bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–03–29
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction.
  2. Metformin reduces senescence induced by obesity-related inflammation in luminal breast cancer through estrogen receptor beta modulation.
  3. MUS81 inhibits cell proliferation and migration in breast cancer by promoting the expression of CDKN2A(p16INK4a).
  4. The role and research progress of FGF21 in breast cancer: a review.
  5. Hypoxia‑induced exosomal CAMTA1 promotes radio‑resistance in MDA‑MB‑231 cells by regulating NRG1 to mediate M2 macrophage polarization.
  6. The role of Notch signalling and its crosstalk with oestrogen receptor signalling in breast cancer.
  7. The Interplay Between Circadian Clocks and the Tumour Microenvironment in Breast Cancer.
  1. Nat Commun. 2026 Mar 25.
    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 risks and poor survival. Here we report 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 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 ECM stiffness, whereas high rigidity causes TYK2 cytoplasmic mislocalization and inactivation. Consistently, normal 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 breast cancer screening in patients receiving TYK2 inhibitors.
    DOI:  https://doi.org/10.1038/s41467-026-70518-9
  2. Biochem Pharmacol. 2026 Mar 25. pii: S0006-2952(26)00263-7. [Epub ahead of print] 117930
    Metformin reduces senescence induced by obesity-related inflammation in luminal breast cancer through estrogen receptor beta modulation.
    Morla-Barcelo Pere Miquel, Melguizo-Salom Lucas, Martinez-Bernabe Toni, Roca Pilar, Sastre-Serra Jorge, Nadal-Serrano Mercedes.
      Obesity contributes to worse outcomes in breast cancer, particularly in the luminal subtype, where cellular senescence could increase tumor aggressiveness. Parallelly, Estrogen Receptor Beta (ERβ) has emerged as an important mediator in the cellular response to obesity-associated inflammation that metformin could counteract. This study explores metformin's role in targeting senescence to mitigate obesity-induced tumor progression. Using the GSE189757 dataset, differentially expressed genes in obese versus lean luminal breast cancer patients were examined by in silico analysis. T47D, BT474, and MCF7 cell lines were treated with an obesity-related inflammatory cocktail (ELIT) and metformin. Protein levels, mRNA expression and functional assays assessed mitochondrial activity, oxidative stress, cell viability, and senescence-related markers. The role of ERβ was investigated through gene silencing, gene overexpression, and correlation studies using datasets. Experimental results show that ELIT exposure increased mitochondrial activity, oxidative stress, and senescence markers, particularly in T47D cells, effects that metformin mitigated. Metformin also reduced SASP-related gene expression, thereby limiting autocrine signaling effects on migration, mammosphere formation, and drug sensitivity. ERβ expression was observed as a potential modulator of ELIT-induced alterations, and metformin reduced its expression. Analysis of patient datasets revealed a positive correlation between ERβ gene (ESR2) expression and senescence-related markers in obese luminal breast cancer patients, particularly MCL1, BCL2L1, CCL2, and ICAM1. These findings indicate that ERβ exhibits a key role as mediator of obesity-induced tumor alterations by promoting senescence-related markers, and that metformin's ability to target ERβ offers a potential strategy to suppress senescence-driven malignancy and improve therapeutic outcomes of obese luminal breast cancer patients.
    Keywords:  Estrogen receptor beta; Luminal breast cancer; Metformin; Mitochondria; Obesity; Senescence
    DOI:  https://doi.org/10.1016/j.bcp.2026.117930
  3. Am J Transl Res. 2026 ;18(2): 1077-1087
    MUS81 inhibits cell proliferation and migration in breast cancer by promoting the expression of CDKN2A(p16INK4a).
    Rong Xie, Deyu Kong, Xinyu Su, Lixi Zhang, Jinnan Wan, Yanhong Yan.
      MUS81 has been recognized as a significant tumor suppressor - essential for DNA damage repair and maintaining chromosomal stability. However, its biological function and expression profile in breast cancer (BC) remain unclear. In this investigation, we examined the relationship between MUS81 expression and the proliferative and migratory capacities of BC cells. MUS81 mRNA and protein levels were markedly lower in breast cancer tissues and cell lines than in adjacent normal tissues and non-tumorigenic MCF-10A cells. Functional assays revealed that MUS81 overexpression suppressed, while MUS81 silencing enhanced, BC cell proliferation and motility, as demonstrated by CCK-8, colony formation, wound-healing, and Transwell experiments. In vivo, MUS81 overexpression markedly reduced Ki-67 expression in xenograft tumors. Although MUS81 did not alter CDKN2A mRNA expression, immunohistochemistry and Western blot analyses showed that p16INK4a protein levels increased following MUS81 overexpression. Furthermore, the modulation of p16INK4a expression by MUS81 was abolished by pretreatment with cycloheximide or MG132, suggesting that MUS81 stabilizes p16INK4a by preventing proteasome-mediated degradation. Collectively, these findings indicate that MUS81 works as a tumor suppressor in BC by inhibiting proliferation and migration through post-translational stabilization of p16INK4a.
    Keywords:  CDKN2A(p16INK4a); MUS81; breast cancer; migration; proliferation
    DOI:  https://doi.org/10.62347/YIBR2904
  4. Front Oncol. 2026 ;16 1792848
    The role and research progress of FGF21 in breast cancer: a review.
    Jiali Chen, Chengyao Chang, Xuan Yang.
       Purpose: To investigate the molecular mechanisms, functional controversies, and clinical significance of Fibroblast Growth Factor 21 (FGF21) in the context of breast cancer.
    Methods: A comprehensive literature search was conducted across databases including PubMed and CNKI to summarize recent advances regarding FGF21 in metabolic reprogramming and immune microenvironment remodeling.
    Results: FGF21 primarily serves as a pro-tumorigenic factor in breast cancer through several key mechanisms: (1) Metabolic Reprogramming: It activates the ERK1/2-SENP2 axis to upregulate CD36, which enhances fatty acid oxidation to fuel tumor metastasis. (2) Immune Evasion: It induces CD8+ T cell exhaustion by persistently activating intracellular cholesterol synthesis pathways. (3) Anti-apoptosis: It enhances chemoresistance by activating signaling pathways such as STAT3. Clinically, elevated FGF21 levels are significantly correlated with disease progression and poor prognosis, particularly in patients with metabolic comorbidities.
    Conclusion: FGF21 acts as a pivotal bridge connecting systemic metabolism with local tumor behavior. Future research should focus on developing precision intervention strategies that preserve its systemic metabolic benefits while selectively blocking its local oncogenic effects.
    Keywords:  FGF21; breast cancer; metabolic reprogramming; signaling pathway; therapeutic target; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1792848
  5. Int J Oncol. 2026 May;pii: 62. [Epub ahead of print]68(5):
    Hypoxia‑induced exosomal CAMTA1 promotes radio‑resistance in MDA‑MB‑231 cells by regulating NRG1 to mediate M2 macrophage polarization.
    Qian Li, Minghua Jiang, Biqing Zhu, Wei Wei, Lei Xia, Jian Huang, Han Gao, Mingyu Du.
      Radiotherapy remains an irreplaceable treatment modality for breast cancer (BC). Calmodulin‑binding Transcription Activator 1 (CAMTA1) has been implicated in tumor progression; however, its role in BC is unclear. The present study aimed to elucidate the mechanistic function of CAMTA1 in BC. RNA sequencing was performed on RAW264.7 macrophages co‑cultured with 4T1 cells and subjected to X‑ray irradiation. In vitro, THP‑1 cells were co‑cultured with MDA‑MB‑231 cells under hypoxic conditions. Exosome morphology was observed under transmission electron microscopy and PKH67 staining was used to trace exosome uptake. Flow cytometry was used to detect CD163 expression while ELISA measured the levels of IL‑10 and IL‑12. Reverse transcription‑quantitative (RT‑q) PCR and immunoblotting analysis were used to detect the expressions of neuregulin 1 (NRG1), CAMTA1 and hypoxia‑inducible factor‑1α. Cell apoptosis, cell cycle distribution, cell viability and proliferation were evaluated using flow cytometry, MTT assay and colony formation assay. In vivo, transfected MDA‑MB‑231 cells were injected into BALB/c nude mice combined with radiotherapy and exosome injection. Histopathological changes in tumor tissues were examined using H&E staining. Immunohistochemistry analysis was performed to assess the expressions of NRG1, Caspase‑3 and CD163. RNA sequencing, RT‑qPCR and immunoblotting analysis revealed that NRG1 expression was markedly increased in RAW264.7 macrophages co‑cultured with 4T1 cells. NRG1 was found to be involved in M2 polarization induced by hypoxia‑treated MDA‑MB‑231 cells, which in turn promoted radio‑resistance. CAMTA1 expression was highly expressed in exosomes derived from hypoxic MDA‑MB‑231 cells and exosomal CAMTA1 promoted the M2 polarization of THP‑1 macrophages. In vivo, CAMTA1 overexpression greatly enhanced tumor growth, increased NRG1 expression, inhibited cell apoptosis and promoted M2 polarization of macrophages in tumor tissue. MDA‑MB‑231 cells were found to deliver CAMTA1 to macrophages via exosomes, leading to upregulation of NRG1 and induction of M2 polarization, thereby enhancing BC cells resistance to radiotherapy. These findings provided novel insights into the mechanisms underlying radio‑resistance in BC and identify exosomal CAMTA1 as a potential therapeutic target.
    Keywords:  Calmodulin‑binding transcription activator 1; M2 macrophage; breast cancer; neuregulin 1; radio‑resistance
    DOI:  https://doi.org/10.3892/ijo.2026.5875
  6. Cancer Metastasis Rev. 2026 Mar 27. pii: 20. [Epub ahead of print]45(2):
    The role of Notch signalling and its crosstalk with oestrogen receptor signalling in breast cancer.
    Aygun Azadova, Orkhan Isayev, Antonio Marco, Greg N Brooke.
      Breast cancer (BCa) is the most frequently diagnosed malignancy in women worldwide, with approximately 70% of cases driven by oestrogen receptor alpha (ERα). Endocrine therapies aim to suppress ERα signalling activity and form the foundation of current therapeutic strategies. However, a substantial proportion of patients either fail to respond due to intrinsic resistance or acquire resistance over the course of the treatment. This resistance arises through a complex interplay of factors including crosstalk with other signalling pathways such as Notch. Notch signalling, essential for mammary gland development, is aberrantly activated in breast tumours, where it contributes to cancer stem cell maintenance, epithelial-mesenchymal transition, angiogenesis, and metastasis. Notch receptors exert context- and subtype-specific roles: Notch1 and 4 promote tumour aggressiveness, whereas Notch2 often exhibits tumour-suppressive roles. In ERα-positive BCa, ERα and Notch signalling cooperate to drive resistance, whereas in ERα-negative disease, Notch promotes stemness and angiogenesis. While anti-oestrogen therapies effectively inhibit tumour growth, they can paradoxically activate Notch signalling and promote therapeutic resistance. Co-targeting Notch alongside endocrine therapy has been proposed as a strategy to delay the onset of therapeutic resistance. However, clinical development of Notch inhibitors has been limited by toxicity associated with pan-Notch blockade. More selective approaches, such as paralogue-specific antibodies, transcription-complex disruption, rational drug combinations, and advanced delivery platforms, are under active development to overcome these limitations. This review outlines the ERα-Notch crosstalk in BCa and examines current and emerging strategies for targeting Notch to overcome endocrine resistance and improve clinical outcomes.
    Keywords:  Breast cancer; Crosstalk; Endocrine resistance; Endocrine therapy; Notch; Notch inhibitors; Oestrogen receptor
    DOI:  https://doi.org/10.1007/s10555-026-10331-4
  7. Cancers (Basel). 2026 Mar 12. pii: 925. [Epub ahead of print]18(6):
    The Interplay Between Circadian Clocks and the Tumour Microenvironment in Breast Cancer.
    Anna-Marie Finger, Carolin Ector, Valerie M Weaver.
      Cancer is a heterogeneous systemic disease that is strongly influenced by dynamic interactions with the tumour microenvironment (TME). Despite major advances in understanding spatial and molecular tumour heterogeneity, the temporal dynamics of tumours have received far less attention. Growing evidence has linked circadian clocks to cancer risk, progression, and treatment response, including in breast cancer. However, temporal regulation has yet to be recognized as a cancer hallmark, and its interaction with the TME remains poorly understood. This review examines how circadian rhythms organize breast cancer biology through bidirectional interactions with the TME. Circadian clocks coordinate proliferation, DNA damage responses, metabolism, and immune surveillance. Ageing, chronic stress, and obesity, all of which are established breast cancer risk modifiers, disrupt these rhythms and are reciprocally exacerbated by circadian dysfunction, establishing feed-forward loops that accelerate disease. Within the TME, the extracellular matrix (ECM) plays a central role in mediating this bidirectional control. Stiffened fibrotic stroma dampens epithelial clock amplitude, while circadian rhythms in turn shape collagen turnover and ECM remodelling. These dynamics can foster inflammation, stem cell expansion, and metastatic dissemination, including time-of-day-dependent release of circulating breast tumour cells. Systemically, circadian clocks gate immune cell trafficking, creating predictable windows of immunosurveillance and therapeutic vulnerability. By integrating insights from mechanobiology, metabolism, immune regulation, and ageing, we position circadian timing as a unifying layer that connects cell-intrinsic programmes with the evolving breast TME. Understanding these connections opens new opportunities for chronotherapeutic strategies in which treatment timing is aligned with circadian rhythms to improve outcomes.
    Keywords:  breast cancer; cancer; circadian clocks; circadian rhythm; extracellular matrix; mechanobiology; mechanotransduction; metastasis; stiffness
    DOI:  https://doi.org/10.3390/cancers18060925
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