bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024‒09‒01
ten papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. LncRNA HAGLROS promotes breast cancer evolution through miR-135b-3p/COL10A1 axis and exosome-mediated macrophage M2 polarization.
  2. PSAT1 Promotes Metastasis via p-AKT/SP1/ITGA2 Axis in Estrogen Receptor-Negative Breast Cancer Cell.
  3. Endogenous osteoprotegerin (OPG) represses ERα and promotes stemness and chemoresistance in breast cancer cells.
  4. Acetylation of PGK1 at lysine 323 promotes glycolysis, cell proliferation, and metastasis in luminal A breast cancer cells.
  5. CircXPO6 promotes breast cancer progression through competitively inhibiting the ubiquitination degradation of c-Myc.
  6. Pharmacologic Hedgehog inhibition modulates the cytokine profile of osteolytic breast cancer cells.
  7. Transcriptional regulation of DLGAP5 by AR suppresses p53 signaling and inhibits CD8+T cell infiltration in triple-negative breast cancer.
  8. Targeting ITGβ3 to Overcome Trastuzumab Resistance through Epithelial-Mesenchymal Transition Regulation in HER2-Positive Breast Cancer.
  9. Inhibition of miR-10b treats metastatic breast cancer by targeting stem cell-like properties.
  10. Ergosterol inhibits the proliferation of breast cancer cells by suppressing AKT/GSK-3beta/beta-catenin pathway.
  1. Cell Death Dis. 2024 Aug 28. 15(8): 633
    LncRNA HAGLROS promotes breast cancer evolution through miR-135b-3p/COL10A1 axis and exosome-mediated macrophage M2 polarization.
    Ziqi Meng, Rui Zhang, Xuwei Wu, Zhengri Piao, Meihua Zhang, Tiefeng Jin.
      Long non-coding RNAs (lncRNAs) play an important role in breast cancer progression, but the function of lncRNAs in regulating tumor-associated macrophages (TAMs) remains unclear. As carriers of lncRNAs, exosomes play an important role as mediators in the communication between cancer cells and the tumor microenvironment. In this study, we found that lncRNA HAGLROS was highly expressed in breast cancer tissues and plasma exosomes, and its high expression was related to the poor prognosis of breast cancer patients. Functionally, breast cancer cell-derived exosomal lncRNA HAGLROS promotes breast cancer cell proliferation, migration, epithelial-mesenchymal transition (EMT) process and angiogenesis by inducing TAM/M2 polarization. Mechanistically, lncRNA HAGLROS competitively binds to miR-135-3p to prevent the degradation of its target gene COL10A1. Collectively, these results indicated that the lncRNA HAGLROS/miR-135b-3p/COL10A1 axis promoted breast cancer progression, and revealed the interactive communication mechanism between breast cancer cells and TAMs, suggesting that lncRNA HAGLROS may be a potential biomarker and therapeutic target for breast cancer.
    DOI:  https://doi.org/10.1038/s41419-024-07020-x
  2. Biomolecules. 2024 Aug 12. pii: 990. [Epub ahead of print]14(8):
    PSAT1 Promotes Metastasis via p-AKT/SP1/ITGA2 Axis in Estrogen Receptor-Negative Breast Cancer Cell.
    Xingda Zhang, Siyu Wang, Wei Li, Jianyu Wang, Yajie Gong, Quanrun Chen, Shihan Cao, Da Pang, Song Gao.
      BACKGROUND: Accumulating evidence indicates that PSAT1 not only reprogrammed metabolic function but also exhibits "moonlighting" functions in promoting tumor malignancy. However, the underlying molecular mechanisms of PSAT1 promoting ER-negative breast cancer cell migration need further investigation.METHODS: Briefly, the PSAT1 and ITGA2 expression in cells and tissues was detected using qRT-PCR, immunofluorescence staining and western blot assay. The effect of PSAT1 and ITGA2 was verified both in vitro and in vivo. RNA-seq analysis explored a series of differently expressed genes. The regulation between SP1 and ITGA2 was investigated by ChIP analysis.
    RESULTS: We reported PSAT1 was highly expressed in ER-breast cancer tissues and tumor cells and positively correlated with metastasis. Moreover, RNA-seq analysis explored a series of differently expressed genes, including ITGA2, in PSAT1 overexpressed cells. Mechanistically, PSAT1 facilitated breast cancer metastasis via the p-AKT/SP1/ITGA2 axis. We further elucidated that PSAT1 promoted the entry of SP1 into the nucleus through the upregulation of p-AKT and confirmed ITGA2 is a target of SP1. In addition, enhanced cell migration was remarkably reversed by ITGA2 depletion or p-AKT inhibitor treatment.
    CONCLUSION: This study clarified the mechanism of PSAT1 in promoting ER-negative breast cancer metastasis, which may provide mechanistic clues for attenuating breast cancer metastasis.
    Keywords:  ITGA2; PSAT1; breast cancer; cell metastasis; p-AKT/SP1/ITGA2 axis
    DOI:  https://doi.org/10.3390/biom14080990
  3. Cell Death Discov. 2024 Aug 24. 10(1): 377
    Endogenous osteoprotegerin (OPG) represses ERα and promotes stemness and chemoresistance in breast cancer cells.
    Noura N Alraouji, Dilek Colak, Falah H Al-Mohanna, Ayodele A Alaiya, Abdelilah Aboussekhra.
      Breast cancer (BC) is the most prevalent cancer and the leading cause of death among women worldwide. The osteoprotegerin (OPG) cytokine, a decoy receptor for RANKL and a key player in bone homeostasis, has pro-and anti-carcinogenic effects in various types of cancer, including breast neoplasms. In the present study, we have shown that ectopic expression of OPG in breast epithelial/cancer cells promotes the pro-metastatic processes epithelial-to-mesenchymal transition (EMT), stemness, angiogenesis as well as the activation of breast stromal fibroblasts. Furthermore, proteomics analysis, which allows the identification and quantification of a plethora of known and unknown proteins, has shown a strong and significant correlation between OPG upregulation and the expression of proteins with functions in EMT and stemness. On the other hand, OPG knockdown in triple-negative breast cancer (TNBC) cells inhibited the formation of cancer stem cells. Importantly, while OPG upregulation significantly enhanced the resistance of luminal BC cells to cisplatin and docetaxel, OPG downregulation sensitized TNBC cells to these chemotherapeutic drugs. We have also shown that OPG negatively controls estrogen receptor α (ERα), and OPG upregulation correlated well with the expression of genes related to ER-negative claudin low cells. Collectively, these results show that OPG promotes stemness and the consequent chemoresistance of breast cancer cells.
    DOI:  https://doi.org/10.1038/s41420-024-02151-8
  4. BMC Cancer. 2024 Aug 27. 24(1): 1054
    Acetylation of PGK1 at lysine 323 promotes glycolysis, cell proliferation, and metastasis in luminal A breast cancer cells.
    Xiuli Gao, Ting Pan, Yu Gao, Wenbin Zhu, Likun Liu, Wenbo Duan, Cuicui Han, Bo Feng, Wenjing Yan, Qiuhang Song, Yunlong Liu, Liling Yue.
      BACKGROUND: In prior research employing iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) technology, we identified a range of proteins in breast cancer tissues exhibiting high levels of acetylation. Despite this advancement, the specific functions and implications of these acetylated proteins in the context of cancer biology have yet to be elucidated. This study aims to systematically investigate the functional roles of these acetylated proteins with the objective of identifying potential therapeutic targets within breast cancer pathophysiology.METHODS: Acetylated targets were identified through bioinformatics, with their expression and acetylation subsequently confirmed. Proteomic analysis and validation studies identified potential acetyltransferases and deacetylases. We evaluated metabolic functions via assays for catalytic activity, glucose consumption, ATP levels, and lactate production. Cell proliferation and metastasis were assessed through viability, cycle analysis, clonogenic assays, PCNA uptake, wound healing, Transwell assays, and MMP/EMT marker detection.
    RESULTS: Acetylated proteins in breast cancer were primarily involved in metabolism, significantly impacting glycolysis and the tricarboxylic acid cycle. Notably, PGK1 showed the highest acetylation at lysine 323 and exhibited increased expression and acetylation across breast cancer tissues, particularly in T47D and MCF-7 cells. Notably, 18 varieties acetyltransferases or deacetylases were identified in T47D cells, among which p300 and Sirtuin3 were validated for their interaction with PGK1. Acetylation at 323 K enhanced PGK1's metabolic role by boosting its activity, glucose uptake, ATP production, and lactate output. This modification also promoted cell proliferation, as evidenced by increased viability, S phase ratio, clonality, and PCNA levels. Furthermore, PGK1-323 K acetylation facilitated metastasis, improving wound healing, cell invasion, and upregulating MMP2, MMP9, N-cadherin, and Vimentin while downregulating E-cadherin.
    CONCLUSION: PGK1-323 K acetylation was significantly elevated in T47D and MCF-7 luminal A breast cancer cells and this acetylation could be regulated by p300 and Sirtuin3. PGK1-323 K acetylation promoted cell glycolysis, proliferation, and metastasis, highlighting novel epigenetic targets for breast cancer therapy.
    Keywords:  Acetyltransferase and deacetylase; Breast cancer; Cell proliferation and metastasis; Glycolysis; PGK1 acetylation
    DOI:  https://doi.org/10.1186/s12885-024-12792-8
  5. Mol Cell Biochem. 2024 Aug 23.
    CircXPO6 promotes breast cancer progression through competitively inhibiting the ubiquitination degradation of c-Myc.
    Aiqi Xu, Xi Li, Qiaoting Cai, Ciqiu Yang, Mei Yang, Hongfei Gao, Minyi Cheng, Xianzhe Chen, Fei Ji, Hailin Tang, Kun Wang.
      The number of breast cancer (BC) patients is increasing year by year, which is severely endangering to human life and health. c-Myc is a transcription factor, studies have shown that it is a very significant factor in tumor progression, but how it is regulated in BC is still not well understood. Here, we used the RIP microarray sequencing to confirm circXPO6, which had a high affinity with c-Myc and highly expressed in triple-negative breast cancer (TNBC) tissues and cells. CircXPO6 overexpression promoted tumor growth in vivo and in vitro. Furthermore, circXPO6 largely promoted the expression of genes related to glucose metabolism, such as GLUT1, HK2, and MCT4 in TNBC cells. Finally, high levels of circXPO6 expression were found to be closely associated with malignant pathological factors, such as tumor size, lymph node metastasis, TNM staging, and histopathological grading of TNBC. Mechanistically, circXPO6 interacted with c-Myc to prevent speckle-type POZ-mediated c-Myc ubiquitination and degradation, thus promoting TNBC progression. Through the regulation of c-Myc-mediated signal transduction, circXPO6 plays a key role in TNBC progresses. This discovery can provide new ideas for TNBC molecular targeted therapy.
    Keywords:  C-Myc; CircXPO6; Glycolysis; Triple-negative breast cancer; Tumor progression
    DOI:  https://doi.org/10.1007/s11010-024-05093-y
  6. J Bone Oncol. 2024 Aug;47 100625
    Pharmacologic Hedgehog inhibition modulates the cytokine profile of osteolytic breast cancer cells.
    Natalie E Bennett, Dominique V Parker, Rachel S Mangano, Jennifer E Baum, Logan A Northcutt, Jade S Miller, Erik P Beadle, Julie A Rhoades.
      The establishment and progression of bone metastatic breast cancer is supported by immunosuppressive myeloid populations that enable tumor growth by dampening the innate and adaptive immune response. Much work remains to understand how to target these tumor-myeloid interactions to improve treatment outcomes. Noncanonical Hedgehog signaling is an essential component of bone metastatic tumor progression, and prior literature suggests a potential role for Hedgehog signaling and its downstream effector Gli2 in modulating immune responses. In this work, we sought to identify if inhibition of noncanonical Hedgehog signaling alters the cytokine profile of osteolytic breast cancer cells and the subsequent communication between the tumor cells and myeloid cells. Examination of large patient databases revealed significant relationships between Gli2 expression and expression of markers of myeloid maturation and activation as well as cytokine expression. We found that treatment with HPI-1 reduced tumor cell expression of numerous cytokine genes, including CSF1, CSF2, and CSF3, as well as CCL2 and IL6. Secreted CSF-1 (M-CSF) was also reduced by treatment. Changes in tumor-secreted factors resulted in polarization of THP-1 monocytes toward a proinflammatory phenotype, characterized by increased CD14 and CD40 surface marker expression. We therefore propose M-CSF as a novel target of Hedgehog inhibition with potential future applications in altering the immune microenvironment in addition to its known roles in reducing tumor-induced bone disease.
    Keywords:  Bone metastasis; Breast cancer; Cytokine; Monocyte; Myeloid; M−CSF
    DOI:  https://doi.org/10.1016/j.jbo.2024.100625
  7. Transl Oncol. 2024 Aug 24. pii: S1936-5233(24)00208-0. [Epub ahead of print]49 102081
    Transcriptional regulation of DLGAP5 by AR suppresses p53 signaling and inhibits CD8+T cell infiltration in triple-negative breast cancer.
    Qing Pan, Dachang Ma, Yi Xiao, Kun Ji, Jun Wu.
      Triple-negative breast cancer (TNBC) is a challenging subtype with unclear biological mechanisms. Recently, the transcription factor androgen receptor (AR) and its regulation of the DLGAP5 gene have gained attention in TNBC pathogenesis. In this study, we found a positive correlation between high AR expression and TNBC cell proliferation and growth. Furthermore, we confirmed DLGAP5 as a critical downstream regulator of AR with high expression in TNBC tissues. Knockdown of DLGAP5 significantly inhibited TNBC cell proliferation, migration, and invasion. AR was observed to directly bind to the DLGAP5 promoter, enhancing its transcriptional activity and suppressing the activation of the p53 signaling pathway. In vivo experiments further validated that downregulation of AR or DLGAP5 inhibited tumor growth and enhanced CD8+T cell infiltration. This study highlights the crucial roles of AR and DLGAP5 in TNBC growth and immune cell infiltration. Taken together, AR inhibits the p53 signaling pathway by promoting DLGAP5 expression, thereby impacting CD8+T cell infiltration in TNBC.
    Keywords:  AR; CD8(+)T cell infiltration; DLGAP5; TNBC; Tumor growth; p53 signaling pathway
    DOI:  https://doi.org/10.1016/j.tranon.2024.102081
  8. Int J Mol Sci. 2024 Aug 08. pii: 8640. [Epub ahead of print]25(16):
    Targeting ITGβ3 to Overcome Trastuzumab Resistance through Epithelial-Mesenchymal Transition Regulation in HER2-Positive Breast Cancer.
    Asiye Busra Boz Er, Idris Er.
      HER2-positive breast cancer, representing 15-20% of all breast cancer cases, often develops resistance to the HER2-targeted therapy trastuzumab. Unfortunately, effective treatments for advanced HER2-positive breast cancer remain scarce. This study aims to investigate the roles of ITGβ3, and Hedgehog signaling in trastuzumab resistance and explore the potential of combining trastuzumab with cilengitide as a therapeutic strategy. Quantitative gene expression analysis was performed to assess the transcription of EMT (epithelial-mesenchymal transition) markers Slug, Snail, Twist2, and Zeb1 in trastuzumab-resistant HER2-positive breast cancer cells. The effects of ITGβ3 and Hedgehog signaling were investigated. Additionally, the combination therapy of trastuzumab and cilengitide was evaluated. Acquired trastuzumab resistance induced the transcription of Slug, Snail, Twist2, and Zeb1, indicating increased EMT. This increased EMT was mediated by ITGB3 and Hedgehog signaling. ITGβ3 regulated both the Hedgehog pathway and EMT, with the latter being independent of the Hedgehog pathway. The combination of trastuzumab and cilengitide showed a synergistic effect, reducing both EMT and Hedgehog pathway activity. Targeting ITGβ3 with cilengitide, combined with trastuzumab, effectively suppresses the Hedgehog pathway and EMT, offering a potential strategy to overcome trastuzumab resistance and improve outcomes for HER2-positive breast cancer patients.
    Keywords:  EMT; HER2-positive; Hedgehog; ITGB3
    DOI:  https://doi.org/10.3390/ijms25168640
  9. Oncotarget. 2024 Aug 26. 15 591-606
    Inhibition of miR-10b treats metastatic breast cancer by targeting stem cell-like properties.
    Alan Halim, Nasreen Al-Qadi, Elizabeth Kenyon, Kayla N Conner, Sujan Kumar Mondal, Zdravka Medarova, Anna Moore.
      Despite advances in breast cancer screening and treatment, prognosis for metastatic disease remains dismal at 30% five-year survival. This is due, in large, to the failure of current therapeutics to target properties unique to metastatic cells. One of the drivers of metastasis is miR-10b, a small noncoding RNA implicated in cancer cell invasion, migration, viability, and proliferation. We have developed a nanodrug, termed MN-anti-miR10b, that delivers anti-miR-10b antisense oligomers to cancer cells. In mouse models of metastatic triple-negative breast cancer, MN-anti-miR10b has been shown to prevent onset of metastasis and eliminate existing metastases in combination with chemotherapy, even after treatment has been stopped. Recent studies have implicated miR-10b in conferring stem cell-like properties onto cancer cells, such as chemoresistance. In this study, we show transcriptional evidence that inhibition of miR-10b with MN-anti-miR10b activates developmental processes in cancer cells and that stem-like cancer cells have increased miR-10b expression. We then demonstrate that treatment of breast cancer cells with MN-anti-miR10b reduces their stemness, confirming that these properties make metastatic cells susceptible to the nanodrug actions. Collectively, these findings indicate that inhibition of miR-10b functions to impair breast cancer cell stemness, positioning MN-anti-miR10b as an effective treatment option for stem-like breast cancer subtypes.
    Keywords:  breast cancer; metastasis; miR-10b; nanoparticle; stem-like cells
    DOI:  https://doi.org/10.18632/oncotarget.28641
  10. Sci Rep. 2024 08 24. 14(1): 19664
    Ergosterol inhibits the proliferation of breast cancer cells by suppressing AKT/GSK-3beta/beta-catenin pathway.
    Sunita Nilkhet, Wudtipong Vongthip, Pattawika Lertpatipanpong, Anchalee Prasansuklab, Tewin Tencomnao, Siriporn Chuchawankul, Seung Joon Baek.
      Breast cancer is a prevalent malignancy affecting women globally, necessitating effective treatment strategies. This study explores the potential of ergosterol, a bioactive compound found in edible mushrooms, as a candidate for breast cancer treatment. Breast cancer cell lines (MCF-7 and MDA-MB-231) were treated with ergosterol, revealing its ability to inhibit cell viability, induce cell cycle arrest, and suppress spheroid formation. Mechanistically, ergosterol demonstrated significant inhibitory effects on the Wnt/beta-catenin signaling pathway, a critical regulator of cancer progression, by attenuating beta-catenin translocation in the nucleus. This suppression was attributed to the inhibition of AKT/GSK-3beta phosphorylation, leading to decreased beta-catenin stability and activity. Additionally, ergosterol treatment impacted protein synthesis and ubiquitination, potentially contributing to its anti-cancer effects. Moreover, the study revealed alterations in metabolic pathways upon ergosterol treatment, indicating its influence on metabolic processes critical for cancer development. This research sheds light on the multifaceted mechanisms through which ergosterol exerts anti-tumor effects, mainly focusing on Wnt/beta-catenin pathway modulation and metabolic pathway disruption. These findings provide valuable insights into the potential of ergosterol as a therapeutic candidate for breast cancer treatment, warranting further investigation and clinical application.
    DOI:  https://doi.org/10.1038/s41598-024-70516-1
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