bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–11–30
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. CAND1 mediates CUL7-dependent HER2 protein stability to drive breast cancer progression.
  2. STAMBP Accelerates Progression and Tamoxifen Resistance of Breast Cancer Through Deubiquitinating ERα.
  3. Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction.
  4. SUN2 downregulation promotes breast cancer cell proliferation via NFATC4 upregulation.
  5. Adipose-mimetic granular hydrogels uncover biophysical cues driving breast cancer invasion.
  6. CELF1 promotes aerobic glycolysis and an aggressive phenotype in ER-positive breast cancer via GLUT1 regulation.
  7. Breast Cancer-Secreted DPP3 Promotes Lung Metastasis by Remodelling the Vascular Niche in Lung via the Rap1 Signalling Pathway.
  1. Breast Cancer Res. 2025 Nov 27. 27(1): 211
    CAND1 mediates CUL7-dependent HER2 protein stability to drive breast cancer progression.
    Xiaohong Xia, Xiaoyue He, Mengfan Tang, Yuanlin Chen, Yuning Liao, Jiangyu Zhang, Hongbiao Huang.
       BACKGROUND: HER2-positive breast cancer is a prevalent pathological subtype of breast cancer. Resistance to anti-HER2 targeted therapies remains a significant challenge in treatment. Understanding the role of HER2 in breast cancer progression is essential.
    METHODS: The proteomics analysis was used to explore the regulated proteins in patients with HER2-positive breast cancer. MTS, EdU staininig, flow cytometry and colony formation assays were used to cell proliferation and apoptosis. Protein expressions and interaction of CAND1 and HER2 were clarified by western blot, immunofluorescence and co-immunoprecipitation experiments. In vivo studies using nude mice demonstrated the role of CAND1 in HER2-positive breast cancer cell growth.
    RESULTS: An increase in CAND1 expression, which is associated with poor prognosis in patients with HER2-positive breast cancer. Functionally, CAND1-KD suppresses the growth of HER2-positive breast cancer cells by inducing cell cycle arrest and apoptosis. In vivo, CAND1-KD inhibits tumor growth in xenograft models. Mechanistically, CAND1 expression is positively correlated with HER2 protein levels in breast cancer tissues. CAND1 directly interacts with HER2, stabilizing its protein expression. The E3 ligase CUL7 promotes HER2 ubiquitination and is essential for the interaction between CAND1 and HER2. CAND1-KD enhances CUL7 neddylation, which activates its ligase activity and leads to HER2 ubiquitination. Importantly, HER2 overexpression reverses the proliferation inhibition caused by CAND1 loss both in vitro and in vivo.
    CONCLUSION: In summary, this study highlights the critical role of CAND1 in regulating HER2 ubiquitination and suggests a potential therapeutic strategy for patients with HER2-positive breast cancer.
    Keywords:  Breast cancer; CAND1; CUL7; HER2; Ubiquitination
    DOI:  https://doi.org/10.1186/s13058-025-02158-8
  2. Biomolecules. 2025 Oct 24. pii: 1502. [Epub ahead of print]15(11):
    STAMBP Accelerates Progression and Tamoxifen Resistance of Breast Cancer Through Deubiquitinating ERα.
    Zhihuai Wang, Likai Gu, Mei Yang, Yi Zhou, Xihu Qin, Chen Xiong.
      Breast cancer (BRCA) remains a global health burden, with endocrine-resistant ER-positive BRCA posing therapeutic challenges. This study investigates STAMBP's role in breast cancer progression and evaluates its potential as a therapeutic target. Through siRNA library screening in ER-positive cell lines, we identified STAMBP as a key regulator of ERα signaling and observed its upregulation in BRCA samples. (fold changes > 2, sample sizes = 30, p < 0.001), particularly in ER-positive subtypes. Prognostic analysis demonstrated that STAMBP overexpression correlates with poor clinical outcomes in ER-positive BRCA patients (p < 0.05). In vitro functional assays showed STAMBP promoted proliferation, metastasis, and epithelial-mesenchymal transition of ER-positive cells by regulating the activity of ERα signaling. Mechanistically, the deubiquitinase STAMBP directly reduces the K48-linked polyubiquitination levels of ERα, enhancing its protein stability and activating downstream oncogenic signaling. STAMBP knockdown restored tamoxifen sensitivity in endocrine-resistant BRCA cells by reducing ERα stability. This study has certain limitations, including the absence of pharmacological validation and reliance on small, single-center clinical cohorts, which should be addressed in future research to further substantiate the clinical relevance of targeting STAMBP in BRCA. Collectively, our findings identified STAMBP as a prognostic marker and demonstrated its dual role in driving ER-positive BRCA malignancy and mediating endocrine resistance. Targeting STAMBP may represent an innovative approach to improve endocrine therapeutic efficacy in ER-positive BRCA.
    Keywords:  STAMBP; breast cancer; deubiquitination; endocrine therapy; estrogen receptor α
    DOI:  https://doi.org/10.3390/biom15111502
  3. bioRxiv. 2025 Oct 31. pii: 2025.10.30.681251. [Epub ahead of print]
    Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction.
    Zhimin Hu, Hannah E Majeski, Aida Mestre-Farrera, Shirong Cai, Arya Lalezarzadeh, Yichi Zhang, Kei-Ichiro Arimoto, Dong-Er Zhang, Helen Piwnica-Worms, Laurent Fattet, Jing Yang.
      Mechanical cues from the extracellular matrix (ECM) regulate various cellular processes. In breast cancer, increased tumor stiffness is associated with elevated metastasis risk and poor survival. We identify a unique role of the JAK family kinase TYK2 in suppressing breast cancer metastasis under low ECM stiffness. Genetic or pharmacological inhibition of TYK2 in mammary acini and patient-derived organoids leads to invasion at low ECM stiffness by promoting Epithelial-Mesenchymal Transition, which is independent of cytokine-induced JAK/STAT signaling. TYK2 blockade promotes metastasis in breast tumor cell- and patient-derived xenografts. TYK2 localizes at the plasma membrane via IFNAR1 association under low stiffness, but it becomes cytoplasmic and inactivated at high stiffness. Normal human breast epithelium displays membrane-localized TYK2, whereas invasive breast tumors exhibit cytoplasmic TYK2. These findings uncover a TYK2-dependent mechanism by which ECM rigidity suppresses breast cancer metastasis and underscore the need for vigilant breast cancer screening in patients receiving TYK2 inhibitors.
    DOI:  https://doi.org/10.1101/2025.10.30.681251
  4. Biochem Biophys Res Commun. 2025 Nov 25. pii: S0006-291X(25)01763-2. [Epub ahead of print]794 153047
    SUN2 downregulation promotes breast cancer cell proliferation via NFATC4 upregulation.
    Jaehyeok Lee, Haein Kim, Mirae Yeo, Hunmin Kim, Eunbeen Lee, Heeyeon Kim, Yuseon Park, Eunjung Jang, Kyeong Sook Choi, Eunhee Kim.
      The linker of nucleoskeleton and cytoskeleton (LINC) complex component Sad1/UNC-84 domain-containing protein 2 (SUN2) is essential for maintaining nuclear envelope integrity and mechanical signaling between the cytoskeleton and the nucleus. However, its functional significance in breast cancer remains unclear. Here, we show that SUN2 expression is markedly reduced in breast cancer tissues and cell lines compared with normal mammary epithelial cells, and that low SUN2 levels correlate with poor overall survival in breast cancer patients. Functional studies revealed that SUN2 depletion significantly enhanced cell proliferation and colony formation, whereas SUN2 overexpression suppressed these phenotypes. Consistently, SUN2 depletion accelerated xenograft tumor growth and increased Ki-67 positivity, confirming enhanced proliferative activity in vivo. Transcriptomic profiling identified nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), a Ca2+/calcineurin-responsive transcription factor, as one of the most strongly upregulated gene following SUN2 loss. Analysis of TCGA-BRCA data further revealed a significant inverse correlation between SUN2 and NFATC4 expression. Mechanistically, SUN2 depletion elevated NFATC4 mRNA and protein levels, while SUN2 overexpression reduced them. NFATC4 overexpression promoted proliferation, whereas co-expression of SUN2 attenuated NFATC4 expression and reversed its growth-promoting effects. Together, these findings reveal a previously unrecognized SUN2-NFATC4 regulatory axis and establish SUN2 as a tumor-suppressive component of the LINC complex in breast cancer.
    Keywords:  Breast cancer; NFATC4; Proliferation; SUN2
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153047
  5. bioRxiv. 2025 Oct 24. pii: 2025.10.23.684224. [Epub ahead of print]
    Adipose-mimetic granular hydrogels uncover biophysical cues driving breast cancer invasion.
    Brianna K Knode, Garrett Farrell Beeghly, Brittany E Schutrum, Dong Wang, Yitong Zheng, Alice Battistella, Ruchi Goswami, Chi-Yong Eom, Aline Bozec, Jochen Guck, Nozomi Nishimura, Salvatore Girardo, Corey O'Hern, Claudia Fischbach.
      Breast cancer cells invade mammary adipose tissue during initial stages of metastasis but how the physical properties of adipose tissue regulate this process remains unclear. Here, we combined single cell mechanical characterization of primary adipocytes with microfluidic hydrogel fabrication, quantitative multiparametric imaging, Discrete Element Method (DEM) simulations, and in vivo experiments to elucidate these connections. First, we quantified the heterogeneous size and stiffness of primary adipocytes, and replicated these properties by fabricating adipocyte-sized polyacrylamide (PAAm) beads with tunable elasticity. Subsequently, we embedded these beads into type I collagen, the primary fibrillar extracellular matrix (ECM) component of breast adipose tissue, to form 3D granular hydrogels mimicking aspects of native adipose tissue architecture. Granular hydrogels embedded with beads demonstrated increased breast cancer cell invasion relative to bead-free controls, an effect that was more pronounced with soft versus stiff beads and correlated with increased collagen fiber alignment and hierarchical organization. In addition, live cell imaging and DEM simulations revealed that soft beads promoted invasion relative to stiff beads by deforming in response to confined cancer cell migration. Fiber alignment and adipocyte deformation trends were validated in vivo via intravital imaging of cancer cell migration in mammary fat pads of mice, and suggest that adipocyte mechanics regulate breast cancer invasion by coordinating both ECM architecture and cellular confinement. Ultimately, this work highlights the utility of tunable PAAm bead-collagen composites as micromechanical models to study the effect of adipose tissue structure on cancer cell invasion.
    DOI:  https://doi.org/10.1101/2025.10.23.684224
  6. Front Genet. 2025 ;16 1687066
    CELF1 promotes aerobic glycolysis and an aggressive phenotype in ER-positive breast cancer via GLUT1 regulation.
    Jinyu Li, Ning Wang, Jianlei Bi, Meihua Guo, Bingbing Xu, Gena Huang.
       Introduction: RNA-binding proteins (RBPs) shape post-transcriptional programs in cancer, yet subtype-specific roles in breast cancer remain unclear. We evaluated whether CUGBP Elav-like family member 1 (CELF1), an RBPs with prognostic relevance in luminal A (ER-positive) breast cancer, drives malignant phenotypes via glycolytic reprogramming through glucose transporter 1 (GLUT1).
    Methods: We surveyed 1,337 RBPs across TCGA to identify luminal A prognosis-related candidates using Cox models and random-forest ranking, then validated CELF1 biologically. Functional assays combined CELF1 knockdown in ER-positive cells (MCF7, T47D) and overexpression in HER2-positive cells (SKBR3, HCC1954), RNA-seq with differential expression and GSEA, qPCR,western blot, migration, colony assays, IHC in clinical tissues, and a nude-mouse xenograft with the GLUT1 inhibitor BAY-876.
    Results: Cox and random-forest analyses prioritized CELF1 among prognosis-related RBPs in luminal A tumors; high CELF1 associated with poorer survival and was overexpressed in breast cancer versus normal tissue. CELF1 modulation bidirectionally altered glycolytic programs and malignant traits: CELF1 loss reduced proliferation, colony formation, migration, and xenograft growth, whereas overexpression enhanced these phenotypes. RNA-seq and enrichment analyses highlighted suppression of glycolysis pathways upon CELF1 loss; GLUT1 (SLC2A1), HK2, and G6PD were consistently downregulated at mRNA and protein levels after CELF1 knockdown and upregulated with CELF1 overexpression. In vivo, combining CELF1 knockout with BAY-876 further curtailed tumor growth and proliferation markers.
    Conclusion: CELF1 promotes aerobic glycolysis and aggressive behavior in ER-positive breast cancer, at least partly by regulating GLUT1. These findings reveal RBP-driven metabolic reprogramming in luminal A disease and nominate the CELF1-GLUT1 axis as a potential therapeutic vulnerability.
    Keywords:  CELF1; GLUT1; RBPs; breast cancer; glycolysis
    DOI:  https://doi.org/10.3389/fgene.2025.1687066
  7. J Extracell Vesicles. 2025 Dec;14(12): e70182
    Breast Cancer-Secreted DPP3 Promotes Lung Metastasis by Remodelling the Vascular Niche in Lung via the Rap1 Signalling Pathway.
    Xu Li, Sheng Hu, Ziqi Yuan, Xiaoyu Fu, Xiaohui Zhang, Liu Liu, Chaoqun Wang, Wei Yan, Juanjuan Li.
      Metastasis is the leading cause of death related to breast cancer. Premetastatic niches (PMNs), which are remodelled by the primary tumours in distant organs, are essential for the colonisation of disseminated cancer cells. The vascular niche is among the most pivotal PMNs in breast cancer lung metastasis, and the underlying mechanism remains unclear. Here, we report that breast cancer cells secrete dipeptidyl peptidase 3 (DPP3) via small extracellular vesicles (sEVs) to promote lung metastasis. Mechanistically, circulating DPP3 upregulates RAPGEF4 to activate the Rap1 signalling pathway in the lung endothelial cells through the DPP3-PFKP-YBX1 axis and promotes angiogenesis to remodel the vascular niche, thereby increasing lung metastasis. In addition, ARF4 recognises ISGylated DPP3, which facilitates its packaging into sEVs in breast cancer cells. Finally, treatment with losartan pharmacologically inhibits the ISGylation of DPP3, preventing its secretion via sEVs. In summary, our findings demonstrate that DPP3, which is encapsulated in sEVs and secreted by breast cancer cells, regulates angiogenesis in the lung and remodels vascular niches to promote breast cancer lung metastasis, making it a potential target for the diagnosis and treatment of breast cancer metastasis.
    Keywords:  Angiogenesis; Dipeptidyl peptidase 3; ISGylation; Lung metastasis; Rap1 signalling pathway; Small extracellular vesicles
    DOI:  https://doi.org/10.1002/jev2.70182
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