasmic Pfn1 promoted cell survival and DNA replication in MCF10a cells. Loss of nuclear Pfn1 in SKBR3 cells inhibited their growth in vivo. Additionally, cytoplasmic Pfn1 upregulated stemness markers (c-Myc, B lymphoma Mo-MLV insertion region 1, and Nijmegen breakage syndrome 1). Pfn1 regulated cell stemness by binding to the nucleosome remodeler sucrose non-fermenting 2 homolog.
    CONCLUSION: Our findings revealed that nuclear Pfn1 acts as a tumor suppressor by inhibiting DNA replication and cell growth, while cytoplasmic Pfn1 promotes tumorigenesis by enhancing stemness and replication efficiency. These results highlight the dual role of Pfn1 in breast cancer progression, governed by its subcellular localization. They suggested that modulating Pfn1 nuclear-cytoplasmic shuttling may be a potential therapeutic strategy.
    Keywords:  Breast Neoplasms; Carcinogenesis; DNA Replication; Profilins
    DOI:  https://doi.org/10.4048/jbc.2025.0079
  5. Sci Rep. 2025 Nov 03. 15(1): 38344
    LINC02159 modulated the glycolysis and proliferation of TNBC cell via targeting miR-1285-3p/G6PI axis.
    Xiaoyan Zhao, Ruilin Zheng, Xingxing Wu, Yating Hao, Qiangqiang Xie, Xiangdong Bai.
      As a leading cause of cancer-related fatalities among women, triple negative breast cancer (TNBC) still remains a clinical challenge. Increasing evidence points to long non-coding RNAs (lncRNAs) as significant regulators in its progression. The aim of this study is to investigate the function and working mechanism of LINC02159 in TNBC. The expression of LINC02159 in TNBC tissues and cells was detected by RT-qPCR analysis. Regulation of LINC02159 on TNBC is determined by the in vitro proliferation and migration assay. Binding of LINC02159 with the targets was tested by the luciferase reporter assay. The function of LINC02159 in the glycolysis of TNBC cells was evaluated via detecting the glucose uptake and lactate production. Our study identified that LINC02159 is overexpressed in TNBC tissues and correlates with decreased overall survival in patients. Functionally, silencing LINC02159 reduced TNBC cell proliferation and migration in vitro and suppressed the tumor growth in vivo. By acting as a competing endogenous RNA (ceRNA), LINC02159 directly engaged with miR-1285-3p to increase the expression of Glucose-6-phosphate isomerase (G6PI). In line with G6PI's role in glycolysis, reducing LINC02159 expression decreased glucose uptake and lactate production in TNBC cells. Restoring G6PI greatly reversed the impact of LINC02159 silencing on the proliferation and glycolysis of TNBC cells. These results demonstrated that LINC02159 drives the aerobic glycolysis and TNBC progression via modulating the miR-1285-3p/G6PI axis, and it might act as a potential target for TNBC anti-tumor therapy.
    Keywords:  G6PI; Glycolysis; LINC02159; TNBC; miR-1285-3p
    DOI:  https://doi.org/10.1038/s41598-025-22197-7
  6. Mol Cell Endocrinol. 2025 Oct 31. pii: S0303-7207(25)00243-6. [Epub ahead of print] 112692
    Serotonin promotes aggressive features in breast cancer cells by modulating proliferation and migration, hormone receptors and HER2 expression.
    Larissa Pereira Paixão, José Xavier do Nascimento Junior, Maria Eduarda Sant'Ana Faria Do Espírito Santo, Ricardo Imbroisi Filho, João Gabriel Bernardo Leandro, Davi Mundim, Jessica Ristow Branco, Luis Eduardo Santos, Sérgio T Ferreira, Luciana Pizzatti, Mauro Sola-Penna, Patricia Zancan.
      Serotonin (5-HT), a key regulator of epithelial homeostasis, plays a paradoxical role in breast cancer progression. This study investigates the impact of 5-HT signaling on hormone receptor expression, cell proliferation, therapeutic response, and tumor aggressiveness in breast cancer cells. We demonstrate that 5-HT activates transcriptional factors in MCF-7 cells, collectively enhancing cancer hallmarks such as sustained proliferation and invasiveness. Notably, 5-HT downregulates mRNA expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, inducing a phenotype reminiscent of triple-negative breast cancer. Despite these phenotypic changes, acute 5-HT treatment does not impair the effectiveness of tamoxifen in vitro. In vivo, administration of fluoxetine, a selective serotonin reuptake inhibitor, accelerates tumor growth and increases malignancy in a murine model. These findings underscore the ability of 5-HT to reprogram hormone receptors expression profiles and to promote a more aggressive cancer phenotype.
    Keywords:  EMT; SSRI; breast cancer; fluoxetine; serotonin
    DOI:  https://doi.org/10.1016/j.mce.2025.112692
  7. J Biochem Mol Toxicol. 2025 Nov;39(11): e70542
    Exosomal miR-155-5p Modulates Breast Cancer Proliferation and Metastasis Via NF-κB Activation.
    Rui Xu, Chen-Xu Guo, Jun Qian, Fa-Xiang Yin, Ming-Liang Zhang.
      Breast cancer (BC) represents a major contributor to cancer-associated deaths among women, underscoring the need for novel therapeutic approaches. This study explores the role of miR-155-5p as an oncogenic driver in BC progression through a multi-omics approach. Elevated miR-155-5p expression was observed in serum exosomes and tumor tissues, with its upregulation correlating with advanced pathological stages, lymph node metastasis, and unfavorable clinical outcomes. Functional experiments demonstrated that miR-155-5p enhances cellular proliferation, motility, and invasive capacity while inhibiting apoptosis in BC. Mechanistically, miR-155-5p exerts its effects by directly suppressing Nedd4 Family Interacting Protein 1 (NDFIP1), thereby initiating activation of the NF-κB axis. This activation was characterized by increased nuclear translocation of NF-κB p65 and enhanced secretion of inflammatory cytokines, including IL-6 and TNF-α. In vivo, knockdown of miR-155-5p effectively suppressed tumor growth and metastasis, with these effects reversed by silencing NDFIP1. These results highlight the miR-155-5p/NDFIP1/NF-κB axis as a critical pathway in BC progression, providing new insights into its molecular mechanisms. miR-155-5p emerges as a promising diagnostic marker and therapeutic candidate, suggesting the feasibility of miRNA-based interventions in BC treatment. This study highlights the pivotal role of integrative omics technologies in uncovering cancer-related regulatory networks.
    Keywords:  Nedd4 Family Interacting Protein 1; Nuclear Factor‐kappa B Signaling Pathway; breast cancer; miR‐155‐5p; multi‐omics analysis
    DOI:  https://doi.org/10.1002/jbt.70542
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