bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–01–04
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. PERP suppresses breast cancer metastasis via the ATF3-HSPA6 signaling pathway.
  2. The Cx43-Mediated Autophagy Mechanism Influences Triple-Negative Breast Cancer Through the Regulation of Rab31.
  3. Neuregulin-1 Secreted by Cancer-Associated Fibroblasts Promotes Growth of Triple-Negative Breast Cancer.
  4. Adiponectin 1 receptor is increased but not adiponectin levels in the tumour microenvironment of postmenopausal women with breast cancer.
  5. Growth factors maintain intratumoral heterogeneity and drive therapeutic resistance in triple-negative breast cancer.
  6. IDO1, IL4I1: Novel Immune Checkpoints in Breast Cancer Tumor-Associated Macrophages.
  1. J Int Med Res. 2025 Dec;53(12): 3000605251406800
    PERP suppresses breast cancer metastasis via the ATF3-HSPA6 signaling pathway.
    Caiping Chen, Chao Han, Li Xue, Wanxin Wu, Lin Zhang, Xiang Lu.
      ObjectiveThe role of the tumor suppressor p53 apoptosis effector related to PMP-22 (PERP) in breast cancer metastasis remains unclear. This study investigated PERP's role in metastatic progression, its clinical significance, and the mechanisms underlying its effects.MethodsPERP expression was assessed in breast cancer cell lines, public datasets, and 142 patient samples using real-time quantitative polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemistry. In vitro migration and invasion assays as well as in vivo metastasis model were performed after PERP overexpression or knockdown in MDA-MB-231 and MCF-7 cells. The roles of activating transcription factor 3 (ATF3) and heat shock protein family A member 6 (HSPA6) were evaluated through small-interfering RNA-mediated modulation, RNA sequencing, western blotting, RT-qPCR, and chromatin immunoprecipitation.ResultsPERP expression was markedly reduced in breast cancer cells and tumor tissues compared with that in normal controls, and low PERP levels were associated with poor prognosis. PERP overexpression suppressed metastasis. Mechanistically, PERP upregulated ATF3 expression, and ATF3 bound to the HSPA6 promoter to activate its transcription. Knockdown of ATF3 or HSPA6 eliminated the antimetastatic effects of PERP.ConclusionsPERP suppresses breast cancer metastasis by inducing ATF3, which in turn activates HSPA6 transcription. This PERP-ATF3-HSPA6 axis represents a key regulatory pathway and serves as a potential therapeutic target in metastatic breast cancer.
    Keywords:  Breast neoplasms; activating transcription factor 3; heat shock protein family A member 6; neoplasm metastasis; p53 apoptosis effector related to PMP-22
    DOI:  https://doi.org/10.1177/03000605251406800
  2. Cancers (Basel). 2025 Dec 08. pii: 3923. [Epub ahead of print]17(24):
    The Cx43-Mediated Autophagy Mechanism Influences Triple-Negative Breast Cancer Through the Regulation of Rab31.
    Jiao Yang, Die Wu, Ting Yang, Zi-Jing Lin, Pei-Yao Jiang, Ting-Rui Wang, Zheng-Jia Lu, Lu Wang, Jia Ming.
      Background: Connexin43 (Cx43) is recognized as a transmembrane protein; its precise expression profile and molecular mechanisms in triple-negative breast cancer (TNBC) remain unclear. Methods: We systematically analyzed Cx43 expression in over 60 breast cancer cell lines from the CCLE and HPA databases. Immunohistochemical evaluation compared Cx43 expression between TNBC tissues and adjacent normal tissues. Cx43 expression was assessed in normal breast epithelial cells (MCF-10A) and two TNBC cell lines (MDA-MB-231 and BT-549) using qRT-PCR and Western blot. Functional assays (CCK8, wound healing, transwell) evaluated TNBC progression following Cx43 interference or overexpression. Rab31, a Cx43-interacting protein, was identified via bioinformatics, immunofluorescence, and Co-IP. Autophagy-related proteins (ULK1, ATG5, LC3, and p62) were analyzed after Cx43 or Rab31 modulation. Finally, a nude mouse model validated Cx43's in vivo effects on tumor growth and associated molecular changes. Results: Cx43 was upregulated in TNBC tissues and cell lines. Overexpression enhanced proliferation, migration, and invasion, while knockdown suppressed these effects. Cx43 co-expressed with Rab31, regulating its protein levels and autophagy. Rab31 interference reversed Cx43-mediated autophagy and oncogenic behaviors. In vivo, Cx43 promoted tumor growth and modulated Rab31/autophagy pathways. Conclusions: The Cx43/Rab31 axis drives autophagy to facilitate TNBC progression, highlighting Cx43 as a potential therapeutic target. Our findings provide mechanistic insights for improving TNBC treatment.
    Keywords:  Cx43; Rab31; TNBC; autophagy; breast cancer
    DOI:  https://doi.org/10.3390/cancers17243923
  3. Breast Cancer (Dove Med Press). 2025 ;17 1413-1425
    Neuregulin-1 Secreted by Cancer-Associated Fibroblasts Promotes Growth of Triple-Negative Breast Cancer.
    Lu Xu, Hongbo Xu, Dengsheng Jiang, Shilong Song, Gengming Wang, Xianwen Zhang, Yajun Zhang, Jing Qian, Jia Kang, Feng Cai.
       Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer lacking estrogen receptor (ER), progesterone receptor (PR), and HER2 expression, which limits targeted therapies. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are known to secrete factors that promote tumor progression. The role of neuregulin-1 (NRG1), a ligand of HER3 and HER4, in TNBC and its association with CAFs remains unclear.
    Methods: We analyzed NRG1 mRNA and protein levels in TNBC tumor and adjacent tissues using qRT-PCR and ELISA, and evaluated their relationship with clinicopathological parameters and prognosis in 174 patients. Serum NRG1 levels were assessed via ELISA in TNBC patients and healthy controls. The effects of CAF-secreted NRG1 on TNBC cells were studied using conditioned medium, siRNA knockdown, and xenograft mouse models. Statistical analyses, including ROC curves and survival analyses, were performed to determine diagnostic and prognostic value.
    Results: NRG1 expression was significantly upregulated in TNBC tissues and serum compared to controls, correlating with advanced TNM stages and poor prognosis. ROC analysis demonstrated diagnostic value of NRG1 in tissues and serum. CAFs secreted higher levels of NRG1 compared to normal fibroblasts. Conditioned medium from CAFs enhanced TNBC cell proliferation, migration, and MMP9 expression, effects reduced by NRG1 knockdown. In vivo, CAF-conditioned medium promoted tumor growth, while NRG1 knockdown reduced this effect.
    Conclusion: Our findings suggest that CAF-secreted NRG1 is closely associated with TNBC progression and may represent a potential biomarker and therapeutic target, although further validation is needed to establish causality.
    Keywords:  NRG1; biomarker; cancer-associated fibroblasts; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.2147/BCTT.S549363
  4. Mol Biol Rep. 2025 Dec 28. 53(1): 220
    Adiponectin 1 receptor is increased but not adiponectin levels in the tumour microenvironment of postmenopausal women with breast cancer.
    Diego García-Mata, Alberto Tenorio-Torres, Ramón Mauricio Coral-Vázquez, Alexandra Dávalos-Herrera, Verónica Bautista-Piña, Patricia Canto.
       BACKGROUND: To analyze the ADIPOQ and ADIPOR1 levels in breast tumour tissue and adjacent adipose tissue of postmenopausal women with this cancer. We hypothesized that the tumour microenvironment (TME) of the breast had lower levels of ADIPOQ and ADIPOR1 in postmenopausal women with obesity than in those with a normal BMI.
    METHODS AND RESULTS: Twenty women with normal body mass index (BMI) and 20 with obesity, all of them postmenopausal and with breast cancer (BC) were included. We obtained during surgery fresh breast tumour tissue and a fragment of breast adipose tissue adjacent to the tumour and analyzed the levels of adiponectin (ADIPOQ) and its receptor ADIPOR1 by Western blot. Statistical power of the study was > 80% with a p < 0.05ADIPOR1 protein levels were higher in breast tumour tissue versus breast adipose tissue adjacent to the tumour in postmenopausal women with normal BMI and postmenopausal women with obesity (p = 0.0012 and p = 0.0001, respectively). Moreover, we observed higher ADIPOR1 levels only in breast adipose tissue adjacent to the tumour in postmenopausal women with obesity and tumour size > 2.0 cm and clinical stage II/III (p = 0.019 and p = 0.025, respectively) versus postmenopausal women with a normal BMI. We did not observe differences in ADIPOQ.
    CONCLUSIONS: ADIPOR1 levels were higher in breast tumour tissue compared to breast adipose tissue adjacent to the tumour in both postmenopausal women with normal BMI or with obesity. Besides, ADIPOR1 levels were higher in breast adipose tissue adjacent to the tumour of postmenopausal women and obesity, with a more aggressive breast tumour.
    Keywords:  ADIPOR1; Adiponectin; Microenvironment of breast cancer, postmenopausal Mexican-Mestizo women, normal weight; Obesity
    DOI:  https://doi.org/10.1007/s11033-025-11392-4
  5. Cell Rep. 2025 Dec 31. pii: S2211-1247(25)01598-0. [Epub ahead of print]45(1): 116826
    Growth factors maintain intratumoral heterogeneity and drive therapeutic resistance in triple-negative breast cancer.
    Kaylyn L Devlin, Rebecca Smith, Elmar Bucher, Mark Dane, Chloe L Bowman, Eric J Carlson, David Kilburn, Damir Sudar, Heidi S Feiler, Laura M Heiser, Ellen M Langer, James E Korkola.
      Triple-negative breast cancer (TNBC) shows considerable intratumoral heterogeneity, which contributes to therapeutic resistance. Recent studies show that targeted therapeutics can steer TNBC toward homogeneous, drug-resistant states, but little is understood about how the microenvironment modulates these responses. We report studies to determine how components of the microenvironment impact response to trametinib and cellular heterogeneity. We find that multiple microenvironmental factors, including HGF and neuregulin 1, can drive therapeutic resistance and that treatment with hepatocyte growth factor (HGF) inhibitors restores trametinib sensitivity. Interestingly, treatment with these ligands reverses trametinib-induced homogeneity, restoring heterogeneity to levels comparable to baseline both in vitro and in vivo. Analysis of patient data demonstrates that TNBC with high HGF expression levels has a poor outcome and increased expression of basal and mesenchymal state markers. Our data suggest that common growth factors drive therapeutic resistance and maintain tumor heterogeneity in TNBC, and that co-targeting these factors may improve therapeutic response.
    Keywords:  CP: Cancer; microenvironment; therapeutic resistance; triple negative breast cancer; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.celrep.2025.116826
  6. Breast Cancer (Dove Med Press). 2025 ;17 1279-1292
    IDO1, IL4I1: Novel Immune Checkpoints in Breast Cancer Tumor-Associated Macrophages.
    Aorong Shi, Yanrong An, Fen Yun, Xia Liu, Yongfeng Jia.
       Purpose: Increasing evidence supports the critical role of immune cell infiltration in breast cancer progression. Tumor-associated macrophages (TAMs) undergo metabolic reprogramming during polarization, which is vital for immune responses. Here, we screened for genes associated with TAMs infiltration and involved in tumor metabolism, and investigated their expression and effects in breast cancer.
    Patients and Methods: Bioinformatics analysis was used to screen genes related to immune cell infiltration and involved in tumor metabolism. Immunohistochemistry (IHC) was performed to validate the expression of selected target genes. Multiplex immunohistochemistry (mIHC) was applied to investigate the localization and expression relationship between target genes and TAMs. Real-time quantitative PCR (qRT-PCR) was used to detect the expression of target genes in TAMs. The Human Protein Atlas was utilized for single-cell clustering analysis of breast cancer to assess the expression patterns of target genes, while also evaluating the correlation between target genes and immune checkpoint expression.
    Results: Database analysis revealed that Indoleamine2,3-Dioxygenase1 (IDO1) and Interleukin 4 Induced 1 (IL4I1) are highly expressed in breast cancer, with their expression closely associated with immune cell infiltration, particularly macrophage infiltration, which exhibited the highest infiltration rate. IHC analysis revealed that both IDO1 and IL4I1 were expressed in breast cancer, which were mostly located in TAMs. mIHC co-localization demonstrated that IDO1 and IL4I1 were both expressed in TAMs, and qRT-PCR results confirmed increased expression of IDO1 and IL4I1 in TAMs. Single-cell analysis of breast cancer revealed that IDO1 and IL4I1 were most highly expressed in c-19 macrophages, and their expression was positively correlated with most immune checkpoints.
    Conclusion: This study suggests that IDO1 and IL4I1, which are involved in tumor metabolism, may play an important role in regulating TAMs immune infiltration in breast cancer. Therefore, IDO1 and IL4I1 are potential therapeutic targets for breast cancer.
    Keywords:  IDO1; IL4I1; breast cancer; immune cell infiltration; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.2147/BCTT.S563049
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒15 at 1:19.