bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024‒11‒17
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. FABP4-mediated lipid accumulation and lipolysis in tumor-associated macrophages promote breast cancer metastasis.
  2. FXR deficiency induced ferroptosis via modulation of the CBP-dependent p53 acetylation to suppress breast cancer growth and metastasis.
  3. Tripartite motif-containing protein 50 suppresses triple-negative breast cancer progression by regulating the epithelial-mesenchymal transition.
  4. EHD1 promotes breast cancer metastasis through upregulating HIF2a expression via activating mTOR pathway.
  5. The acyltransferase transmembrane protein 68 regulates breast cancer cell proliferation by modulating triacylglycerol metabolism.
  6. Evaluation of MYC Oncogene Expression in Human Breast Cancer and Its Relationship with ACSL4 and Lipin-1 Expression.
  7. Significance of LIF/LIFR Signaling in the Progression of Obesity-Driven Triple-Negative Breast Cancer.
  1. Elife. 2024 Nov 08. pii: RP101221. [Epub ahead of print]13
    FABP4-mediated lipid accumulation and lipolysis in tumor-associated macrophages promote breast cancer metastasis.
    Matthew Yorek, Xingshan Jiang, Shanshan Liu, Jiaqing Hao, Jianyu Yu, Anthony Avellino, Zhanxu Liu, Melissa Curry, Henry Keen, Jianqiang Shao, Anand Kanagasabapathy, Maying Kong, Yiqin Xiong, Edward R Sauter, Sonia L Sugg, Bing Li.
      A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in murine macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cell lines, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in murine macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.
    Keywords:  FABP4; breast cancer; cancer biology; human; lipid droplet formation; metastasis; mouse; tumor associated macrophages; unsaturated fats
    DOI:  https://doi.org/10.7554/eLife.101221
  2. Cell Death Dis. 2024 Nov 14. 15(11): 826
    FXR deficiency induced ferroptosis via modulation of the CBP-dependent p53 acetylation to suppress breast cancer growth and metastasis.
    Ping Huang, Han Zhao, Hua Dai, Jinying Li, Xiafang Pan, Wentian Pan, Chunhua Xia, Fanglan Liu.
      Farnesoid X receptor (NR1H4/FXR) functions as a scavenger of lipid peroxide products and drives the proliferation and metastasis of various cancers. However, the underlying molecular mechanisms remain poorly understood. In our study, we found that the expression levels of FXR, vimentin and SLC7A11 were significantly higher in breast cancer tissues, particularly in metastatic cancer tissues compared to non-metastatic ones. Furthermore, the increased FXR expression was positively correlated with vimentin and SLC7A11 in clinical tumor specimens. In addition, a high level of FXR correlated with poor prognosis in patients with breast cancer. Both Z-Guggulsterone (Z-GS), as a pharmacological inhibitor of FXR, and silencing FXR curbed proliferation and migration of breast cancer cells by promoting ferroptosis. Notably, our results showed that FXR competitively bound to CREB-binding protein (CBP) to suppress the interaction between p53 and CBP in the nucleus, and thus prevented p53 acetylation at lys382, which was essential for upregulating the expression of SLC7A11. Conversely, FXR knockdown increased the interaction between p53 and CBP and promoted p53 acetylation, which ultimately led to facilitating ferroptosis in breast cancer cells. More importantly, we also found that Z-GS inhibited TGF-β1-induced tumor growth and metastasis of breast cancer primarily through ferroptosis via regulating CBP-dependent p53 acetylation in nude mice. In conclusion, the FXR was first reported as a tumor promoter that enhanced the proliferation and metastasis of breast cancer cells through regulating CBP-dependent p53 K382 acetylation. It proposes that FXR may serve as a potential therapeutic target for the treatment of breast cancer.
    DOI:  https://doi.org/10.1038/s41419-024-07222-3
  3. Cancer Biol Ther. 2024 Dec 31. 25(1): 2427410
    Tripartite motif-containing protein 50 suppresses triple-negative breast cancer progression by regulating the epithelial-mesenchymal transition.
    Danxiang Chen, Jing Jiang, Wei Zhang, Xinlin Li, Qidong Ge, Xia Liu, Xujun Li.
      BACKGROUND AND OBJECTIVES: Tripartite motif-containing protein 50 (TRIM50) is a recently discovered E3 ubiquitin ligase that participates in tumor progression. TRIM50 is overexpressed in many cancers, although few studies focused on TRIM50's role in breast cancer.METHODS: We overexpressed TRIM50 in triple-negative breast cancer cell lines using plasmid and found that TRIM50 upregulation markedly reduced breast cancer cell proliferation, clone formation, and migration, as well as promoted breast cancer cell apoptosis. Western blotting revealed that accumulated TRIM50 resulted in both mRNA and protein depletion of SNAI1, and partially attenuated the epithelial-mesenchymal transition (EMT) induced by SNAI1.
    RESULTS: In this study, we demonstrate that TRIM50 is downregulated in human breast cancer and that its overexpression closely correlates with diminished invasion capacity in breast cancer, suggesting that TRIM50 may serve as a diagnostic marker and therapeutic target.
    CONCLUSION: TRIM50 plays a key role in breast cancer proliferation and potentially serves as a prognostic and therapeutic target.
    Keywords:  EMT; TRIM50; biomarker; triple-negative breast cancer
    DOI:  https://doi.org/10.1080/15384047.2024.2427410
  4. FASEB J. 2024 Nov 15. 38(21): e70168
    EHD1 promotes breast cancer metastasis through upregulating HIF2a expression via activating mTOR pathway.
    Xiaoqian Gao, Juan Li, Xuefei Feng, Yuchen Xie, Juan Zhang, Jie Liu, Bo Wang, Peijun Liu.
      The multistep dynamic process of metastasis is the primary cause of breast cancer deaths. C-terminal Eps15-homology domain-containing protein 1 (EHD1), a translocator associated with endocytic recycling, has been implicated in various oncogenic processes. However, the precise molecular mechanisms of EHD1-induced breast cancer metastases remain largely unexplored. Here we found that the upregulation of EHD1 in breast cancer was positively associated with distant lymph node metastasis in patients. Meanwhile, EHD1 promoted epithelial-mesenchymal transition (EMT), invasion, and metastasis of breast cancer cells in both two-dimensional (2D) and three-dimensional (3D) culture models in vitro, as well as in vivo. Remarkably, EHD1 can activate the AKT-mTOR pathway to upregulate the protein expression of hypoxia-inducible factor 2α (HIF2α) under normoxic conditions and subsequently enhance the invasive and metastatic breast cancer. Our findings indicated EHD1 as a new regulator of HIF2α and a potential therapeutic target for inhibiting breast cancer metastasis.
    Keywords:  EHD1; HIF2α; breast cancer; mTOR; metastasis
    DOI:  https://doi.org/10.1096/fj.202401919R
  5. Lipids Health Dis. 2024 Nov 15. 23(1): 378
    The acyltransferase transmembrane protein 68 regulates breast cancer cell proliferation by modulating triacylglycerol metabolism.
    Zheng Zhao, Huimin Pang, Qing Yu, Fansi Zeng, Xiaohong He, Quan Sun, Pingan Chang.
      BACKGROUND: Cellular carcinogenesis is often marked by the accumulation of lipid droplets (LDs) due to reprogrammed lipid metabolism. LDs are dynamic organelles that primarily store intracellular triacylglycerol (TAG) and cholesteryl esters (CEs). Transmembrane protein 68 (TMEM68), a potential modifier of human breast cancer risk and outcomes, functions as a diacylglycerol acyltransferase, synthesizing TAG. However, the specific roles of TMEM68 in breast cancer cells remain unclear.METHODS: Gene expression profiling interactive analysis and survival analysis were conducted. TMEM68 was overexpressed or knockdown in breast cancer cells to assess its impact on cell proliferation, migration and invasion. Targeted quantitative lipidomic analysis and quantitative polymerase chain reaction were used to profile lipid alterations and examine gene expression related to lipid metabolism following changes in TMEM68 levels.
    RESULTS: TMEM68 gene was upregulated in breast cancer patients and higher TMEM68 levels were associated with poorer survival outcomes. Overexpression of TMEM68 increased breast cancer cell proliferation and invasion, whereas knockdown had minimal or no impact on reducing proliferation and invasion. Altering TMEM68 levels resulted in corresponding changes in TAG levels and cytoplasmic LDs, with overexpression increasing both and knockdown decreasing them. Lipidomic analysis revealed that TMEM68 regulated TAG levels and altered diacylglycerol content in breast cancer cells. Additionally, TMEM68 influenced the metabolism of glycerophospholipids, CEs and acylcarnitines. TMEM68 also modified the expression of key genes encoding enzymes related to neutral lipid metabolism, including TAG and CEs.
    CONCLUSIONS: TMEM68 is highly expressed in breast cancer and negatively correlated with survival. Its overexpression promotes breast cancer cell proliferation while knockdown has varied effects depending on TMEM68 levels. TMEM68 regulates intracellular TAG and LDs contents along with alterations in glycerophospholipids. These findings suggest that TMEM68 may drive breast cancer cells proliferation by modulating TAG and LD content.
    Keywords:  Breast cancer cell proliferation; Glycerophospholipid; Lipid droplet; Transmembrane protein 68; Triacylglycerol
    DOI:  https://doi.org/10.1186/s12944-024-02369-6
  6. Adv Biomed Res. 2024 ;13 83
    Evaluation of MYC Oncogene Expression in Human Breast Cancer and Its Relationship with ACSL4 and Lipin-1 Expression.
    Negar Dinarvand, Reza Azizi, Sedighe Rastaghi, Farzaneh Karimi, Abdolkarim Sheikhi, Morteza Pourfarzam.
      Background: Disturbances in lipid metabolism are one of the hallmarks of cancer cells. Fatty acid synthesis and oxidation play a crucial role in the proliferation, growth, and survival of cancer cells. Several enzymes are involved in lipid metabolism. MYC is an oncogene and plays various regulatory roles in lipid metabolism. This study aimed to evaluate MYC expression and its association with the expressions of Lipin-1, ACSL4 (enzymes involved in lipid metabolism), in pairs of breast cancer (BC) and adjacent normal tissues to further understand the MYC influence on metabolic regulation.Materials and Methods: Fifty-five pairs of samples of BC and noncancerous adjacent tissues were utilized in the present study to analyze MYC, Lipin-1, and ACSL4 by quantitative real-time polymerase chain reaction. Further, the expression of Lipin-1 and ACSL4 proteins and a number of other clinicopathologically relevant variables were studied employing immunohistochemistry staining.
    Results: MYC expression was substantially higher in BC tissues than in adjacent normal tissues, according to our findings. This upregulation was positively correlated with tumor size and stage. Although MYC expression was not correlated with that of ACSL4 and Lipin-1 expression, this may result from the complex metabolic changes that occur when cells become malignant.
    Conclusions: Although further research is required to assess MYC's impact on tumor metabolic regulation, the correlations seen here between MYC, the pathological stage, and tumor size may indicate its prognostic significance in BC. Hence, it may be considered as a potential therapeutic target for further studies.
    Keywords:  ACSL4; Lipin-1; MYC; breast cancer
    DOI:  https://doi.org/10.4103/abr.abr_419_23
  7. Cancers (Basel). 2024 Oct 28. pii: 3630. [Epub ahead of print]16(21):
    Significance of LIF/LIFR Signaling in the Progression of Obesity-Driven Triple-Negative Breast Cancer.
    Lois Randolph, Jaitri Joshi, Alondra Lee Rodriguez Sanchez, Uday P Pratap, Rahul Gopalam, Yidong Chen, Zhao Lai, Bindu Santhamma, Edward R Kost, Hareesh B Nair, Ratna K Vadlamudi, Panneerdoss Subbarayalu, Suryavathi Viswanadhapalli.
      American women with obesity have an increased incidence of triple-negative breast cancer (TNBC). The impact of obesity conditions on the tumor microenvironment is suspected to accelerate TNBC progression; however, the specific mechanism(s) remains elusive. This study explores the hypothesis that obesity upregulates leukemia inhibitory factor receptor (LIFR) oncogenic signaling in TNBC and assesses the efficacy of LIFR inhibition with EC359 in blocking TNBC progression. TNBC cell lines were co-cultured with human primary adipocytes, or adipocyte-conditioned medium, and treated with EC359. The effects of adiposity were measured using cell viability, colony formation, and invasion assays. Mechanistic studies utilized RNA-Seq, Western blotting, RT-qPCR, and reporter gene assays. The therapeutic potential of EC359 was tested using xenograft and patient-derived organoid (PDO) models. The results showed that adipose conditions increased TNBC cell proliferation and invasion, and these effects correlated with enhanced LIFR signaling. Accordingly, EC359 treatment reduced cell viability, colony formation, and invasion under adipose conditions and blocked adipose-mediated organoid growth and TNBC xenograft tumor growth. RNA-Seq analysis identified critical pathways modulated by LIF/LIFR signaling in diet-induced obesity mouse models. These findings suggest that adiposity contributes to TNBC progression via the activation of the LIF/LIFR pathway, and LIFR inhibition with EC359 represents a promising therapeutic approach for obesity-associated TNBC.
    Keywords:  EC359; LIF/LIFR signaling; RNA-seq; TNBC; obesity
    DOI:  https://doi.org/10.3390/cancers16213630
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒17 at 22:17.