bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024‒10‒06
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Elevated expression of ELK1 promotes breast cancer cell growth and correlates with poor prognosis of breast cancer patients.
  2. CircGSK3β mediates PD-L1 transcription through miR-338-3p/PRMT5/H3K4me3 to promote breast cancer cell immune evasion and tumor progression.
  3. Hypoxic stabilization of RIPOR3 mRNA via METTL3-mediated m6A methylation drives breast cancer progression and metastasis.
  4. Induction of the TEAD Co-activator VGLL1 by Estrogen Receptor-Targeted Therapy Drives Resistance in Breast Cancer.
  5. Withaferin A decreases glycolytic reprogramming in breast cancer.
  6. HSP90 promotes tumor associated macrophage differentiation during triple-negative breast cancer progression.
  1. Ann Med Surg (Lond). 2024 Oct;86(10): 5767-5775
    Elevated expression of ELK1 promotes breast cancer cell growth and correlates with poor prognosis of breast cancer patients.
    Xiuping Xu, Yanan Wang, Qing Wang, Shanmei Lv, Guofeng Mao.
      Background: Breast cancer is the most common tumor in women and poses a serious threat to women's physical and mental health. The ETS-like gene 1 (ELK1), upregulated in various malignancies, serves as a transcription regulatory factor. This study primarily investigates the biological functions and prognostic significance of ELK1 in breast cancer.Materials and methods: The authors conducted an analysis of ELK1 expression in breast cancer and adjacent tissues using data from The Cancer Genome Atlas (TCGA), and validated these findings with clinical specimens. Additionally, the authors employed siRNA transfection, proliferation and apoptosis assays to elucidate the roles of ELK1 in breast cancer cells. Furthermore, we assessed the correlations between ELK1 expression and the tumor microenvironment, as well as tumor-infiltrating immune cells (TIICs), utilizing the ESTIMATE and CIBERSORT algorithms. Finally, we used Kaplan-Meier plots and COX regressions to identify prognostic factors, and developed a predictive alignment diagram to evaluate the prognostic significance of ELK1 in breast cancer.
    Results: A marked increase in ELK1 expression is evident in breast cancer tissues (P<0.01). Experimental findings demonstrate that silencing ELK1 suppresses proliferation and promotes apoptosis in breast cancer cells. ELK1 plays a pivotal role in regulating the immune microenvironment of breast cancer. Furthermore, the alignment diagram indicates that ELK1 may serve as an independent prognostic factor for breast cancer patients.
    Conclusion: The authors' study reveals that ELK1 exhibits a high expression level in breast cancer tissues and is associated with disease progression and poor prognosis.
    Keywords:  ELK1; apoptosis; breast cancer; prognosis; proliferation
    DOI:  https://doi.org/10.1097/MS9.0000000000002256
  2. Cell Death Discov. 2024 Oct 04. 10(1): 426
    CircGSK3β mediates PD-L1 transcription through miR-338-3p/PRMT5/H3K4me3 to promote breast cancer cell immune evasion and tumor progression.
    Lin Liang, Mengxiang Gao, Wentao Li, Jingqiong Tang, Qian He, Feng Zeng, Jiaying Cao, Siyi Liu, Yan Chen, Xin Li, Yanhong Zhou.
      Circular RNA (circRNA) plays a pivotal role in breast cancer onset and progression. Understanding the biological functions and underlying molecular mechanisms of dysregulated circRNAs in breast cancer is crucial for elucidating its pathogenesis and identifying potential therapeutic targets. In this study, we investigated the role and molecular mechanism of circGSK3β in breast cancer. We found that circGSK3β is highly expressed in breast cancer cell lines, where it promotes cell proliferation, migration, and invasion, thereby driving breast cancer progression. Furthermore, we observed a close association between circGSK3β expression levels and immune evasion in breast cancer cells. Mechanistically, circGSK3β acts as a competing endogenous RNA (ceRNA) by interacting with miR-338-3p, thereby promoting breast cancer cell proliferation, migration, and invasion. Additionally, circGSK3β positively regulates the expression of the target gene PRMT5 through its interaction with miR-338-3p. This, in turn, enhances H3K4me3 recruitment to the promoter region of PD-L1, resulting in upregulation of PD-L1 expression and consequent immune evasion in breast cancer. In summary, our findings underscore the significance of the circGSK3β-miR-338-3p-PRMT5-H3K4me3 axis in promoting breast cancer progression and immune evasion. CircGSK3β emerges as a critical player in breast cancer pathogenesis, potentially serving as a diagnostic and prognostic marker, and offering novel insights into the role of circRNAs in breast cancer progression.
    DOI:  https://doi.org/10.1038/s41420-024-02197-8
  3. Oncogene. 2024 Sep 28.
    Hypoxic stabilization of RIPOR3 mRNA via METTL3-mediated m6A methylation drives breast cancer progression and metastasis.
    Jingjing Xiong, Zirui Zhou, Yulong Jiang, Qifang Li, Zuhan Geng, Jiahao Guo, Chaojun Yan, Jing Zhang.
      Dysregulated N6-methyladenosine (m6A) modification has been associated with breast cancer pathogenesis. Hypoxia which characterizes solid tumors is known to reprogram the m6A epitranscriptome, but the underlying mechanisms of how this process contributes to breast cancer progression remain poorly understood. Through integrative analyses of m6A-RIP sequencing and RNA sequencing databases, we reveal a cluster of mRNAs with upregulated m6A methylation and expression under hypoxia, that are enriched by many oncogenic pathways, including PI3K-Akt signaling. Furthermore, we identify the mRNA, RIPOR3, as a target of METTL3-mediated m6A methylation in response to hypoxia. We find that m6A methylation stabilizes RIPOR3, increasing its protein expression in a METTL3 catalytic activity-dependent manner, and consequently driving breast tumor growth and metastasis. RIPOR3 is found to be overexpressed in breast cancer cell lines and tumor tissues from breast cancer patients, in whom elevated RIPOR3 is associated with a worse prognosis. Mechanistically, we show that RIPOR3 interacts with EGFR and is essential for the PI3K-Akt pathway activation. In conclusion, we identify RIPOR3 as a hypoxia-stabilized oncogenic driver via METTL3-mediated m6A methylation, thus provide a potential therapeutic target for breast cancer.
    DOI:  https://doi.org/10.1038/s41388-024-03180-4
  4. Cancer Res. 2024 Oct 02.
    Induction of the TEAD Co-activator VGLL1 by Estrogen Receptor-Targeted Therapy Drives Resistance in Breast Cancer.
    Carolina Gemma, Chun-Fui Lai, Anup K Singh, Antonino Belfiore, Neil Portman, Heloisa Z Milioli, Manikandan Periyasamy, Sara Raafat, Alyssa J Nicholls, Claire M Davies, Naina R Patel, Georgia M Simmons, Hailing Fan, Van T M Nguyen, Luca Magnani, Emad Rakha, Lesley-Ann Martin, Elgene Lim, R Charles Coombes, Giancarlo Pruneri, Laki Buluwela, Simak Ali.
      Resistance to endocrine therapies (ET) is common in estrogen receptor (ER) positive breast cancer, and most relapsed patients die with ET-resistant disease. While genetic mutations provide explanations for some relapses, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming has been shown to provide possible routes to resistance. By analyzing histone H3 lysine 27 acetylation (H3K27ac) profiles and transcriptional reprogramming in models of ET resistance, we discovered that selective ER degraders (SERDs), such as fulvestrant, promote expression of VGLL1, a co-activator for TEAD transcription factors. VGLL1, acting via TEADs, promoted expression of genes that drive growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1/TEAD4 interaction inhibited VGLL1/TEAD-induced transcriptional programs to prevent growth of resistant cells. EGFR was among the VGLL1/TEAD-regulated genes, and VGLL1-directed EGFR upregulation sensitized fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, these findings identify VGLL1 as a transcriptional driver in ET resistance and advance therapeutic possibilities for relapsed ER+ breast cancer patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0013
  5. Sci Rep. 2024 Oct 04. 14(1): 23147
    Withaferin A decreases glycolytic reprogramming in breast cancer.
    Asifa Khan, Asad Ur Rehman, Shumaila Siddiqui, Jiyauddin Khan, Sheersh Massey, Prithvi Singh, Daman Saluja, Syed Akhtar Husain, Mohammad Askandar Iqbal.
      Reprogrammed glucose metabolism is considered as the hallmark of cancer with therapeutic implications. Phytocompounds have potential to inhibit cancer metabolism. Here, we tested the ability of Withaferin A (WA), a withanolide derived from Withania somnifera, in modulating cancer metabolism. The assessed effect of WA on aerobic glycolysis in breast cancer cell lines showed that WA decreases the glucose uptake, lactate production and ATP generation by inhibiting the expression of key glycolytic enzymes i.e., GLUT1, HK2 and PKM2. We also identified that WA induced inhibition of cancer glycolysis by targeting c-myc as validated by silencing experiments followed by metabolic readouts. Decreased glycolysis resulted in reduced cell viability, biomass and colony forming ability of breast cancer cells. To further validate our in vitro findings in breast cancer patients, we analyzed 90 metabolic pathways in ~ 2000 breast tumors and observed that glycolysis is the most deregulated pathway in breast tumors. Deregulated glycolysis also predicted poor prognosis in breast cancer patients. In addition, patient data showed correlation between c-myc expression and glycolytic deregulation in breast cancer. Taken together, our results highlight the role of WA in inhibiting breast cancer metabolism via c-myc/glycolysis axis.
    DOI:  https://doi.org/10.1038/s41598-024-72221-5
  6. Sci Rep. 2024 09 29. 14(1): 22541
    HSP90 promotes tumor associated macrophage differentiation during triple-negative breast cancer progression.
    Lingjia Hong, Manami Tanaka, Masato Yasui, Mariko Hara-Chikuma.
      Tumor-associated macrophages (TAMs) originating from monocytes are crucial for cancer progression; however, the mechanism of TAM differentiation is unclear. We investigated factors involved in the differentiation of monocytes into TAMs within the tumor microenvironment of triple-negative breast cancer (TNBC). We screened 172 compounds and found that a heat shock protein 90 (HSP90) inhibitor blocked TNBC-induced monocyte-to-TAM differentiation in human monocytes THP-1. TNBC-derived conditional medium (CM) activated cell signaling pathways, including MAP kinase, AKT and STAT3, and increased the expression of TAM-related genes and proteins. These inductions were suppressed by HSP90 inhibition or by knockdown of HSP90 in TNBC. Additionally, we confirmed that TNBC secreted HSP90 extracellularly and that HSP90 itself promoted TAM differentiation. In a mouse tumor model, treatment with an HSP90 inhibitor suppressed tumor growth and reduced TAMs in the tumor microenvironment. Our findings demonstrate the role of HSP90 in TAM differentiation, suggesting HSP90 as a potential target for TNBC immunotherapy due to its regulatory role in monocyte-to-TAM differentiation.
    DOI:  https://doi.org/10.1038/s41598-024-73394-9
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