bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024–08–18
eleven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. UBE2M forms a positive feedback loop with estrogen receptor to drive breast cancer progression and drug resistance.
  2. COA6 promotes the oncogenesis and progression of breast cancer by oxidative phosphorylation pathway.
  3. CYB561 is a potential therapeutic target for breast cancer and is associated with immune cell infiltration.
  4. β2-microglobulin induced apoptosis of tumor cells via the ERK signaling pathway by directly interacting with HFE in HER2-overexpressing breast cancer.
  5. RGS10 deficiency facilitates distant metastasis by inducing epithelial-mesenchymal transition in breast cancer.
  6. Adipocytes promote metastasis of breast cancer by attenuating the FOXO1 effects and regulating copper homeostasis.
  7. HTB50-2 Inhibits Growth and Migration of Triple-negative Breast Cancer via FOSL2/FOXC1 Signaling Axis and Subsequent Ferroptosis.
  8. Orai1 and Orai3 act through distinct signalling axes to promote stemness and tumorigenicity of breast cancer stem cells.
  9. Tumor-derived exosomal ICAM1 promotes bone metastasis of triple-negative breast cancer by inducing CD8+ T cell exhaustion.
  10. Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle.
  11. Oncogenic fusion of CD63-BCAR4 contributes cancer stem cell-like properties via ALDH1 activity.
  1. Cell Death Dis. 2024 Aug 13. 15(8): 590
    UBE2M forms a positive feedback loop with estrogen receptor to drive breast cancer progression and drug resistance.
    Xiongzhi Lin, Dongsheng Sun, Shuhan Yang, Kai Cheng, XingYi Wang, Weijia Meng, Haowei Wu, Wenlin Liu, Xiaoyu Wu, Hui Yang, Xiaojun Wang, Lisha Zhou.
      UBE2M, a NEDD8-conjugating enzyme, is dysregulated in various human cancers and promotes tumor cell proliferation. However, its role in estrogen receptor-positive (ER+) breast cancer remains unknown. We found that UBE2M expression was significantly higher in ER+ breast cancer tissues than in ER-negative (ER-) breast cancer tissues. Higher expression of UBE2M indicated a poorer prognosis in patients with ER+ breast cancer but not in those with ER- breast cancer. Of interest, a positive feedback loop was observed between UBE2M and ERα. Specifically, ERα enhanced the HIF-1α-mediated transcription of UBE2M. In turn, UBE2M maintained ERα expression by inhibiting its ubiquitination and degradation through UBE2M-CUL3/4A-E6AP-ERα axis. Functionally, silencing of UBE2M suppressed the growth of breast cancer cells by inducing cell cycle arrest and apoptosis and improved their sensitivity to fulvestrant both in vitro and in vivo. Altogether, our findings reveal that the UBE2M-ERα feedback loop drives breast cancer progression and fulvestrant resistance, suggesting UBE2M as a viable target for endocrine therapy of ER+ breast cancer.
    DOI:  https://doi.org/10.1038/s41419-024-06979-x
  2. J Cancer. 2024 ;15(15): 5072-5084
    COA6 promotes the oncogenesis and progression of breast cancer by oxidative phosphorylation pathway.
    Xiaoxia Jin, Xinyan Chen, Haiyan Yu, Yushan Liu, Xiaoyun Lu, Haibing Yin, Wencheng Dai.
      Mitochondrial oxidative phosphorylation (OXPHOS) has long been considered the primary energy source in breast cancer cells. Cytochrome c oxidase assembly factor 6 (COA6), which functions as a metal chaperone to transport copper to complex Ⅳ during the OXPHOS process, plays a crucial role in the carcinogenesis of lung adenocarcinoma. Nevertheless, its specific function in breast cancer is undefined. The present investigation aimed to clarify COA6's expression profile and regulatory functions in breast cancer, as well as to unveil its underlying mechanisms. Initially, our findings revealed a significant upregulation of COA6 in breast cancer, as evidenced by an analysis of the TCGA database and tissue microarrays. This upregulation correlated with tumor size and histological grade. Additionally, survival analysis revealed that elevated COA6 amounts were correlated with decreased overall survival (OS) in breast cancer. To delve deeper into the functions of COA6, both COA6-overexpressing and COA6-knockdown breast cancer cell models were established. These experiments demonstrated COA6 is pivotal in regulating cell proliferation, apoptosis, migration, and invasion, thereby promoting cancer progression in vitro. Notably, functional enrichment analysis indicated COA6 might be involved in breast cancer progression by modulating oxidative phosphorylation (OXPHOS). Collectively, this study reveals an overt tumorigenic role for COA6 in breast cancer and sheds light on its potential mechanisms, offering valuable therapeutic targets for breast cancer therapy.
    Keywords:  Breast cancer; COA6; OXPHOS; The Cancer Genome Atlas (TCGA)
    DOI:  https://doi.org/10.7150/jca.98570
  3. Eur J Med Res. 2024 Aug 12. 29(1): 414
    CYB561 is a potential therapeutic target for breast cancer and is associated with immune cell infiltration.
    Jian Zhuo, Yanchun Zhao, Ruiying Hao, He Li, Zilin Zheng, Luxian Dai, Ankang Sheng, Hanyu Yao, Yubao Tang, Rao Wang, Xiaohong Yang, Weiguang Liu.
       BACKGROUND: Breast cancer (BC), a common malignant tumor originating from the terminal ductal lobular unit of the breast, poses a substantial health risk to women. Previous studies have associated cytochrome b561 (CYB561) with a poor prognosis in BC; however, its underlying mechanism of this association remains unclear.
    METHODS: We investigated the expression of CYB561 mRNA in BC using databases such as The Cancer Genome Atlas, Gene Expression Omnibus, Tumor-Normal-Metastatic plot, and Kaplan-Meier plotter databases. The prognostic value of CYB561 protein in BC was assessed in relation to its expression levels in tumor tissue samples from 158 patients with BC. The effect of CYB561 on BC progression was confirmed using in vivo and in vitro experiments. The biological functions and related signaling pathways of CYB561 in BC were explored using gene microarray, Innovative Pathway, Gene Ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The correlation between CYB561 and the BC tumor immune microenvironment was evaluated using the CIBERSORT algorithm and single-cell analysis and further validated through immunohistochemistry of serial sections.
    RESULTS: Our study demonstrated that upregulation of CYB561 expression predicted poor prognosis in patients with BC and that CYB561 knockdown inhibited the proliferation, migration, and invasive ability of BC cells in vitro. CYB561 knockdown inhibited BC tumor formation in vivo.CYB561 was observed to modulate downstream tropomyosin 1 expression. Furthermore, CYB561 expression was associated with macrophage M2 polarization in the BC immune microenvironment.
    CONCLUSIONS: Elevated CYB561 expression suggests a poor prognosis for patients with BC and is associated with macrophage M2 polarization in the BC microenvironment. Therefore, CYB561 could potentially serve as a therapeutic target for BC treatment.
    Keywords:  Bioinformatics; Breast cancer (BC); Cytochrome b561 (CYB561); Immune infiltration; Prognosis; Single-cell sequence
    DOI:  https://doi.org/10.1186/s40001-024-02010-3
  4. BMC Cancer. 2024 Aug 12. 24(1): 991
    β2-microglobulin induced apoptosis of tumor cells via the ERK signaling pathway by directly interacting with HFE in HER2-overexpressing breast cancer.
    Kesheng Li, Dandan Chai, Shiyang Ren, Xiaowen Lian, Xiaoling Shi, Yang Xu, Lie Bao, Suisheng Yang, Yurong Liang, Xiaoqin Li, Huifen Du.
       BACKGROUND: Our previous study demonstrated that β2-microglobulin (β2M) promoted ER+/HER2- breast cancer survival via the SGK1/Bcl-2 signaling pathway. However, the role of β2M has not been investigated in ER-/HER2+ breast cancer. Here, we aimed to determine the role of β2M in ER-/HER2+ breast cancer.
    METHODS: The interaction between β2M and HFE was confirmed by co-immunoprecipitation, mass spectrometry, yeast two-hybrid screening, and His pull-down. The knockdown and overexpression of β2M or HFE were performed in MDA-MB-453 cells, and ERK signaling pathway was subsequently analyzed via western blotting. Apoptotic cells were detected using flow cytometer. β2M, HFE, and p-ERK1/2 were examined in tumor and paired adjacent tissues via immunohistochemistry.
    RESULTS: HFE was found to be an interacting protein of β2M in ER-/HER2+ breast cancer cells MDA-MB-453 by co-immunoprecipitation and mass spectrometry. A yeast two-hybrid system and His-pull down experiments verified that β2M directly interacted with HFE. β2M and HFE as a complex were mainly located in the cytoplasm, with some on the cytomembrane of MDA-MB-453 cells. In addition to breast cancer cells BT474, endogenous β2M directly interacted with HFE in breast cancer cells MDA-MB-453, MDA-MB-231, and MCF-7. β2M activated the ERK signaling pathway by interacting with HFE and induced apoptosis of MDA-MB-453 cells. The expression of HFE and p-ERK1/2 showed significantly high levels in HER2-overexpressing breast cancer tumor tissue compared with adjacent normal tissue, consistent with the results obtained from the cell experiments.
    CONCLUSIONS: β2M induced apoptosis of tumor cells via activation of the ERK signal pathway by directly interacting with HFE in HER2-overexpressing breast cancer.
    Keywords:  Apoptosis; ERK signaling pathway; HER2-overexpressing breast cancer; Protein–protein interaction; β2M
    DOI:  https://doi.org/10.1186/s12885-024-12757-x
  5. Elife. 2024 Aug 15. pii: RP97327. [Epub ahead of print]13
    RGS10 deficiency facilitates distant metastasis by inducing epithelial-mesenchymal transition in breast cancer.
    Yang Liu, Yi Jiang, Peng Qiu, Tie Ma, Yang Bai, Jiawen Bu, Yueting Hu, Ming Jin, Tong Zhu, Xi Gu.
      Distant metastasis is the major cause of death in patients with breast cancer. Epithelial-mesenchymal transition (EMT) contributes to breast cancer metastasis. Regulator of G protein-signaling (RGS) proteins modulates metastasis in various cancers. This study identified a novel role for RGS10 in EMT and metastasis in breast cancer. RGS10 protein levels were significantly lower in breast cancer tissues compared to normal breast tissues, and deficiency in RGS10 protein predicted a worse prognosis in patients with breast cancer. RGS10 protein levels were lower in the highly aggressive cell line MDA-MB-231 than in the poorly aggressive, less invasive cell lines MCF7 and SKBR3. Silencing RGS10 in SKBR3 cells enhanced EMT and caused SKBR3 cell migration and invasion. The ability of RGS10 to suppress EMT and metastasis in breast cancer was dependent on lipocalin-2 and MIR539-5p. These findings identify RGS10 as a tumor suppressor, prognostic biomarker, and potential therapeutic target for breast cancer.
    Keywords:  EMT; RGS10; breast cancer; cancer biology; human; metastasis; miRNA; mouse
    DOI:  https://doi.org/10.7554/eLife.97327
  6. Cancer Cell Int. 2024 Aug 12. 24(1): 284
    Adipocytes promote metastasis of breast cancer by attenuating the FOXO1 effects and regulating copper homeostasis.
    Xiu Chen, Heda Zhang, Zheng Fang, Dandan Wang, Yuxin Song, Qian Zhang, Junchen Hou, Sujin Yang, Di Xu, Yinjiao Fei, Wei Zhang, Jian Zhang, Jinhai Tang, Lei Li.
       BACKGROUND: Obesity and the forkhead box O1(FOXO1) affect the survival of breast cancer patients, but the underlying mechanism remains unclear. We aimed to investigate the role of FOXO1 in obesity-associated-breast cancer.
    METHODS: We screened 383 breast disease patients from the first affiliated hospital with Nanjing Medical University in 2020. We performed wound healing, transwell, matrigel assays to assess the metastatic ability of cancer cells. We adopted mRNAs sequencing to select the differentially expressed transcripts in breast cancer. We applied immunohistochemistry, western blot, tissue microarrays to assess the level of FOXO1 and epithelial-mesenchymal transition (EMT) pathways. We conducted bioinformatic analysis to investigate interactions between FOXO1 and miR-135b. We used fluorescence in situ hybridization, RT-qPCR to confirm the characteristics of circCNIH4. We conducted luciferase reporter assay, rescue experiments to investigate interactions between circCNIH4 and miR-135b.
    RESULTS: Obesity was positively correlated with the incidence and progression of breast cancer. Adipocytes enhanced the migration of breast cancer and attenuated the effects of FOXO1. MiR-135b was a binding gene of FOXO1 and was regulated by circCNIH4. CircCNIH4 exhibited antitumor activity in vitro and in vivo.
    CONCLUSION: Adipocytes might accelerate the progression of breast cancer by modulating FOXO1/miR-135b/ circCNIH4 /EMT axis and regulating copper homeostasis.
    Keywords:  Adipocyte; Breast cancer; Copper homeostasis; FOXO1; Metastasis
    DOI:  https://doi.org/10.1186/s12935-024-03433-y
  7. Curr Med Chem. 2024 Aug 09.
    HTB50-2 Inhibits Growth and Migration of Triple-negative Breast Cancer via FOSL2/FOXC1 Signaling Axis and Subsequent Ferroptosis.
    Na Liu, Wen-Ying Yin, Wen-Qi Duan, Yu-Zhu Lyu, Shan Xie, Lei Fang, Yan Ji, Feng-Ying Yang, Di Ge.
       BACKGROUND: The manipulation of ferroptosis in cancer cells is a possible therapeutic technique that has been investigated for use in the treatment of cancer. Consequently, ferroptosis-inducing medications have recently received increased interest in cancer therapy. In this research, we assessed the anticancer efficacy of 14β-hydroxy- 3β-(β-D-Glucopyranosyloxy)-5α-bufa-20,22-dienolide (HTB50-2), a natural product derived from the plant Helleborus thibetanus Franch, in Triple-Negative Breast Cancer (TNBC). Moreover, we also studied its potential mechanisms.
    METHODS: The biological effects of HTB50-2 in a series of breast cancer cell lines were analyzed using sulforhodamine B (SRB) and other methods. The migration ability was analyzed using three methods: wound healing assay, transwell assay, and Western blot. Meanwhile, the potential therapeutic value of HTB50-2 was evaluated in BALB/c mice by orthotopic transplantation. Transcriptome sequencing was conducted to explore the FOS-like antigen 2 (FOSL2) gene, and its role in ferroptosis was verified by Western blot and immunohistochemistry. The association of FOSL2 and ferroptosis-related genes was analyzed using NetworkAnalyst databases, and a TF-Gene interaction network was constructed.
    RESULTS: Ferroptosis was found to be induced in TNBC cells by HTB50-2. Furthermore, HTB50-2 inhibited tumor development by inducing ferroptosis in TNBC in vivo. Mechanistically, we demonstrated that a transcription factor FOSL2 mediated ferroptosis by HTB50-2. Additionally, it was found that Forkhead box C1 (FOXC1) was regulated by FOSL2 and correlated with ferroptosis.
    CONCLUSION: Our data suggest that HTB50-2 exerts its anti-cancer properties by ferroptosis via FOSL2/FOXC1 signaling pathway. Hence, HTB50-2 has an important application potential in the treatment of TNBC.
    Keywords:  CGs; FOSL2; FOXC1.; TNBC; ferroptosis; migration
    DOI:  https://doi.org/10.2174/0109298673306760240802062909
  8. Stem Cell Res Ther. 2024 Aug 13. 15(1): 256
    Orai1 and Orai3 act through distinct signalling axes to promote stemness and tumorigenicity of breast cancer stem cells.
    Duan Zhuo, Zhenchuan Lei, Lin Dong, Andrew Man Lok Chan, Jiacheng Lin, Liwen Jiang, Beibei Qiu, Xiaohua Jiang, Youhua Tan, Xiaoqiang Yao.
       BACKGROUND: One of major challenges in breast tumor therapy is the existence of breast cancer stem cells (BCSCs). BCSCs are a small subpopulation of tumor cells that exhibit characteristics of stem cells. BCSCs are responsible for progression, recurrence, chemoresistance and metastasis of breast cancer. Ca2+ signalling plays an important role in diverse processes in cancer development. However, the role of Ca2+ signalling in BCSCs is still poorly understood.
    METHODS: A highly effective 3D soft fibrin gel system was used to enrich BCSC-like cells from ER+ breast cancer lines MCF7 and MDA-MB-415. We then investigated the role of two Ca2+-permeable ion channels Orai1 and Orai3 in the growth and stemness of BCSC-like cells in vitro, and tumorigenicity in female NOD/SCID mice in vivo.
    RESULTS: Orai1 RNA silencing and pharmacological inhibition reduced the growth of BCSC-like cells in tumor spheroids, decreased the expression levels of BCSC markers, and reduced the growth of tumor xenografts in NOD/SCID mice. Orai3 RNA silencing also had similar inhibitory effect on the growth and stemness of BCSC-like cells in vitro, and tumor xenograft growth in vivo. Mechanistically, Orai1 and SPCA2 mediate store-operated Ca2+ entry. Knockdown of Orai1 or SPCA2 inhibited glycolysis pathway, whereas knockdown of Orai3 or STIM1 had no effect on glycolysis.
    CONCLUSION: We found that Orai1 interacts with SPCA2 to mediate store-independent Ca2+ entry, subsequently promoting the growth and tumorigenicity of BCSC-like cells via glycolysis pathway. In contrast, Orai3 and STIM1 mediate store-operated Ca2+ entry, promoting the growth and tumorigenicity of BCSC-like cells via a glycolysis-independent pathway. Together, our study uncovered a well-orchestrated mechanism through which two Ca2+ entry pathways act through distinct signalling axes to finely control the growth and tumorigenicity of BCSCs.
    Keywords:  Breast cancer stem cells; Glycolysis; Orai1; Orai3
    DOI:  https://doi.org/10.1186/s13287-024-03875-1
  9. Int J Biochem Cell Biol. 2024 Aug 13. pii: S1357-2725(24)00129-8. [Epub ahead of print] 106637
    Tumor-derived exosomal ICAM1 promotes bone metastasis of triple-negative breast cancer by inducing CD8+ T cell exhaustion.
    Mingcang Chen, Zhengwei Fu, Chunyu Wu.
      Exosomes, which are nanosized extracellular vesicles, have emerged as crucial mediators of the crosstalk between tumor cells and the immune system. Intercellular adhesion molecule 1 (ICAM1) plays a crucial role in multiple immune functions as well as in the occurrence, development and metastasis of cancer. As a glycoprotein expressed on the cell membrane, ICAM1 is secreted extracellularly on exosomes and regulates the immunosuppressive microenvironment. However, the role of exosomal ICAM1 in the immune microenvironment of breast cancer bone metastases remains unclear. This study aimed to elucidated the role of exosomal ICAM1 in facilitating CD8+ T cell exhaustion and subsequent bone metastasis in triple-negative breast cancer (TNBC). We demonstrated that TNBC cells release ICAM1-enriched exosomes, and the binding of ICAM1 to its receptor is necessary for the suppressive effect of CD8 T cell proliferation and function. This pivotal engagement not only inhibits CD8+ T cell proliferation and activation but also initiates the development of an immunosuppressive microenvironment that is conducive to TNBC tumor growth and bone metastasis. Moreover, ICAM1 blockade significantly impairs the ability of tumor exosomes to bind to CD8+ T cells, thereby inhibiting their immunosuppressive effects. The present study elucidates the complex interaction between primary tumors and the immune system that is mediated by exosomes and provides a foundation for the development of novel cancer immunotherapies that target ICAM1 with the aim of mitigating TNBC bone metastasis.
    Keywords:  CD8+ T cell exhaustion; Exosomes; ICAM1; PD-L1; TNBC; bone metastasis; immunotherapy
    DOI:  https://doi.org/10.1016/j.biocel.2024.106637
  10. Nat Commun. 2024 Aug 12. 15(1): 6915
    Hypoxia-induced downregulation of PGK1 crotonylation promotes tumorigenesis by coordinating glycolysis and the TCA cycle.
    Zihao Guo, Yang Zhang, Haoyue Wang, Liming Liao, Lingdi Ma, Yiliang Zhao, Ronghui Yang, Xuexue Li, Jing Niu, Qiaoyun Chu, Yanxia Fu, Binghui Li, Chuanzhen Yang.
      Protein post-translational modifications (PTMs) are crucial for cancer cells to adapt to hypoxia; however, the functional significance of lysine crotonylation (Kcr) in hypoxia remains unclear. Herein we report a quantitative proteomics analysis of global crotonylome under normoxia and hypoxia, and demonstrate 128 Kcr site alterations across 101 proteins in MDA-MB231 cells. Specifically, we observe a significant decrease in K131cr, K156cr and K220cr of phosphoglycerate kinase 1 (PGK1) upon hypoxia. Enoyl-CoA hydratase 1 (ECHS1) is upregulated and interacts with PGK1, leading to the downregulation of PGK1 Kcr under hypoxia. Abolishment of PGK1 Kcr promotes glycolysis and suppresses mitochondrial pyruvate metabolism by activating pyruvate dehydrogenase kinase 1 (PDHK1). A low PGK1 K131cr level is correlated with malignancy and poor prognosis of breast cancer. Our findings show that PGK1 Kcr is a signal in coordinating glycolysis and the tricarboxylic acid (TCA) cycle and may serve as a diagnostic indicator for breast cancer.
    DOI:  https://doi.org/10.1038/s41467-024-51232-w
  11. Mol Carcinog. 2024 Aug 13.
    Oncogenic fusion of CD63-BCAR4 contributes cancer stem cell-like properties via ALDH1 activity.
    Kieun Bae, Dong Eon Kim, Jin Hee Kim, Ja Young Lee, Kyong-Ah Yoon.
      Gene fusions are common somatic alterations in cancers, and fusions with tumorigenic features have been identified as novel drivers of cancer and therapeutic targets. Few studies have determined whether the oncogenic ability of fusion genes is related to the induction of stemness in cells. Cancer stem cells (CSCs) are a subset of cells that contribute to cancer progression, metastasis, and recurrence, and are critical components of the aggressive features of cancer. Here, we investigated the CSC-like properties induced by CD63-BCAR4 fusion gene, previously reported as an oncogenic fusion, and its potential contribution for the enhanced metastasis as a notable characteristic of CD63-BCAR4. CD63-BCAR4 overexpression facilitates sphere formation in immortalized bronchial epithelial cells. The significantly enhanced sphere-forming activity observed in tumor-derived cells from xenografted mice of CD63-BCAR4 overexpressing cells was suppressed by silencing of BCAR4. RNA microarray analysis revealed that ALDH1A1 was upregulated in the BCAR4 fusion-overexpressing cells. Increased activity and expression of ALDH1A1 were observed in the spheres of CD63-BCAR4 overexpressing cells compared with those of the empty vector. CD133 and CD44 levels were also elevated in BCAR4 fusion-overexpressing cells. Increased NANOG, SOX2, and OCT-3/4 protein levels were observed in metastatic tumor cells derived from mice injected with CD63-BCAR4 overexpressing cells. Moreover, DEAB, an ALDH1A1 inhibitor, reduced the migration activity induced by CD63-BCAR4 as well as the sphere-forming activity. Our findings suggest that CD63-BCAR4 fusion induces CSC-like properties by upregulating ALDH1A1, which contributes to its metastatic features.
    Keywords:  ALDH; BCAR4; CD63‐BCAR4; cancer stem cells; fusion gene
    DOI:  https://doi.org/10.1002/mc.23808
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