bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024–09–29
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. NEDD9 is transcriptionally regulated by HDAC4 and promotes breast cancer metastasis and macrophage M2 polarization via the FAK/NF-κB signaling pathway.
  2. UHRF1 knockdown induces cell cycle arrest and apoptosis in breast cancer cells through the ZBTB16/ANXA7/Cyclin B1 axis.
  3. FABP4-mediated lipid metabolism promotes TNBC progression and breast cancer stem cell activity.
  4. Junctional adhesion molecular 3 (JAM3) is a novel tumor suppressor and improves the prognosis in breast cancer brain metastases via the TGF-β/Smad signal pathway.
  5. USP1-mediated deubiquitination of KDM1A promotes the malignant progression of triple-negative breast cancer.
  6. TPTEP1 impedes the reprogramming of fatty acid metabolism in triple negative breast cancer via miR-1343-3p/SIRT3 axis.
  7. A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers.
  8. B3GALT4 modulates tumor progression and autophagy by AKT/mTOR signaling pathway in breast cancer.
  1. Neoplasia. 2024 Sep 25. pii: S1476-5586(24)00100-3. [Epub ahead of print]57 101059
    NEDD9 is transcriptionally regulated by HDAC4 and promotes breast cancer metastasis and macrophage M2 polarization via the FAK/NF-κB signaling pathway.
    Wenhong Liu, Guanghua Luo.
       BACKGROUND: Breast cancer is a malignancy with a generally poor prognosis. With the advancement of molecular research, we have gained deeper insights into the cellular processes that drive breast cancer development. However, the precise mechanisms remain elusive.
    RESULTS: Based on the CPTAC database, we found that NEDD9 expression is up-regulated in breast cancer tissues and is associated with poor prognosis in breast cancer patients. Functional experiments showed that NEDD9 promotes tumor growth and metastasis both in vitro and in vivo. Overexpression of NEDD9 disrupts mammary epithelial acinus formation and triggers epithelial-mesenchymal transition in breast cancer cells, effects that are reversed upon NEDD9 gene silencing. Mechanistically, NEDD9 upregulates its expression by inhibiting HDAC4 activity, leading to enhanced H3K9 acetylation of the NEDD9 gene promoter and activation of the FAK/NF-κB signaling pathway. Furthermore, NEDD9 overexpression promotes IL-6 secretion, which further drives breast cancer progression. Notably, NEDD9 activation fosters the pro-tumoral M2 macrophage polarization in the tumor microenvironment. NEDD9 stimulates IL-6 secretion, polarizes monocytes towards an M2-like phenotype, and enhances BC cell invasiveness.
    CONCLUSIONS: These findings suggest that NEDD9 upregulation plays a pivotal role in breast cancer metastasis and macrophage M2 polarization via the FAK/NF-κB signaling axis. Targeting NEDD9 may offer a promising therapeutic approach for breast cancer treatment.
    Keywords:  Breast cancer; EMT; FAK/NF-κB pathway; HDAC4; M2 macrophages; NEDD9
    DOI:  https://doi.org/10.1016/j.neo.2024.101059
  2. Acta Biochim Biophys Sin (Shanghai). 2024 Sep 23.
    UHRF1 knockdown induces cell cycle arrest and apoptosis in breast cancer cells through the ZBTB16/ANXA7/Cyclin B1 axis.
    Di Liu, Qin Du, Yuxuan Zhu, Yize Guo, Ya Guo.
      Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) is involved in tumorigenicity through DNA methylation in various cancers, including breast cancer. This study aims to investigate the regulatory mechanisms of UHRF1 in breast cancer progression. Herein, we show that UHRF1 is upregulated in breast cancer tissues and cell lines as measured by western blot analysis and immunohistochemistry. Breast cancer cells are transfected with a UHRF1 overexpression plasmid (pcDNA-UHRF1) or short hairpin RNA targeting UHRF1 (sh-UHRF1), followed by detection of cell proliferation, invasion, apoptosis, and cell cycle. UHRF1 overexpression promotes proliferation and invasion and attenuates cell cycle arrest and apoptosis in breast cancer cells, while UHRF1 knockdown shows the opposite effect. Moreover, methylation-specific PCR and ChIP assays indicate that UHRF1 inhibits zinc finger and BTB domain containing 16 (ZBTB16) expression by promoting ZBTB16 promoter methylation via the recruitment of DNA methyltransferase 1 (DNMT1). Then, a co-IP assay is used to verify the interaction between ZBTB16 and the annexin A7 (ANXA7) protein. ZBTB16 promotes ANXA7 expression and subsequently inhibits Cyclin B1 expression. Rescue experiments reveal that ZBTB16 knockdown reverses the inhibitory effects of UHRF1 knockdown on breast cancer cell malignancies and that ANXA7 knockdown abolishes the inhibitory effects of ZBTB16 overexpression on breast cancer cell malignancies. Additionally, UHRF1 knockdown significantly inhibits xenograft tumor growth in vivo. In conclusion, UHRF1 knockdown inhibits proliferation and invasion, induces cell cycle arrest and apoptosis in breast cancer cells via the ZBTB16/ANXA7/Cyclin B1 axis, and reduces xenograft tumor growth in vivo.
    Keywords:  DNA methylation; UHRF1; breast cancer; cell cycle; the ZBTB16/ANXA7/Cyclin B1 axis
    DOI:  https://doi.org/10.3724/abbs.2024148
  3. Cancer Lett. 2024 Sep 19. pii: S0304-3835(24)00666-9. [Epub ahead of print]604 217271
    FABP4-mediated lipid metabolism promotes TNBC progression and breast cancer stem cell activity.
    Liya Yu, Wei Wei, Jian Lv, Yu Lu, Zhihua Wang, Cheguo Cai.
      Metabolic remodeling is a pivotal feature of cancer, with cancer stem cells frequently showcasing distinctive metabolic behaviors. Nonetheless, understanding the metabolic intricacies of triple-negative breast cancer (TNBC) and breast cancer stem cells (BCSCs) has remained elusive. In this study, we meticulously characterized the metabolic profiles of TNBC and BCSCs and delved into their potential implications for TNBC treatment. Our findings illuminated the robust lipid metabolism activity within TNBC tumors, especially in BCSCs. Furthermore, we discovered that Fabp4, through its mediation of fatty acid uptake, plays a crucial role in regulating TNBC lipid metabolism. Knocking down Fabp4 or inhibiting its activity significantly suppressed TNBC tumor progression in both the MMTV-Wnt1 spontaneous TNBC model and the TNBC patient-derived xenograft model. Mechanistically, Fabp4's influence on TNBC tumor progression was linked to its regulation of mitochondrial stability, the CPT1-mediated fatty acid oxidation process, and ROS production. Notably, in a high-fat diet model, Fabp4 deficiency proved to be a substantial inhibitor of obesity-accelerated TNBC progression. Collectively, these findings shed light on the unique metabolic patterns of TNBC and BCSCs, underscore the biological significance of Fabp4-mediated fatty acid metabolism in governing TNBC progression, and offer a solid theoretical foundation for considering metabolic interventions in breast cancer treatment. SIGNIFICANCE: Triple-negative breast cancer progression and breast cancer stem cell activity can be restricted by targeting a critical regulator of lipid responses, FABP4.
    Keywords:  Cancer stem cells; FABP4; Lipid metabolism; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.canlet.2024.217271
  4. J Neurooncol. 2024 Sep 25.
    Junctional adhesion molecular 3 (JAM3) is a novel tumor suppressor and improves the prognosis in breast cancer brain metastases via the TGF-β/Smad signal pathway.
    Kaitao Zhu, Shiwei Li, Hongru Yao, Jilong Hei, WenGuo Jiang, Tracey Martin, Shanyi Zhang.
       PURPOSE: Breast cancer brain metastasis (BCBM) is a deadly clinical problem, and the exact underlying mechanisms remain elusive. Junctional adhesion molecule (JAM), a tight junction protein, is a key negative regulator of cancer cell invasion and metastasis.
    METHODS: Junction adhesion molecule 3 (JAM3) expression in breast cancer was analyzed using bioinformatics methods and confirmed by PCR, western blotting, and immunofluorescence (IF) in cell lines. The effects of exogenous expression of JAM3 using lentiviral vectors on invasion, adhesion, and apoptosis were verified using transwell assays and flow cytometry. Differentially expressed genes (DEGs) were detected by RNA sequencing and verified by q‒PCR and Western blotting. The effect of JAM3 silencing using siRNA was assessed by an adhesion assay. Kaplan‒Meier analysis was applied to calculate the impact of JAM3 expression and classic clinicopathologic characteristics on survival.
    RESULTS: Bioinformatics analysis revealed that JAM3 expression was reduced in BCBM. Exogenous expression of JAM3 minimizes the ability of breast cancer cells to invade and adhere and promotes their apoptosis. Silencing JAM3 results in morphology changes and the recovery of invasion and adhesion to ECMs, and the TGF-β/Smad signaling pathway may be involved. JAM3 predicts less metastasis and good survival in patients with BCBM. Statistical analysis of BCBM samples detected by immunohistochemistry (IHC) and the associated clinicopathological characteristics revealed that low levels of JAM3 expression and high levels of TNF-β1 are linked to the clinical progression of both primary and metastatic breast tumors. Kaplan-Meier analysis revealed that a high expression level of JAM3 was associated with longer survival.
    CONCLUSION: JAM3 can serve as a key negative regulator of breast cancer cell invasion, apoptosis, and brain metastasis, possibly through the TGF/Smad signaling pathway. JAM3 is anticipated to be a promising biomarker for the diagnosis and prognosis of breast cancer.
    Keywords:  Breast cancer brain metastasis; ECMs; Invasion; Junction adhesion molecule 3; TGF-β1/Smad
    DOI:  https://doi.org/10.1007/s11060-024-04797-x
  5. J Biochem Mol Toxicol. 2024 Oct;38(10): e23864
    USP1-mediated deubiquitination of KDM1A promotes the malignant progression of triple-negative breast cancer.
    Yang Su, Yan Du, Wenguang He.
      Previous research has indicated the highly expressed lysine-specific histone demethylase 1A (KDM1A) in several human malignancies, including triple-negative breast cancer (TNBC). However, its detailed mechanisms in TNBC development remain poorly understood. The mRNA levels of KDM1A and Yin Yang 1 (YY1) were determined by RT-qPCR analysis. Western blot was performed to measure KDM1A and ubiquitin-specific protease 1 (USP1) protein expression. Cell proliferation, apoptosis, invasion, migration and stemness were evaluated by MTT assay, EdU assay, flow cytometry, transwell invasion assay, wound-healing assay and sphere-formation assay, respectively. ChIP and dual-luciferase reporter assays were conducted to determine the relationship between YY1 and KDM1A. Xenograft tumor experiment and IHC were carried out to investigate the roles of USP1 and KDM1A in TNBC development in vivo. The highly expressed KDM1A was demonstrated in TNBC tissues and cells, and KDM1A knockdown significantly promoted cell apoptosis, and hampered cell proliferation, invasion, migration, and stemness in TNBC cells. USP1 could increase the stability of KDM1A via deubiquitination, and USP1 depletion restrained the progression of TNBC cells through decreasing KDM1A expression. Moreover, YY1 transcriptionally activated KDM1A expression by directly binding to its promoter in TNBC cells. Additionally, USP1 inhibition reduced KDM1A expression to suppress tumor growth in TNBC mice in vivo. In conclusion, YY1 upregulation increased KDM1A expression via transcriptional activation. USP1 stabilized KDM1A through deubiquitination to promote TNBC progression.
    Keywords:  KDM1A; USP1; YY1; triple‐negative breast cancer
    DOI:  https://doi.org/10.1002/jbt.23864
  6. Int J Biol Macromol. 2024 Sep 19. pii: S0141-8130(24)06600-5. [Epub ahead of print]280(Pt 2): 135792
    TPTEP1 impedes the reprogramming of fatty acid metabolism in triple negative breast cancer via miR-1343-3p/SIRT3 axis.
    Lin Jia, Junning Peng, Hongying Chen, Zhenyu Liu, Jiaxin Gong, Nan Sun, Qingyuan Zhang, Liru Li.
      Recently, the important role of fatty acid (FA) metabolism in cancers has been highlighted. Sirtuin 3 (SIRT3) is determined as an important regulator in the FA metabolism of cancer cells. We are going to verify whether and how lncRNA transmembrane phosphatase with tensin homology pseudogene 1 (TPTEP1) and SIRT3 may exert certain impact on the FA metabolism in triple-negative breast cancer (TNBC). Firstly, TPTEP1 was verified to be with low expression in TNBC cells. Moreover, down-regulation of TPTEP1 was caused by YY1 transcription factor. Functional assays determined the effects of TPTEP1 on the process of TNBC. The results disclosed that TPTEP1 up-regulation significantly repressed cell proliferation, migration, invasion, EMT and the reprogramming of FA metabolism in TNBC. Mechanism experiments detected the regulatory mechanism between TPTEP1 and SIRT3, which turned out that TPTEP1 positively regulated SIRT3 to affect FOXO3a and inhibit the Wnt/β-catenin pathway via sponging miR-1343-3p. All in all, TPTEP1 functioned as a tumor suppressor to regulate TNBC progression via the miR-1343-3p/SIRT3/FOXO3a/Wnt/β-catenin signaling.
    Keywords:  SIRT3; TPTEP1; Triple-negative breast cancer; Wnt/β-catenin
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135792
  7. Cell Commun Signal. 2024 Sep 26. 22(1): 454
    A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers.
    Charlotte Zoe Angel, Shannon Beattie, Ezanee Azlina Mohamad Hanif, Micheal P Ryan, Francisco D C Guerra Liberal, Shu-Dong Zhang, Scott Monteith, Niamh E Buckley, Emma Parker, Shannon Haynes, Alexander J McIntyre, Paula Haddock, Madina Sharifova, Cristina M Branco, Paul B Mullan.
       BACKGROUND: Treatment options for the Triple-Negative Breast Cancer (TNBC) subtype remain limited and the outcome for patients with advanced TNBC is very poor. The standard of care is chemotherapy, but approximately 50% of tumors develop resistance.
    METHODS: We performed gene expression profiling of 58 TNBC tumor samples by microarray, comparing chemosensitive with chemoresistant tumors, which revealed that one of the top upregulated genes was TGFβ2. A connectivity mapping bioinformatics analysis predicted that the SRC inhibitor Dasatinib was a potential pharmacological inhibitor of chemoresistant TNBCs. Claudin-low TNBC cell lines were selected to represent poor-outcome, chemoresistant TNBC, for in vitro experiments and in vivo models.
    RESULTS: In vitro, we identified a signaling axis linking SRC, AKT and ERK2, which in turn upregulated the stability of the transcription factors, Slug and Snail. Slug was shown to repress TGFβ2-antisense 1 to promote TGFβ2 signaling, upregulating cell survival via apoptosis and DNA-damage responses. Additionally, an orthotopic allograft in vivo model demonstrated that the SRC inhibitor Dasatinib reduced tumor growth as a single agent, and enhanced responses to the TNBC mainstay drug, Epirubicin.
    CONCLUSION: Targeting the SRC-Slug-TGFβ2 axis may therefore lead to better treatment options and improve patient outcomes in this highly aggressive subpopulation of TNBCs.
    DOI:  https://doi.org/10.1186/s12964-024-01793-6
  8. Discov Oncol. 2024 Sep 27. 15(1): 488
    B3GALT4 modulates tumor progression and autophagy by AKT/mTOR signaling pathway in breast cancer.
    Yongliang Sha, Huijie Zhuang, Jin Shi, Song Ge, Shiqing He, Yiqiu Wang, Li Ma, Hao Guo, Hui Cheng.
       BACKGROUND: β-1,3-Galactosyltransferase-4 (B3GALT4), a member of the β-1,3-galactosyltransferase gene family, is essential to the development of many malignancies. However, its biological function in breast cancer is still unknown.
    METHOD: Publically accessible datasets, as well as quantitative real-time PCR, western blot, and immunohistochemistry on our patient cohort were used to investigate the expression levels of B3GALT4 in breast cancer. The correlation of B3GALT4 expression with clinical histopathological data and mortality in breast cancer patients was investigated. The effects of B3GALT4 in breast cancer in vitro and in vivo were investigated. RNA-seq, western blot, autophagolysosomes, and the fluorescence intensity of LC3 were used to explore the effects of B3GALT4 on autophagy. Western blot and gene set enrichment analysis (GSEA) were used to identify the AKT/mTOR pathway.
    RESULTS: B3GALT4 was significantly overexpressed in breast cancer tissues and was positively correlated with some aspects of clinicopathological status and poor prognosis. B3GALT4 overexpression significantly promoted cell proliferation, migration, and invasion, both in vitro and in vivo. B3GALT4 inhibition suppressed breast cancer cell proliferation, migration, and invasion in vitro. Suppression of B3GALT4 triggered autophagy and hindered the AKT/mTOR signaling pathway.
    CONCLUSION: According to the present research, B3GALT4 blocked autophagy via the AKT/mTOR pathway and accelerated the growth of breast cancer. B3GALT4 may be an effective target for patients with breast cancer.
    Keywords:  AKT/mTOR pathway; Autophagy; B3GALT4; Breast cancer; Metastasis
    DOI:  https://doi.org/10.1007/s12672-024-01371-9
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