bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–04–19
eleven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. In vivo exposure to CXCL12-high CAFs and chronic CXCL12 stimulation in vitro is sufficient to enhance metastasis of ER-positive breast cancer.
  2. PINK1‑mediated mitophagy enhances breast cancer proliferation through metabolic reprogramming.
  3. Extracellular ATP promotes endocrine resistance in ER+ breast cancer through upregulation of PYGL.
  4. RUNX1-deficiency drives immune-active ER + mammary tumorigenesis through activation of interferon signaling.
  5. Oncogenic role and potential mechanisms of MYO1B in breast cancer.
  6. Exploring the Connection Between Ultra-Processed Foods and Breast Cancer: From Adiposity to Inflammation and Beyond.
  7. TLR7 signature of tumour innervation reveals two distinct pathways of triple-negative breast cancer progression.
  8. Extracellular vesicle-derived CDCP1 promotes chemoresistance and macrophage polarization in breast cancer.
  9. Age and Sex in Breast Cancer: Moving Beyond a One-Size-Fits-All Approach.
  10. Dysregulation of adipokines in the serum of breast cancer patients - role in pathogenesis and potential clinical application (preliminary studies).
  11. Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.
  1. Breast Cancer Res Treat. 2026 Apr 17. pii: 21. [Epub ahead of print]217(2):
    In vivo exposure to CXCL12-high CAFs and chronic CXCL12 stimulation in vitro is sufficient to enhance metastasis of ER-positive breast cancer.
    Philip C Miller, Utsav Sharma, JiaXiang Tao, Jun Sun, Kelsie Medina-Saenz, Manuel Picon-Ruiz, Cynthia Morata-Tarifa, Susan M Bare, Joyce M Slingerland, Dorraya El-Ashry, Marc E Lippman.
       PURPOSE: Cancer-associated fibroblasts (CAFs) play important roles in breast cancer (BC) progression and metastasis. Here we investigated whether CAFs from indolent vs. aggressive BCs differ in gene expression profiles and how they impact metastasis.
    EXPERIMENTAL DESIGN: Genotypic differences in CAF lines from basal-like (CAF23BAS) and luminal-A BC (CAF19LA), were compared and effects on CAF-induced phenotypes of estrogen receptor (ER) positive BC models evaluated.
    RESULTS: Co-injection of MCF7 with CAF23BAS cells enhanced tumor metastasis in vivo, while CAF19LA did not. CXCL12 was strongly overexpressed in CAF23BAS. BC cells isolated from MCF7 + CAF23BAS tumors were enriched in epithelial-mesenchymal transition (EMT) genes and cancer stem cell (CSC)-like behavior. Chronic CXCL12 exposure in vitro, as may occur in BC with high CXCL12-secreting CAFs, phenocopied CAF23BAS-enhanced metastasis. Single cell analysis of primary human BC revealed CAFs are the major source of CXCL12 in breast tumors. A high CXCL12-CAF gene expression profile was prognostic of poor BC outcome and was strongly over-represented in CAFs within BC metastases. Finally, gene expression changes induced in MCF7 cells by co-injection with CAF23BAS in vivo correlated significantly with gene expression differences between normal and malignant epithelial cells in BC containing high CXCL12 CAFs.
    CONCLUSIONS: These findings suggest that CXCL12 overexpressing CAFs can induce gene expression changes in breast cancer that promote breast cancer metastasis, potentially through expansion of the CSC population. Targeting the CAF CXCL12/CXCR4 axis may offer a novel treatment strategy for metastatic breast cancer and warrants further investigation.
    STATEMENT OF TRANSLATIONAL RELEVANCE: Cancer associated fibroblasts (CAF) within the breast tumor microenvironment influence breast cancer behavior. Our study indicates that high CXCL12-expressing CAFs can induce a stable metastatic phenotype in estrogen receptor positive breast cancer models. Gene expression similarities between a high CXCL12 CAF line and high CXCL12-expressing CAFs from primary and metastatic human breast cancers define a CXCL12-high CAF signature that is prognostic of poor BC patient outcome. Furthermore, gene expression changes induced in MCF7 cells by CXCL12 high CAFs in vivo were similar to the gene expression differences between normal and malignant breast epithelial cells in breast cancers containing CXCL12 high CAFs. Disruption of CAF-driven, CXCL12-mediated reprogramming of breast cancer cells might provide an opportunity to prevent or treat breast cancer metastasis.
    Keywords:  CXCL12; Cancer associated fibroblast; ER positive; Metastasis; SDF1; Xenograft
    DOI:  https://doi.org/10.1007/s10549-026-07970-0
  2. Oncol Rep. 2026 Jun;pii: 112. [Epub ahead of print]55(6):
    PINK1‑mediated mitophagy enhances breast cancer proliferation through metabolic reprogramming.
    Zong Jin Guo, Qian Yu, Rui Sha, Wei Li, Hui Juan Dai.
      Breast cancer is a predominant cause of cancer‑related mortality among women, particularly aggressive subtypes such as triple‑negative breast cancer (TNBC), which currently lack effective targeted therapies. While PTEN‑induced kinase 1 (PINK1) is known for its role in maintaining mitochondrial homeostasis via mitophagy, its specific contributions to breast cancer progression and metabolic regulation remain poorly defined. The present study aimed to investigate the oncogenic potential of PINK1 and its influence on metabolic reprogramming. To achieve this, the PINK1 expression levels in breast cancer tissues and cell lines were assessed. Gain‑ and loss‑of‑function methodologies were employed in luminal (MCF‑7) and TNBC (MDA‑MB‑231) cells. Then, mitophagy was evaluated by measuring LC3‑II levels, Parkin expression and utilizing transmission electron microscopy. Glucose uptake assays and metabolite quantification (including pyruvate and acetyl‑CoA) were conducted. Reverse transcription‑quantitative polymerase chain reaction identified phosphoglycerate kinase 2 (PGK2) as a downstream target of PINK1. Functional assays were then performed to examine the proliferation, migration and invasion of cells with PINK1 overexpression. The results demonstrated that PINK1 overexpression increased mitophagy and induced a glycolytic phenotype, characterized by enhanced glucose uptake and elevated PGK2 levels. Elevated concentrations of pyruvate and acetyl‑CoA indicated increased metabolic flux. Functionally, PINK1 promoted proliferation, migration and invasion in both cell types. Knockdown of PGK2 reversed these effects, underscoring its critical role in PINK1‑mediated metabolic reprogramming. Transcriptomic data obtained from online databases revealed a correlation between high PINK1 expression and immunosuppressive tumor microenvironments, as well as poor prognosis. The PINK1‑PGK2 axis constitutes a critical mechanism linking mitophagy to glycolytic reprogramming in breast cancer, representing a novel therapeutic target, particularly for TNBC. Targeting this axis may yield new strategies for addressing treatment‑resistant, metabolically adaptive breast cancer.
    Keywords:  PTEN‑induced kinase 1‑phosphoglycerate kinase 2 axis; breast cancer; glycolysis; mitophagy; therapeutic target
    DOI:  https://doi.org/10.3892/or.2026.9117
  3. Cell Death Dis. 2026 Apr 13.
    Extracellular ATP promotes endocrine resistance in ER+ breast cancer through upregulation of PYGL.
    Yu-Qing Yu, Xin-Yao Yu, Xiao-Fei Li, Yi-Fan Cheng, Yan-Ting Zhou, Fang Mei, Liang Weng, Xin-Xia Tian.
      Hormone receptor (HR)-positive breast cancer accounts for approximately 60% of all breast cancer cases, for which endocrine therapy represents the mainstay of treatment; however, the development of therapeutic resistance substantially limits its clinical efficacy. Extracellular adenosine 5'-triphosphate (ATP) has been implicated as a key mediator of metastasis and chemotherapy resistance in multiple malignancies, including breast cancer, yet its role in endocrine resistance remains poorly defined. Here, we demonstrate that extracellular ATP upregulates glycogen phosphorylase L (PYGL) expression in ER-positive breast cancer cells following endocrine treatment, thereby promoting endocrine resistance. Mechanistically, extracellular ATP activates the P2Y12-AhR signaling axis, leading to increased PYGL expression, enhanced glycolytic activity, and subsequent resistance to endocrine therapy. Moreover, elevated PYGL expression was strongly associated with reduced endocrine therapy sensitivity in breast cancer organoids and clinical tumor specimens. Collectively, these findings identify extracellular ATP-driven PYGL activation as a critical mechanism underlying endocrine resistance and suggest that targeting this pathway may represent a promising strategy to improve endocrine therapy efficacy in breast cancer patients.
    DOI:  https://doi.org/10.1038/s41419-026-08736-8
  4. bioRxiv. 2026 Apr 09. pii: 2026.04.06.716728. [Epub ahead of print]
    RUNX1-deficiency drives immune-active ER + mammary tumorigenesis through activation of interferon signaling.
    Sen Han, Dongxi Xiang, Xueqing Chen, Dongyi Zhao, Guyu Qin, Roderick T Bronson, Zhe Li.
      Recurrent loss-of-function mutations in RUNX1 occur in estrogen receptor-positive (ER + ) breast cancers, yet how RUNX1-loss contributes to breast tumorigenesis remains unclear. Here we used genetically engineered mouse models with luminal mammary epithelial cell (MEC)-restricted gene disruption to investigate its role in breast cancer initiation. Loss of RUNX1 alone, or together with RB1, was insufficient to drive tumor formation. In contrast, combined loss of RUNX1 and p53 induced mammary tumors with full penetrance. These tumors contained ER + cancer cells and exhibited extensive T cell and macrophage infiltration, indicative of an immune hot microenvironment. Mechanistically, RUNX1-deficiency activated interferon signaling in luminal MECs, associated with derepression of RUNX1 target STAT1 and enhanced inflammatory responses. Consistent with these findings, human ER + breast cancers with low RUNX1 expression displayed elevated immune signatures and poorer patient survival. Together, our results identify RUNX1-loss as a driver of an immune-active subtype of ER + breast cancer.
    DOI:  https://doi.org/10.64898/2026.04.06.716728
  5. In Vitro Cell Dev Biol Anim. 2026 Apr 15.
    Oncogenic role and potential mechanisms of MYO1B in breast cancer.
    Mei Dai, Qin Jiang, Danhua Zhang, Lun Li.
      Myosin IB (MYO1B), a member of the type I myosin family, is overexpressed in various tumor tissues. MYO1B facilitates tumor progression by regulating cellular proliferation, migration, and the epithelial-mesenchymal transition (EMT). However, the precise function of MYO1B in breast cancer (BRCA) is still not well understood. We analyzed MYO1B expression, prognostic significance, immune infiltration, and its correlation with drug resistance in BRCA using meta-analysis and public databases. Functional assays in BRCA cells were performed to evaluate the effects of MYO1B on cell proliferation, apoptosis, and sensitivity to tamoxifen and palbociclib. MYO1B mRNA levels showed no significant difference between BRCA and normal tissues, whereas MYO1B protein was upregulated in tumor tissues. High MYO1B expression was associated with poor prognosis in BRCA patients. Functionally, MYO1B promoted BRCA cell proliferation, inhibited apoptosis, and increased resistance to tamoxifen and palbociclib. Mechanistically, MYO1B activated the Pi3k-AKT signaling pathway. Our study suggests that MYO1B promotes the progression of BRCA and may serve as a new target for overcoming endocrine therapy resistance.
    Keywords:  Breast cancer; Drug resistance; MYO1B; Oncogenesis; Prognosis
    DOI:  https://doi.org/10.1007/s11626-025-01149-5
  6. Int J Mol Sci. 2026 Mar 31. pii: 3173. [Epub ahead of print]27(7):
    Exploring the Connection Between Ultra-Processed Foods and Breast Cancer: From Adiposity to Inflammation and Beyond.
    Rodrigo Soares Pereira Lima, Jheniffer da Silva Sousa, Dallyla Jennifer Morais de Sousa, Jorddam Almondes Martins, Irislene Costa Pereira, Rebeca Lima Monteiro, Maria Shelda de Oliveira Neres, Juliana Soares Severo, Felipe Cavalcanti Carneiro da Silva, Moisés Tolentino Bento da Silva, Francisco Leonardo Torres-Leal.
      In this narrative review, we synthesize current epidemiological and mechanistic evidence on the association between ultra-processed food (UPF) consumption, obesity, and breast cancer (BC) risk. The global increase in UPF intake has been linked to substantial metabolic alterations, including weight gain, insulin resistance, low-grade chronic inflammation, and hormonal imbalances-factors that contribute to a tumor-promoting microenvironment. Given the established role of obesity in breast carcinogenesis, understanding the intermediary role of UPFs is critical. Articles were selected from PubMed, SciELO, and ScienceDirect databases using descriptors related to ultra-processed foods, obesity, and breast cancer. The synthesis of current evidence supports the view that excessive UPFs consumption represents a modifiable and preventable risk factor for obesity and BC, underscoring the need for integrated strategies in dietary guidance, public health policy, and cancer prevention.
    Keywords:  breast cancer; eating patterns; nutrition; obesity; ultra-processed foods
    DOI:  https://doi.org/10.3390/ijms27073173
  7. Br J Cancer. 2026 Apr 16.
    TLR7 signature of tumour innervation reveals two distinct pathways of triple-negative breast cancer progression.
    Dong-Yu Wang, Zhe Jiang, Yaacov Ben-David, Susan J Done, Eldad Zacksenhaus.
       BACKGROUND: Emerging evidence indicates that tumour innervation promotes cancer progression via a non-canonical TLR7 signalling pathway. However, its impact across breast cancer subtypes, patient populations, associated molecular pathways, and oncogenic drivers remains poorly defined.
    METHODS: We analysed TLR7 signature scores in human breast cancer across multiple datasets and evaluated their associations with prognosis, clinical outcomes, TNBC subtypes, metastasis, molecular signatures, oncogenic signalling, and pathological complete response.
    RESULTS: We demonstrate that the TLR7score signature is significantly elevated in triple-negative breast cancer (TNBC) - the most aggressive breast cancer subtype-compared with ER⁺ disease. Within TNBC, high TLR7 signalling characterises basal- and mesenchymal-like tumours relative to the luminal androgen receptor (LAR) subtype. Across multiple breast cancer cohorts, including TNBC, TLR7score alone does not uniformly predict prognosis, as both high- and low-scoring tumours are associated with reduced survival. Using sequential cut-off analysis in seven independent clinical cohorts, we show that both TLR7score-high (e.g.
    , SCAN-B: HR = 4.7, P = 0.01) and TLR7score-low (HR = 3.37, P = 0.038) tumours are associated with unfavourable outcomes relative to intermediate-score tumours. TLR7score-high lesions are enriched for cell proliferation, neuronal, and mast cell-related pathways, as well as RB1 and TP53 loss and elevated E2F, PI3K, MET, and MYC signalling. In contrast, TLR7score-low tumours show increased ER signalling and are enriched for T cell-associated but not neuronal pathways, delineating innervated versus non-innervated TNBC phenotypes. Moreover, TLR7score correlates with pathological complete response (pCR) in a treatment-dependent manner.
    CONCLUSIONS: Collectively, these findings suggest that TNBC progression involves both TLR7-dependent and TLR7-independent mechanisms and that TLR7score may enable patient stratification for distinct therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41416-026-03419-9
  8. Hum Cell. 2026 Apr 13. pii: 65. [Epub ahead of print]39(4):
    Extracellular vesicle-derived CDCP1 promotes chemoresistance and macrophage polarization in breast cancer.
    Yibing Liu, Li Ma, Ting Zhu, Di Wu, Yonglei Liu.
      Breast cancer derived extracellular vesicles (EVs) mediate tumor progression through surface protein-dependent intercellular communication; however, their molecular heterogeneity remains poorly characterized. In this study, we employed a proximity-dependent barcoding assay (PBA) together with patient-derived organoid (PDO) models and identified CDCP1 as a key driver of EV-mediated oncogenesis. PBA-based surface proteomics revealed CDCP1 as the most upregulated protein in breast cancer-derived EVs compared with EVs from normal tissues. Clinical validation confirmed elevated CDCP1 expression in tumor tissues and matched EVs. PDOs generated from fresh clinical specimens recapitulated CDCP1 expression levels of the parental tumors and secreted CDCP1-enriched EVs. Functional experiments showed that CDCP1-knockdown EVs suppressed PDO proliferation and sensitized tumors to chemotherapy. Mechanistically, CDCP1-positive EVs promoted macrophage polarization toward an M2 phenotype, accompanied by upregulation of IL-10 and TGF-β and CCL22. Multiplex immunofluorescence confirmed that CDCP1-high tumors exhibited increased co-localization of CD68⁺ and CD163⁺ macrophages. These results establish CDCP1 as a master regulator of EV driven breast cancer progression, linking surface proteome remodeling to chemo-resistance and immunosuppressive microenvironment reprogramming. The integration of single-EV profiling and PDO modeling establishes a translational framework for targeting CDCP1 as a promising therapeutic target and a candidate biomarker for future liquid biopsy development in aggressive breast cancer subtypes.
    Keywords:  Breast cancer; CDCP1; Extracellular vesicles; Macrophage polarization; Patient-derived organoids
    DOI:  https://doi.org/10.1007/s13577-026-01371-7
  9. Clin Breast Cancer. 2026 Apr 14. pii: S1526-8209(26)00047-9. [Epub ahead of print]26(5): 71-74
    Age and Sex in Breast Cancer: Moving Beyond a One-Size-Fits-All Approach.
    José Pablo Leone, Mina S Sedrak.
      Breast cancer is not a uniform disease. Despite decades of research showing that age and sex shape breast cancer biology and treatment response, clinical and research frameworks continue to rely on a one-size-fits-all approach. Too often, we extrapolate findings from one population to another, assuming that what works for one group will work just as well for another. Ignoring age and sex variables has real consequences. Older adults, who make up the majority of breast cancer cases, are still underrepresented in clinical trials, leaving us with gaps in knowledge about how best to treat them. Male breast cancer is still treated largely by analogy to female breast cancer despite growing evidence that the 2 diseases have distinct molecular features. Here, we discuss a framework on the relationships between age and sex with regard to breast cancer biology and treatment to advance precision medicine and optimize patient outcomes.
    Keywords:  Breast Cancer in the Elderly; Male Breast Cancer; Treatment; Treatment response; Tumor biology
    DOI:  https://doi.org/10.1016/j.clbc.2026.03.015
  10. Front Immunol. 2026 ;17 1724900
    Dysregulation of adipokines in the serum of breast cancer patients - role in pathogenesis and potential clinical application (preliminary studies).
    Maria-Laura Morawiec, Dominika Wendlocha, Jacek Kabut, Aleksandra Mielczarek-Palacz.
       Introduction: The pathogenesis and diagnosis of breast cancer remain the subject of intensive research, as many aspects of these processes still require further elucidation. The dominant component of breast tissue stroma, adipose tissue, is composed of adipocytes, which secrete various cytokines, including adipokines, whose role in breast cancer is not fully understood.
    Methods: In this study, selected new adipokines were measured for the first time, including: progranulin (PGRN), follistatin-like protein 1 (FSTL1), asprosin (Asp), meteorin (METRN), adipsin (CFD), nesfatin (NES1), neuregulin 4 (NRG4), and isthmin (ISM1) in the serum of breast cancer patients, divided according to the molecular subtype and grade of the tumor. For the first time, the relationship between the adipokines studied and numerous standard laboratory parameters was also analyzed.
    Results: The study revealed a statistically significant difference in serum concentrations of adipsin and isthmin in breast cancer patients compared to the reference group, which may indicate systemic immune and inflammatory response disorders involving the studied adipokines.
    Discussion: The correlations between the studied adipokines in the course of breast cancer indicate their multifaceted effects on the pathogenesis of breast cancer, which requires further detailed research.
    Keywords:  adipokines; adipsin; breast cancer; follistatin-like 1 (FSTL1); inflammation; isthmin; nesfatin; progranulin
    DOI:  https://doi.org/10.3389/fimmu.2026.1724900
  11. Nat Rev Immunol. 2026 Apr 15.
    Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.
    Neil T Sprenkle, Evanna L Mills.
      Tissue-resident macrophages are crucial sentinel cells of the innate immune system that sense nutrient fluctuations and orchestrate adaptive responses to support steady-state metabolic homeostasis. When dysregulated, these cells have major roles in the pathogenesis of numerous diseases, including obesity-associated metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated fatty liver disease and atherosclerotic cardiovascular disease. Cellular and phenotypic remodelling of macrophage populations in response to metabolic alterations linked to obesity perturbs homeostatic interactions and promotes low-grade sterile tissue inflammation, which propagates tissue dysfunction. Much of the seminal initial work in the field of 'immunometabolism' explored the role of metabolic pathways in the regulation of distinct immune cell types. More recently, however, it has become appreciated that intermediary metabolites can function as signals that regulate macrophages at the level of the whole tissue or organism. As we discuss here, recent work has identified intermediary metabolites such as lactate, succinate and itaconate, and nutrients including glucose, amino acids and free fatty acids, as crucial regulatory signals that control macrophage function in obesity and metabolic disease.
    DOI:  https://doi.org/10.1038/s41577-026-01292-4
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒28 at 18:40.