bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–09–21
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. TRIM21-mediated ubiquitination of SIX2 attenuates breast cancer stemness via LGSN suppression.
  2. CLDN6 induces chemoresistance through protective autophagy in breast cancer.
  3. Microglial TBK1 Signaling Promotes Breast Cancer Brain Metastasis.
  4. Loss of estrogen receptor alpha promotes distant metastasis through epithelial-mesenchymal transition in luminal-type breast cancer.
  5. PNO1 served as a potential biomarker to promote the stemness and progression of breast cancer via the NF-κB signaling pathway.
  6. Targeting the tumor microenvironment in triple-negative breast cancer: Biological insights and therapeutic opportunities.
  1. Oncogene. 2025 Sep 15.
    TRIM21-mediated ubiquitination of SIX2 attenuates breast cancer stemness via LGSN suppression.
    Haitao Chen, Yi Zhou, Yunnan Zhang, Yannan Fan, Lufeng Zheng, Qianqian Guo.
      Breast cancer stem cells (BCSCs) are pivotal drivers of breast tumor initiation, metastasis, and therapy resistance. Our previous studies identified the transcription factor SIX2 as a key regulator in maintaining breast cancer stemness. Here, we demonstrate that TRIM21, as an E3 ubiquitin ligase downregulated in breast cancer tissues, binds to SIX2 via its PRY-SPRY domain and catalyzes K48-type ubiquitination at lysine residues K82, K89, and K97. This modification promotes the degradation of SIX2 via the ubiquitin-proteasome pathway, consequently attenuating the stemness and metastatic potential of breast cancer cells. Furthermore, SIX2 transcriptionally activates LGSN expression through direct binding to its promoter region, thereby promoting the stemness and metastatic capabilities of breast cancer cells. Clinically, elevated expression of both SIX2 and LGSN correlates with poor prognosis in breast cancer patients. These results establish that TRIM21-mediated degradation of SIX2 suppresses LGSN expression, ultimately inhibiting the stemness and metastatic abilities of breast cancer cells, underscoring the critical regulatory role of the TRIM21-SIX2-LGSN axis in breast cancer progression.
    DOI:  https://doi.org/10.1038/s41388-025-03572-0
  2. Int J Biol Sci. 2025 ;21(12): 5444-5459
    CLDN6 induces chemoresistance through protective autophagy in breast cancer.
    Huinan Qu, Qiu Jin, Mingzi Zhang, Da Qi, Minghao Sun, Yuan Dong, Chengshi Quan.
      Protective autophagy, a defensive response of cancer cells to chemotherapeutic stress, plays a critical role in the development of chemoresistance. Our previous research has demonstrated that the tight junction protein Claudin-6 (CLDN6) can induce autophagy and chemoresistance respectively. However, it remains unclear whether CLDN6 triggers protective autophagy under chemotherapeutic conditions. In this study, we focused on the role and mechanism of CLDN6 in inducing protective autophagy and promoting chemoresistance in breast cancer. We found that CLDN6 promoted chemoresistance by inducing protective autophagy in response to adriamycin (ADM) and paclitaxel (PTX). Mechanistically, CLDN6 interacted with LKB1 through its PDZ-binding motif, leading to the activation of AMPK/ULK1 signaling and subsequent promotion of protective autophagy. Notably, we discovered that chemotherapy increased CLDN6 expression through the reactive oxygen species (ROS)/GATA4 axis. Our results suggest that CLDN6 plays a pivotal role in breast cancer chemoresistance through protective autophagy, highlighting its potential as a therapeutic target to improve treatment outcomes of breast cancer patients.
    Keywords:  CLDN6; LKB1; breast cancer; chemoresistance; protective autophagy
    DOI:  https://doi.org/10.7150/ijbs.116340
  3. Cancer Res. 2025 Sep 18.
    Microglial TBK1 Signaling Promotes Breast Cancer Brain Metastasis.
    Fatima Khan, Edgar Petrosyan, Yang Liu, Atousa Bahrami, Erfan Taefi, Changiz Geula, Maciej S Lesniak, Peiwen Chen.
      Breast cancer brain metastasis (BCBM) is the most common and lethal form of brain tumor, marked by abundant infiltration of tumor-associated microglia (TAMG). TAMG can promote the seeding and growth of metastatic breast cancer cells, highlighting the need to elucidate the molecular mechanisms underlying their function to enable development of effective strategies to target TAMG in BCBM. Here, using tumor samples from BCBM patients and mouse models, and in vitro microglia culture systems, we demonstrated that TANK-binding kinase 1 (TBK1) signaling is enriched and activated in TAMG. TBK1 inhibition in TAMG reduced epithelial-mesenchymal transition (EMT), migration, invasion, and proliferation of breast cancer cells. Through integrated analyses of transcriptomic profiles, patient survival data, and secretome dataset, followed by experimental validation, granulocyte-macrophage colony-stimulating factor (GM-CSF) was identified as the key secreted protein mediating TBK1-regulated metastatic behaviors of breast cancer cells. Pharmacological inhibition of TBK1 in BCBM mouse models reduces BCBM and extends survival. Together, these data indicate that TBK1 signaling in TAMG contributes to BCBM and, along with its downstream effector GM-CSF, represents a promising therapeutic target for this deadly disease.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1791
  4. Biochim Biophys Acta Mol Basis Dis. 2025 Sep 16. pii: S0925-4439(25)00403-X. [Epub ahead of print] 168055
    Loss of estrogen receptor alpha promotes distant metastasis through epithelial-mesenchymal transition in luminal-type breast cancer.
    Wen-Der Lin, Yu-Chia Chen, Forn-Chia Lin, Jhih-Kai Pan, Meng-Han Chen, Hsiang-Ling Chen, Wei-Pang Chung, Hui-Chuan Cheng, Michael Hsiao, Chia-Ning Yang, Pei-Jung Lu.
      Breast cancer (BC) is a global health challenge, with approximately 75 % of cases classified as estrogen receptor alpha (ER-α)-positive luminal subtype. Although hormone therapies such as tamoxifen have improved outcomes, a subset of ER-α-positive BC patients develop resistance, resulting in early metastasis. Our research shows that ER-α loss is more frequent in distant metastases and is associated with poorer survival. We investigated the role of ER-α expression in BC progression, metastasis, and recurrence using comprehensive in vitro and in vivo models. Low ER-α expression in primary tumors was associated with increased metastasis and recurrence in ER-α-positive BC. Luminal BC cells with low ER-α expression exhibited increased invasiveness, whereas ER-α overexpression in triple-negative BC cells suppressed metastatic behavior. Mechanistically, ER-α downregulation promoted epithelial-mesenchymal transition (EMT) and upregulated MMP9 expression in BC cells. These findings suggest that ER-α loss facilitates BC metastasis through the EMT process. Relatively low ER-α expression may serve as a potential prognostic indicator in ER-positive luminal BC. These results have potential implications for predicting outcomes in ER-positive BC and highlight the importance of personalized treatment strategies.
    Keywords:  Breast cancer; EMT; Estrogen receptor-alpha; Metastasis
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168055
  5. Stem Cells. 2025 Sep 14. pii: sxaf060. [Epub ahead of print]
    PNO1 served as a potential biomarker to promote the stemness and progression of breast cancer via the NF-κB signaling pathway.
    Xiaorui Wang, Ping Yue, Dongming Liu, Xinrui Wen, Xiehua Zhang, Bo Sun, Yi Luo, Liwei Chen, Weidong Li, Hong Liu, Yuchao He, Zhongsheng Tong, Hua Guo.
       BACKGROUND: Breast cancer is a highly heterogeneous disease with diverse phenotypes. At present, increasing evidence supports the role of ribosomal biogenesis in human diseases and tumorigenesis. PNO1, as a ribosome assembly factor, plays a key role in the biological synthesis of ribosomes and ribosomal protein mutations associated with human diseases and tumor development. This study explored PNO1's role as a prognostic biomarker for breast cancer.
    METHODS: Clinical samples and online datasets were used to determine PNO1 expression in breast cancers with different molecular phenotypes and clinicopathological subtypes. CCK-8 assays, colony formation assays, wound healing and transwell assays were performed to investigate tumor cell proliferation, migration and invasion. Western blot, flow cytometry, and sphere- formation assays were used to assess the effect of PNO1 on breast cancer stemness. RNA-sequencing analysis was also performed to elucidate the underlying mechanism.
    RESULTS: Result showed that the expression level of PNO1 was upregulated in breast cancer samples. In addition, high PNO1 expression was positively correlated with poor survival in breast cancer patients with different molecular types. Moreover, PNO1 was associated with breast cancer heterogeneity by promoting its stem-like properties both in vitro and in vivo through the NF-κB signaling pathway which can be suppressed by JSH-23.
    CONCLUSIONS: Our study found that PNO1 expression was positively correlated with poor survival in different molecular subtypes of breast cancer, and that PNO1 promoted stem-like properties of breast cancer by activating NF-κB activity. Collectively, PNO1 is a potential prognostic biomarker that plays an important role in breast cancer progression.
    Keywords:  NF-kB signaling pathway; PNO1; biomarker; breast cancer; stemness
    DOI:  https://doi.org/10.1093/stmcls/sxaf060
  6. Pathol Res Pract. 2025 Sep 10. pii: S0344-0338(25)00419-4. [Epub ahead of print]275 156226
    Targeting the tumor microenvironment in triple-negative breast cancer: Biological insights and therapeutic opportunities.
    Teresa Maria Martorana, Gabriele Ricciardi, Pietro Tralongo, Vincenzo Fiorentino, Cristina Pizzimenti, Mariausilia Franchina, Maria Adele Marino, Mariacarmela Santarpia, Giovanni Tuccari, Antonio Ieni, Guido Fadda, Maurizio Martini, Valeria Zuccalà.
      Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. Despite initial chemosensitivity, TNBC often relapses, and nearly half of patients develop distant metastases, particularly to visceral organs and the brain. In recent years, growing attention has been given to the tumor microenvironment (TME) as a critical driver of disease progression, immune evasion, and therapeutic resistance. TME is composed of a dynamic network of immune and stromal cells, extracellular matrix components, and soluble mediators that influence tumor behavior and shape response to treatment. In this review, we provide a comprehensive overview of the cellular and molecular composition of the TME in TNBC, highlight key prognostic and predictive markers, and discuss emerging therapeutic strategies aimed at targeting TME components. Understanding the complex crosstalk between the tumor and its microenvironment is essential for developing effective, personalized approaches to managing TNBC in the future.
    Keywords:  Biomarkers; Immunotherapy; Triple-negative breast cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.prp.2025.156226
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