bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–08–24
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Exploring the critical role of SDHA in breast cancer proliferation: implications for novel therapeutic strategies.
  2. Targeting mTOR and Its Associated Signaling to Induce Cell Death in Breast Cancer Stem Cells.
  3. In vivo CRISPR screening links NFKB1 to endocrine resistance in ER⁺ breast cancer.
  4. Inhibition of CPT1A activates the cGAS/STING pathway to enhance neutrophil-mediated tumor abrogation in triple-negative breast cancer.
  5. The impact of extracellular vesicles on breast cancer metastasis and therapeutics: genetic considerations.
  6. PFKP Mediates Breast Cancer Metastasis Through Altered Glycolysis.
  1. Am J Transl Res. 2025 ;17(7): 5221-5240
    Exploring the critical role of SDHA in breast cancer proliferation: implications for novel therapeutic strategies.
    Sikandar Ali Khan, Ayesha Iftikhar, Muhammad Haider, Samarah Naeem, Saima Qadeer, Asma Ashraf, Afshan Syed Abbas, Mumtaz Hussain, Mostafa A Abdel-Maksoud, Salamn Alrokayan, Ashnah Iqbali, Tahani Alnumasi, Bushra Hafeez Kiani, Abdulaziz Alamri, Yasir Hameed.
       OBJECTIVES: This study aims to evaluate Succinate Dehydrogenase Complex Flavoprotein Subunit A (SDHA) expression across various breast cancer subtypes, its prognostic significance, and the impact of SDHA knockdown on breast cancer cell functions.
    METHODS: To assess SDHA expression in breast cancer, we utilized multiple publicly available databases. Prognostic significance was also evaluated using relevant databases. Methylation status, and enrichment analysis were performed using the GSCA database. The mutational status of SDHA was examined using cBioPortal, and its relationship with immune infiltration and drug sensitivity was assessed. Functional assays, including cell proliferation, colony formation, wound healing, and SDHA knockdown, were performed using MCF-7 and SKBR3 breast cancer cell lines.
    RESULTS: Our results showed that SDHA was significantly overexpressed in breast cancer tissues compared to normal tissues. High SDHA expression was correlated with worse survival in breast cancer patients. Pathological stage analysis revealed that SDHA expression increased as the disease progressed, with lower methylation levels in tumor tissues suggesting epigenetic regulation of its expression. Functionally, SDHA knockdown in MCF-7 and SKBR3 cells led to significant reductions in cell proliferation, colony formation, and migration, highlighting its role in supporting breast cancer cell growth and metastasis.
    CONCLUSION: SDHA was upregulated in breast cancer and associated with poor prognosis. Our findings also suggest that SDHA plays a crucial role in promoting breast cancer cell growth and migration, indicating its therapeutic potential. Targeting SDHA could provide a novel strategy for breast cancer treatment, particularly in overcoming chemoresistance and inhibiting tumor progression.
    Keywords:  Breast cancer; SDHA; prognosis; proliferation; therapeutic target
    DOI:  https://doi.org/10.62347/XAKQ8090
  2. Cell Biol Int. 2025 Aug 20.
    Targeting mTOR and Its Associated Signaling to Induce Cell Death in Breast Cancer Stem Cells.
    Kirti S Prabhu, Zahwa Mariyam, Syed A Rahman, Shilpa Kuttikrishnan, Fareed Ahmad, Ummu Habeeba, Abdul Q Khan, Afsheen Raza, Said Dermime, Salahddin A Gehani, Kulsoom Junejo, Shahab Uddin.
      Breast cancer (BC) is a frequently diagnosed neoplasm in women and the second major cause of cancer-related deaths. Many BC patients develop metastasis and advanced tumors, increasing morbidity and mortality. There is substantial evidence that tumor relapses in BC patients are driven by a unique population of cells called cancer stem cells (CSCs). Breast CSCs confer stemness to BC and survive through the maintenance of several mechanisms, among which is the involvement of the mTOR signaling pathway. mTOR and its associated AKT signaling play a crucial role in regulating CSCsin various human cancers, including breast cancer. This study investigated the role of targeting mTOR/AKT signaling in the modulation of cell death in 2D and 3D breast cancer models. Torin-2, a dual mTOR inhibitor, effectively suppressed cell proliferation by inducing mitochondrial apoptosis. The inhibition of mTOR led to a decrease in AKT activity and downregulation of key translational machinery components, including 4EBP1, eIF4E, and p70S6K. Torin-2 treatment activated autophagy signaling in both 2D and 3D cell models. The induction of autophagy was evidenced by an increase in the autophagy protein LC3II/I in response to Torin-2 treatment. In addition, Torin-2 treatment of spheroids derived from breast cancer cells suppressed the expression of stem cell marker ALDH. Altogether, the dual inhibition of mTORC1 and mTORC2 by Torin-2 resulted in a more profound antitumor activity. This broader and more potent inhibition of the mTOR pathway contributes to effectiveness in suppressing 2D and 3D breast cancer cell growth and survival.
    DOI:  https://doi.org/10.1002/cbin.70071
  3. bioRxiv. 2025 Aug 13. pii: 2025.08.11.669793. [Epub ahead of print]
    In vivo CRISPR screening links NFKB1 to endocrine resistance in ER⁺ breast cancer.
    Cancan Lyu, Sam Hall, Mark A Stamnes, Songhai Chen.
      Resistance to endocrine therapy (ET) remains a major clinical challenge in the treatment of estrogen receptor-positive (ER⁺) breast cancer, underscoring the need for novel therapeutic targets. To identify genetic drivers of ET resistance, we conducted an in vivo genome-wide CRISPR-Cas9 screen in MCF7 cells implanted into ovariectomized nude mice under estrogen-deprived conditions. NFKB1 emerged as a top candidate whose loss promoted estrogen-independent tumor growth and recurrence. Functional studies confirmed that NFKB1 deficiency enhanced tumorigenicity and conferred resistance to tamoxifen and fulvestrant both in vitro and in vivo. Mechanistically, transcriptomic and biochemical analyses revealed that NFKB1 loss activated canonical NF-κB signaling, leading to inflammatory gene induction and hyperactivation of ER signaling. Importantly, pharmacologic inhibition of NF-κB signaling restored ET sensitivity in NFKB1-deficient cells. Clinically, NFKB1 downregulation was enriched in ER⁺ breast tumors and associated with poor patient outcomes. Collectively, these findings establish NFKB1 as a key suppressor of ET resistance, uncover a mechanistic link between inflammation and ER reactivation, and highlight NF-κB signaling as a therapeutic vulnerability in NFKB1-deficient ER⁺ breast cancer.
    DOI:  https://doi.org/10.1101/2025.08.11.669793
  4. Cancer Lett. 2025 Aug 16. pii: S0304-3835(25)00561-0. [Epub ahead of print]633 217991
    Inhibition of CPT1A activates the cGAS/STING pathway to enhance neutrophil-mediated tumor abrogation in triple-negative breast cancer.
    Chenglong Li, Tingfang Gao, Qiuling Zhao, Zhi Li, Zhidong Wang, Shuaishuai Ding, Mengsi Zhang, Yan Qin, Xinwen Xue, Xiao Zhang, Gan Tian, Xiu-Wu Bian, Yi Yang.
      Triple-negative breast cancer (TNBC) remains a challenging malignancy to treat, underscoring the urgent need to explore novel and effective therapeutic targets. In this study, we found that carnitine palmitoyltransferase 1A (CPT1A), the central and rate-limiting enzyme for fatty acid oxidation (FAO) in lipid metabolism, is significantly correlates with poor survival outcomes in TNBC patients and is highly expressed in TNBC patient samples. Inhibition of CPT1A greatly suppresses TNBC tumor growth. Mechanistically, we discovered that beyond disruption of the canonical metabolic functions for tumor cell survival, CPT1A depletion markedly triggers cGAS/STING activation due to lipid accumulation-induced elevation of mitochondrial reactive oxygen species (ROS), leading to mitochondrial damage and subsequent mtDNA cytosolic release, which ultimately promotes neutrophil intratumoral infiltration and acquisition of a tumor-killing phenotype, thereby effectively inhibiting tumor growth. Our current findings suggest that inhibition of CPT1A potently activates the cGAS/STING pathway, significantly enhancing the engagement of neutrophils for tumor abrogation.
    Keywords:  CPT1A; Fatty acid oxidation; Neutrophils; Triple-negative breast cancer (TNBC); cGAS/STING
    DOI:  https://doi.org/10.1016/j.canlet.2025.217991
  5. Cancer Genet. 2025 Aug 12. pii: S2210-7762(25)00097-3. [Epub ahead of print]298-299 1-9
    The impact of extracellular vesicles on breast cancer metastasis and therapeutics: genetic considerations.
    Leila Jahangiri.
      Breast cancer is a significant health problem across the world, and a better understanding of the cellular and molecular properties of the microenvironment in which the breast cancer cells reside is paramount. Breast cancer cells exhibit an intricate bilateral interaction with the tumour microenvironment, which can contribute to tumour progression. This tumour microenvironment comprises a host of proteins, proteoglycans, glycoproteins, signalling molecules, stromal and immune cells, in addition to extracellular vesicles. Extracellular vesicles encompass a range of vesicles that facilitate cell-to-cell communication and signal relay. Examples of these extracellular vesicles include microvesicles, exosomes and apoptotic bodies. Other categorisations divide extracellular vesicles into exosomes and ectosomes based on their biogenesis. The content of extracellular vesicles can be DNA, RNA, miRNA, proteins, glycans and lipids. This content can affect the tumour microenvironment and tumour metastasis and progression. As such, this review article aims to understand the content of extracellular vesicles and those that promote invasion and metastasis in the context of the tumour microenvironment. The implications of these extracellular vesicles for breast cancer therapeutics will be addressed. Finally, the genes indicated in these processes will be discussed.
    Keywords:  Breast cancer; Exosomes; Extracellular vesicles; Metastasis; Therapeutics
    DOI:  https://doi.org/10.1016/j.cancergen.2025.08.003
  6. Cureus. 2025 Jul;17(7): e87880
    PFKP Mediates Breast Cancer Metastasis Through Altered Glycolysis.
    Summayya Anwar, Farhan Haq, Muhammad Saeed.
      Background Despite recent breakthroughs in genetic profiling, breast cancer metastasis remains a considerable challenge affecting treatment and overall patient survival. Therefore, the discovery of target alternatives to restrain metastasis is urgently needed. In the current study, we aimed to identify novel targets driving metastasis and elucidate the underlying mechanisms. Methods We initially identified differentially expressed genes between primary breast tumors and metastatic breast cancer patients using datasets from the Gene Expression Omnibus (GEO) database. Subsequently, we validated these findings by examining the changes in gene expression and their direction in external datasets. Furthermore, we identified the significantly enriched pathways associated with gene expression. We analyzed PFKP expression patterns in 100 samples (normal, primary breast tumor, and metastasis) using quantitative real-time polymerase chain reaction (qRT-PCR), and survival analyses were performed. Results We identified 34 differentially expressed genes in metastatic breast tumors, with CCDC6, PKIA, UACA, and PFKP significantly upregulated (p < 0.05). PFKP was highly expressed in metastasis, negatively correlated with ER/PR/HER2 status, and linked to glycolysis-related genes (ENO1, PGM1, LDHB, and PGK1). Gene set enrichment analysis (GSEA) highlighted its role in glucose metabolism, hypoxia, and angiogenesis. qRT-PCR confirmed PFKP (p < 0.001) and Ki67 (p < 0.001) upregulation in 100 breast cancer samples. PFKP correlated with Ki67, and receiver operating characteristic (ROC) analysis (area under the curve (AUC) > 71%) indicated a strong predictive value. Higher PFKP expression was associated with poor survival, supporting its role as a prognostic marker. Conclusion The current study showed that PFKP promotes tumor metastasis through hypoxia-mediated altered glycolysis and can be a potential prognostic marker used to identify breast cancer metastasis.
    Keywords:  breast cancer; hypoxia; metabolism; metastasis; phosphofructokinase (pfkp)
    DOI:  https://doi.org/10.7759/cureus.87880
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