bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024–06–30
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. SCARB2 associates with tumor-infiltrating neutrophils and predicts poor prognosis in breast cancer.
  2. Integrin β3 Reprogramming Stemness in HER2-Positive Breast Cancer Cell Lines.
  3. Prolactin-activated PAK1 potentiates estrogen response to breast cancer cell epithelial-mesenchymal transition, migration and invasion.
  4. Inhibition of ABI2 ubiquitination-dependent degradation suppresses TNBC cell growth via down-regulating PI3K/Akt signaling pathway.
  5. UBR7 in concert with EZH2 inhibits the TGF-β signaling leading to extracellular matrix remodeling.
  6. SMAD4 depletion contributes to endocrine resistance by integrating ER and ERBB signaling in HR + HER2- breast cancer.
  7. The Role of Salivary Vascular Endothelial Growth Factor A, Cytokines, and Amino Acids in Immunomodulation and Angiogenesis in Breast Cancer.
  1. Breast Cancer Res Treat. 2024 Jun 24.
    SCARB2 associates with tumor-infiltrating neutrophils and predicts poor prognosis in breast cancer.
    Dan Zhang, Jun Fang, Jiali Shan, Lijun Xu, Yunxi Wu, Bing Lu, Xiaojing Zhang, Chongyu Wang, Pingping Sun, Qingqing Wang.
       BACKGROUND: The tumor microenvironment (TME) plays a crucial role in various aspects of breast cancer development and metastasis. Nevertheless, the expression, prognostic significance, and correlation with clinical features of SCARB2 in breast cancer, as well as the infiltrative characteristics of TME, remain largely unknown.
    METHODS: We analyzed the differential presentation of SCARB2 mRNA in breast cancer tissues and nontumorous breast tissues and prognosis by The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. Additionally, the Tumor Immunity Estimation Resource (TIMER) was taken to evaluate the correlation between SCARB2 mRNA presence and tumor-infiltrating immune cells and immune checkpoints in the TME in breast cancer. We performed multiple immunohistochemical staining to verify the SCARB2 protein expression in breast cancer tissues and its relationship to immune cells and checkpoints and clinicopathological features.
    RESULTS: We identified elevated SCARB2 expression in breast cancer tissues, and high SCARB2 protein presentation was associated with advanced clinical stage and unfavorable prognosis. In addition, enhanced SCARB2 protein presence was closely correlated with up-regulation CD66b+ neutrophils infiltration in tumor tissues (r = 0.210, P < 0.05) and CD68 + CD163+ M2 macrophages in the interstitium (r = 0.233, P < 0.05), as well as the immune checkpoints, including PD-1 (r = 0.314, P < 0.01) protein expression.
    CONCLUSION: SCARB2 holds promise for predicting the clinical outcome of breast cancer patients and could serve as a potential therapeutic target.
    Keywords:  Breast cancer; Prognosis; SCARB2; TME
    DOI:  https://doi.org/10.1007/s10549-024-07401-y
  2. Biology (Basel). 2024 Jun 11. pii: 429. [Epub ahead of print]13(6):
    Integrin β3 Reprogramming Stemness in HER2-Positive Breast Cancer Cell Lines.
    Asiye Busra Boz Er.
      HER2-positive breast cancer, characterised by overexpressed HER2 levels, is associated with aggressive tumour behaviour and poor prognosis. Trastuzumab is a standard treatment; however, approximately 50% of patients develop resistance within one year. This study investigates the role of ITGβ3 in promoting stemness and resistance in HER2-positive breast cancer cell lines (HCC1599 and SKBR3). The findings demonstrate that chronic exposure to trastuzumab upregulates stem cell markers (SOX2, OCT4, KLF4, NANOG, SALL4, ALDH, BMI1, Nestin, Musashi 1, TIM3, CXCR4). Given the documented role of RGD-binding integrins in drug resistance and stemness, we specifically investigated their impact on resistant cells. Overexpression of ITGβ3 enhances the expression of these stem cell markers, while silencing ITGβ3 reduces their expression, suggesting a major role for ITGβ3 in maintaining stemness and resistance. Further analysis reveals that ITGβ3 activates the Notch signalling pathway, known for regulating stem cell maintenance. The combination of trastuzumab and cilengitide, an integrin inhibitor, significantly decreases the expression of stem cell markers in resistant cells, indicating a potential therapeutic strategy to overcome resistance. These results identify the importance of ITGβ3 in mediating stemness and trastuzumab resistance through Notch signalling in HER2-positive breast cancer, offering new approaches for enhancing treatment efficacy.
    Keywords:  HER2-positive breast cancer; Notch; integrin; stemness; trastuzumab resistance
    DOI:  https://doi.org/10.3390/biology13060429
  3. MicroPubl Biol. 2024 ;2024
    Prolactin-activated PAK1 potentiates estrogen response to breast cancer cell epithelial-mesenchymal transition, migration and invasion.
    Alan Hammer, Maria Diakonova.
      Hormones estrogen and prolactin exert independent effects on breast cancer while their crosstalk synergistically enhance breast cancer cell proliferation. We have previously shown that the serine/threonine kinase PAK1 is responsible for this effect and proposed the mechanism of PAK1 action. Here we extended our previous data to demonstrate that the PAK1 kinase is a common interplay in PRL and E2 crosstalk to regulate epithelial-mesenchymal transition, cell migration and invasiveness of human breast cancer cells.
    DOI:  https://doi.org/10.17912/micropub.biology.001195
  4. Cancer Cell Int. 2024 Jun 27. 24(1): 222
    Inhibition of ABI2 ubiquitination-dependent degradation suppresses TNBC cell growth via down-regulating PI3K/Akt signaling pathway.
    Linlin Lv, Shujing Li, Jie Kang, Yulin Li, Nannan Zhao, Dongman Ye, Fengying Qin, Jing Sun, Tao Yu, Huijian Wu.
      Triple negative breast cancer (TNBC) is a type of cancer that lacks receptor expression and has complex molecular mechanisms. Recent evidence shows that the ubiquitin-protease system is closely related to TNBC. In this study, we obtain a key ubiquitination regulatory substrate-ABI2 protein by bioinformatics methods, which is also closely related to the survival and prognosis of TNBC. Further, through a series of experiments, we demonstrated that ABI2 expressed at a low level in TNBC tumors, and it has the ability to control cell cycle and inhibit TNBC cell migration, invasion and proliferation. Molecular mechanism studies proved E3 ligase CBLC could increase the ubiquitination degradation of ABI2 protein. Meanwhile, RNA-seq and IP experiments indicated that ABI2, acting as a crucial factor of tumor suppression, can significantly inhibit PI3K/Akt signaling pathway via the interaction with Rho GTPase RAC1. Finally, based on TNBC drug target ABI2, we screened and found that FDA-approved drug Colistimethate sodium(CS) has significant potential in suppressing the proliferation of TNBC cells and inducing cell apoptosis, making it a promising candidate for impeding the progression of TNBC.
    Keywords:  ABI2; CBLC; Colistimethate sodium; PI3K/Akt; TNBC
    DOI:  https://doi.org/10.1186/s12935-024-03407-0
  5. Cell Rep. 2024 Jun 25. pii: S2211-1247(24)00722-8. [Epub ahead of print]43(7): 114394
    UBR7 in concert with EZH2 inhibits the TGF-β signaling leading to extracellular matrix remodeling.
    Swagata Adhikari, Vipin Singh, Sandhik Nandi, Manorama Ghosal, Nidharshan Sundar Raj, Jayati Khanna, Apoorva Bhattacharya, Aindrila Kabiraj, Atanu Mondal, Madavan Vasudevan, Dulal Senapati, Himansu Roy, Kundan Sengupta, Dimple Notani, Chandrima Das.
      The intricate interplay between resident cells and the extracellular matrix (ECM) profoundly influences cancer progression. In triple-negative breast cancer (TNBC), ECM architecture evolves due to the enrichment of lysyl oxidase, fibronectin, and collagen, promoting distant metastasis. Here we uncover a pivotal transcription regulatory mechanism involving the epigenetic regulator UBR7 and histone methyltransferase EZH2 in regulating transforming growth factor (TGF)-β/Smad signaling, affecting the expression of ECM genes. UBR7 loss leads to a dramatic reduction in facultative heterochromatin mark H3K27me3, activating ECM genes. UBR7 plays a crucial role in matrix deposition in adherent cancer cells and spheroids, altering collagen content and lysyl oxidase activity, directly affecting matrix stiffness and invasiveness. These findings are further validated in vivo in mice models and TNBC patients, where reduced UBR7 levels are accompanied by increased ECM component expression and activity, leading to fibrosis-mediated matrix stiffness. Thus, UBR7 is a master regulator of matrix stiffening, influencing the metastatic potential of TNBC.
    Keywords:  CP: Cell biology; EZH2; UBR7; cancer progression; cell signaling; extracellular matrix; spheroid; tumor suppressor
    DOI:  https://doi.org/10.1016/j.celrep.2024.114394
  6. Cell Death Dis. 2024 Jun 24. 15(6): 444
    SMAD4 depletion contributes to endocrine resistance by integrating ER and ERBB signaling in HR + HER2- breast cancer.
    Kang Li, Dan Shu, Han Li, Ailin Lan, Wenjie Zhang, Zhaofu Tan, Man Huang, Maria Lauda Tomasi, Aishun Jin, Haochen Yu, Meiying Shen, Shengchun Liu.
      Endocrine resistance poses a significant clinical challenge for patients with hormone receptor-positive and human epithelial growth factor receptor 2-negative (HR + HER2-) breast cancer. Dysregulation of estrogen receptor (ER) and ERBB signaling pathways is implicated in resistance development; however, the integration of these pathways remains unclear. While SMAD4 is known to play diverse roles in tumorigenesis, its involvement in endocrine resistance is poorly understood. Here, we investigate the role of SMAD4 in acquired endocrine resistance in HR + HER2- breast cancer. Genome-wide CRISPR screening identifies SMAD4 as a regulator of 4-hydroxytamoxifen (OHT) sensitivity in T47D cells. Clinical data analysis reveals downregulated SMAD4 expression in breast cancer tissues, correlating with poor prognosis. Following endocrine therapy, SMAD4 expression is further suppressed. Functional studies demonstrate that SMAD4 depletion induces endocrine resistance in vitro and in vivo by enhancing ER and ERBB signaling. Concomitant inhibition of ER and ERBB signaling leads to aberrant autophagy activation. Simultaneous inhibition of ER, ERBB, and autophagy pathways synergistically impacts SMAD4-depleted cells. Our findings unveil a mechanism whereby endocrine therapy-induced SMAD4 downregulation drives acquired resistance by integrating ER and ERBB signaling and suggest a rational treatment strategy for endocrine-resistant HR + HER2- breast cancer patients.
    DOI:  https://doi.org/10.1038/s41419-024-06838-9
  7. Biomedicines. 2024 Jun 14. pii: 1329. [Epub ahead of print]12(6):
    The Role of Salivary Vascular Endothelial Growth Factor A, Cytokines, and Amino Acids in Immunomodulation and Angiogenesis in Breast Cancer.
    Elena A Sarf, Elena I Dyachenko, Lyudmila V Bel'skaya.
      In this work, we focused on the analysis of VEGF content in saliva and its relationship with pro-inflammatory cytokines and amino acids involved in immunomodulation and angiogenesis in breast cancer. The study included 230 breast cancer patients, 92 patients with benign breast disease, and 59 healthy controls. Before treatment, saliva samples were obtained from all participants, and the content of VEGF and cytokines in saliva was determined by an enzyme-linked immunosorbent assay, as well as the content of amino acids by high-performance liquid chromatography. It was found that VEGF was positively correlated with the level of pro-inflammatory cytokines IL-1β (r = 0.6367), IL-6 (r = 0.3813), IL-8 (r = 0.4370), and IL-18 (r = 0.4184). Weak correlations were shown for MCP-1 (r = 0.2663) and TNF-α (r = 0.2817). For the first time, we demonstrated changes in the concentration of VEGF and related cytokines in saliva in different molecular biological subtypes of breast cancer depending on the stage of the disease, differentiation, proliferation, and metastasis to the lymph nodes. A correlation was established between the expression of VEGF and the content of aspartic acid (r = -0.3050), citrulline (r = -0.2914), and tryptophan (r = 0.3382) in saliva. It has been suggested that aspartic acid and citrulline influence the expression of VEGF via the synthesis of the signaling molecule NO, and then tryptophan ensures tolerance of the immune system to tumor cells.
    Keywords:  VEGF; amino acids; angiogenesis; breast cancer; immunomodulation; pro-inflammatory cytokine; saliva
    DOI:  https://doi.org/10.3390/biomedicines12061329
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