bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024‒09‒22
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. The deubiquitinating enzyme USP11 regulates breast cancer progression by stabilizing PGAM5.
  2. Single-cell RNA-sequencing reveals a unique landscape of the tumor microenvironment in obesity-associated breast cancer.
  3. Combined knockdown of CD151 and MMP9 may inhibit the malignant biological behaviours of triple-negative breast cancer through the GSK-3β/β-catenin-related pathway.
  4. Estrogen receptors and extracellular matrix: the critical interplay in cancer development and progression.
  5. Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.
  6. ZFP64 drives glycolysis-mediated stem cell-like properties and tumorigenesis in breast cancer.
  7. Obesity-Senescence-Breast Cancer: Clinical Presentation of a Common Unfortunate Cycle.
  1. Breast Cancer Res. 2024 Sep 19. 26(1): 135
    The deubiquitinating enzyme USP11 regulates breast cancer progression by stabilizing PGAM5.
    Nannan Zhang, Quhui Wang, Yunpeng Lu, Feiran Wang, Zhixian He.
      Breast cancer is common worldwide. Phosphoglycerate mutase 5 (PGAM5) belongs to the phosphoglycerate mutase family and plays an important role in many cancers. However, research on its role in breast cancer remains unclear. The present investigation highlights the significant expression of PGAM5 in breast cancer and its essential role in cell proliferation, invasion, apoptosis and the regulation of ferroptosis in breast cancer cells. Overexpression or knockdown of ubiquitin-specific protease 11 (USP11) promotes or inhibits the growth and metastasis of breast cancer cells, respectively, in vitro and in vivo. Mechanistically, USP11 stabilizes PGAM5 via de-ubiquitination, protecting it from proteasome-mediated degradation. In addition, the USP11/PGAM5 complex promotes breast cancer progression by activating iron death-related proteins, indicating that the synergy between USP11 and PGAM5 may serve as a predictor of disease outcome and provide a new treatment strategy for breast cancer.
    Keywords:  Breast cancer; Ferroptosis; PGAM5; USP11
    DOI:  https://doi.org/10.1186/s13058-024-01892-9
  2. Oncogene. 2024 Sep 16.
    Single-cell RNA-sequencing reveals a unique landscape of the tumor microenvironment in obesity-associated breast cancer.
    Guanghui Zhao, Xiaodong Zhang, Liying Meng, Ke Dong, Shipeng Shang, Tengfei Jiang, Ziqian Liu, Haidong Gao.
      As two diseases with rapidly increasing incidence, the molecular linkages between obesity and breast cancer (BC) are intriguing. Overall, obesity may be a negative prognostic factor for BC. Single-cell RNA-sequencing (scRNA-seq) was performed on tumor tissues from 6 obese and non-obese BC patients. With 48,033 cells analyzed, we found heterogeneous tumor epithelium and microenvironment in these obese and lean BC patients. Interestingly, the obesity-associated epithelial cells exhibited specific expression signatures which linked tumor growth and hormone metabolism in BC. Notably, one population of obesity-specific macrophage up-regulated the nuclear receptor subfamily 1 group H member 3 (NR1H3), which acted a transcription factor and regulated FABP4 expression through its interaction with the DNA of SREBP1, and further increased the proliferation of tumor cells in BC. Using single-cell signatures, our study illustrate cell diversity and transcriptomic differences in tumors from obese and non-obese BC patients, and sheds light on potential molecular link between lipid metabolism and BC.
    DOI:  https://doi.org/10.1038/s41388-024-03161-7
  3. Sci Rep. 2024 09 18. 14(1): 21786
    Combined knockdown of CD151 and MMP9 may inhibit the malignant biological behaviours of triple-negative breast cancer through the GSK-3β/β-catenin-related pathway.
    Fan Li, Liucheng Chen, Qing Xia, Zhenzhong Feng, Nan Li.
      Triple-negative breast cancer (TNBC) represents a significant health concern for women worldwide, and the overproduction of MMP9 and CD151 is associated with various cancers, influencing tumour growth and progression. This study aimed to investigate how CD151 and MMP9 affect TNBC cell migration, apoptosis, proliferation, and invasion. Immunohistochemical experiments revealed that CD151 and MMP9 were positively expressed in triple-negative breast cancer, and lymph node metastasis, the histological grade, and CD151 and MMP9 expression were found to be independent prognostic factors for the survival of patients with triple-negative breast cancer. Cytological experiments indicated that the knockdown of CD151 or MMP9 slowed triple-negative breast cancer cell growth, migration, and invasion and increased the apoptosis rate. Compared with CD151 knockdown, double MMP9 and CD151 knockdown further promoted cell death and inhibited TNBC cell proliferation, migration, and invasion. Moreover, β-catenin and p-GSK-3β were significantly downregulated. In summary, simultaneously silencing CD151 and MMP9 further suppressed the proliferation, migration and invasion of TNBC cells and promoted their apoptosis. One possible strategy for inducing this effect is to block the GSK-3β/β-catenin pathway.
    DOI:  https://doi.org/10.1038/s41598-024-71533-w
  4. FEBS J. 2024 Sep 16.
    Estrogen receptors and extracellular matrix: the critical interplay in cancer development and progression.
    Sylvia Mangani, Zoi Piperigkou, Nikolaos E Koletsis, Paraskevi Ioannou, Nikos K Karamanos.
      Cancer remains a significant global health concern. Breast cancer is a multifaceted and prevalent disease influenced by several factors, among which estrogen receptors (ERs) and the extracellular matrix (ECM) play pivotal roles. ERs, encompassing ERα and ERβ, exert significant diversity on tumor behavior, cell signaling, invasion, and metastatic potential, thus guiding breast cancer prognosis. Understanding the multifunctional connections between ERs and ECM that mediate the dynamics of tumor microenvironment is vital for unraveling the complexity of breast cancer pathobiology and identifying novel therapeutic targets. This critical review delves into the intricate nature of ERs, emphasizing their structural isoforms and the consequential impact on breast cancer outcomes. A detailed examination of ER-mediated cell signaling pathways reveals how differential expression of ERα and ERβ isoforms influence breast cancer cell behavior. The functional ERs-matrix interactions emerge as a pivotal factor in modulating epigenetic mechanisms of breast cancer cells, orchestrating changes in cellular phenotype and expression patterns of matrix modulators. Specifically, ERα isoforms are shown to regulate ECM signaling cascades, while the effects of ECM components on ERα activity highlight a bidirectional regulatory axis. The diversity of ERβ isoforms is also highlighted, illustrating their distinct contribution to ECM-mediated cellular responses. This review underscores the complex interplay between ERα/β isoforms and the ECM, shedding light onto the potential therapeutic strategies targeting these interactions to improve breast cancer management.
    Keywords:  breast cancer; cell signaling; epigenetics; estrogen receptor alpha; estrogen receptor beta; extracellular matrix; molecular targeting
    DOI:  https://doi.org/10.1111/febs.17270
  5. Cell Biol Int. 2024 Sep 16.
    Breast cancer cell derived exosomes reduces glycolysis of activated CD8 + T cells in a AKT-mTOR dependent manner.
    Abhishek Choudhury, Soumya Chatterjee, Shauryabrota Dalui, Pronabesh Ghosh, Altamas Hossain Daptary, Golam Kibria Mollah, Arindam Bhattacharyya.
      Cytotoxic CD8+ T cells plays a pivotal role in the adaptive immune system to protect the organism against infections and cancer. During activation and response, T cells undergo a metabolic reprogramming that involves various metabolic pathways, with a predominant reliance on glycolysis to meet their increased energy demands and enhanced effector response. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Recent reports indicates that exosomes may transfer biologically functional molecules to the recipient cells, thereby facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells. This study sought to enlighten possible involvement of cancer-derived exosomes in CD8 + T cell glucose metabolism and discover a regulated signalome as a mechanism of action. We observed reduction in glucose metabolism due to downregulation of AKT/mTOR signalome in activated CD8 + T cells after cancer derived exosome exposure. In-vivo murine breast tumor studies showed better tumor control and antitumor CD8 + T cell glycolysis and effector response after abrogation of exosome release from breast cancer cells. Summarizing, the present study establishes an immune evasion mechanism of breast cancer cell secreted exosomes that will act as a foundation for future precision cancer therapeutics.
    Keywords:  CD8 + T cells; breast cancer; effector response; exhaustion; exosomes; glycolysis
    DOI:  https://doi.org/10.1002/cbin.12241
  6. Biol Direct. 2024 Sep 18. 19(1): 83
    ZFP64 drives glycolysis-mediated stem cell-like properties and tumorigenesis in breast cancer.
    Jiayi Sun, Jinquan Liu, Yudong Hou, Jianheng Bao, Teng Wang, Longbi Liu, Yidan Zhang, Rui Zhong, Zhenxuan Sun, Yan Ye, Jintao Liu.
      BACKGROUND: Breast cancer (BC) is a great clinical challenge because of its aggressiveness and poor prognosis. Zinc Finger Protein 64 (ZFP64), as a transcriptional factor, is responsible for the development and progression of cancers. This study aims to investigate whether ZFP64 regulates stem cell-like properties and tumorigenesis in BC by the glycolytic pathway.RESULTS: It was demonstrated that ZFP64 was overexpressed in BC specimens compared to adjacent normal tissues, and patients with high ZFP64 expression had shorter overall survival and disease-free survival. The analysis of the association of ZFP64 expression with clinicopathological characteristics showed that high ZFP64 expression is closely associated with N stage, TNM stage, and progesterone receptor status. Knockdown of ZFP64 suppressed the viability and colony formation capacity of BC cells by CCK8 and colony formation assays. The subcutaneous xenograft models revealed that ZFP64 knockdown reduced the volume of formatted tumors, and decreased Ki67 expression in tumors. The opposite effects on cell proliferation and tumorigenesis were demonstrated by ZFP64 overexpression. Furthermore, we suggested that the stem cell-like properties of BC cells were inhibited by ZFP64 depletion, as evidenced by the decreased size and number of formatted mammospheres, the downregulated expressions of OCT4, Nanog, and SOX2 proteins, as well as the reduced proportion of CD44+/CD24- subpopulations. Mechanistically, glycolysis was revealed to mediate the effect of ZFP64 using mRNA-seq analysis. Results showed that ZFP64 knockdown blocked the glycolytic process, as indicated by decreasing glycolytic metabolites, inhibiting glucose consumption, and reducing lactate and ATP production. As a transcription factor, we identified that ZFP64 was directly bound to the promoters of glycolysis-related genes (ALDOC, ENO2, HK2, and SPAG4), and induced the transcription of these genes by ChIP and dual-luciferase reporter assays. Blocking the glycolytic pathway by the inhibition of glycolytic enzymes ENO2/HK2 suppressed the high proliferation and stem cell-like properties of BC cells induced by ZFP64 overexpression.
    CONCLUSIONS: These data support that ZFP64 promotes stem cell-like properties and tumorigenesis of BC by activating glycolysis in a transcriptional mechanism.
    Keywords:  Breast cancer; Glycolysis; Stem cell-like property; Tumorigenesis; ZFP64
    DOI:  https://doi.org/10.1186/s13062-024-00533-7
  7. Adv Exp Med Biol. 2024 ;1460 821-850
    Obesity-Senescence-Breast Cancer: Clinical Presentation of a Common Unfortunate Cycle.
    Ayse Basak Engin, Atilla Engin.
      There are few convincing studies establishing the relationship between endogenous factors that cause obesity, cellular aging, and telomere shortening. Without a functional telomerase, a cell undergoing cell division has progressive telomere shortening. While obesity influences health and longevity as well as telomere dynamics, cellular senescence is one of the major drivers of the aging process and of age-related disorders. Oxidative stress induces telomere shortening, while decreasing telomerase activity. When progressive shortening of telomere length reaches a critical point, it triggers cell cycle arrest leading to senescence or apoptotic cell death. Telomerase activity cannot be detected in normal breast tissue. By contrast, maintenance of telomere length as a function of human telomerase is crucial for the survival of breast cancer cells and invasion. Approximately three-quarters of breast cancers in the general population are hormone-dependent and overexpression of estrogen receptors is crucial for their continued growth. In obesity, increasing leptin levels enhance aromatase messenger ribonucleic acid (mRNA) expression, aromatase content, and its enzymatic activity on breast cancer cells, simultaneously activating telomerase in a dose-dependent manner. Meanwhile, applied anti-estrogen therapy increases serum leptin levels and thus enhances leptin resistance in obese postmenopausal breast cancer patients. Many studies revealed that shorter telomeres of postmenopausal breast cancer have higher local recurrence rates and higher tumor grade. In this review, interlinked molecular mechanisms are looked over between the telomere length, lipotoxicity/glycolipotoxicity, and cellular senescence in the context of estrogen receptor alpha-positive (ERα+) postmenopausal breast cancers in obese women. Furthermore, the effect of the potential drugs, which are used for direct inhibition of telomerase and the inhibition of human telomerase reverse transcriptase (hTERT) or human telomerase RNA promoters as well as approved adjuvant endocrine therapies, the selective estrogen receptor modulator and selective estrogen receptor down-regulators are discussed.
    Keywords:  Aromatase inhibitor; Breast cancer; Cytotoxic T cell; Epithelial-to-mesenchymal transition; Estrogen receptor; Fulvestrant; Human telomerase reverse transcriptase (hTERT); Imetelstat; Lipotoxicity; Oxidative stress; Selective estrogen receptor down-regulator; Selective estrogen receptor modulator; Senescence-associated secretory phenotype (SASP); Senescence-associated β galactosidase; Telomerase; Telomerase reactivation concept; Telomere attrition; Telomere length; Telomeric RNA component
    DOI:  https://doi.org/10.1007/978-3-031-63657-8_27
This page is being maintained by Thomas Krichel. It was last updated on 2024‒09‒23 at 2:03.