bims-merabr 2025-12-14 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–12–14
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Breast Cancer Progression by the FGF/FGFR Axis: A Metabolic Perspective.
JAB1/CRL4B complex represses PPARG/ACSL5 expression to promote breast tumorigenesis.
Fascin Drives Breast Cancer Cell Proliferation Partly by Modulating the Cell Cycle Checkpoint Regulators of the G1-S Phase.
17 β-Estradiol Inhibits GSDME-Mediated Pyroptosis in ERα-Positive Breast Cancer Cells by Promoting GSDME Promoter Methylation.
SLX1 Inhibition Enhances Olaparib Sensitivity by Impairing Homologous Recombination Repair in Breast Cancer.
Dual Inhibition of PARP and Akt Induces Metabolic Collapse and Apoptosis in Breast Cancer Cells.
Tamoxifen metabolites acting via BKCa orchestrate the dynamics of K+ and Ca2+ in breast cancer cells.
Investigating the Role of Peroxisomes in Regulating Breast Cancer Stem Cell Mechanisms.

J Mammary Gland Biol Neoplasia. 2025 Dec 10.

Breast Cancer Progression by the FGF/FGFR Axis: A Metabolic Perspective.

Jennifer E Tuokkola, Kathryn L Schwertfeger.

  Fibroblast growth factor receptors (FGFRs) are critical mediators of cellular signaling involved in development, tissue repair, and metabolic homeostasis. Dysregulated FGFR signaling is also a common feature in multiple cancer types, including breast cancer. In breast cancer, aberrant FGFR signaling can occur by amplification, mutation, isoform switching, or gene fusion and has emerged as a driver of tumor progression, metastasis, and therapeutic resistance. Beyond its canonical roles in proliferation and survival, recent evidence highlights FGFRs as key regulators of cancer cell metabolism. This review summarizes current findings on how FGFR signaling reprograms metabolic pathways in breast cancer, specifically glycolytic and lipid metabolism. We explore the interplay between FGFR activity and metabolic enzymes, transcription factors, and nutrient-sensing pathways, emphasizing subtype-specific metabolic vulnerabilities. Furthermore, we discuss how FGFR-mediated metabolic plasticity contributes to tumor heterogeneity and resistance to targeted therapies. Understanding the metabolic functions of FGFR signaling offers new opportunities for therapeutic intervention and biomarker development in breast cancer.

Keywords:  Breast Cancer; Cancer Biology; Cell Signaling; Metabolism

DOI:  https://doi.org/10.1007/s10911-025-09594-4
Cell Death Differ. 2025 Dec 12.

JAB1/CRL4B complex represses PPARG/ACSL5 expression to promote breast tumorigenesis.

Ting Hu, Tianyu Ma, Miaomiao Huo, Jiaxiang Liu, Die Zhang, Yu Li, Jinyuan Chang, Min Zhang, Yinuo Wang, Tianyang Gao, Baowen Yuan, Siqi Wang, Qing Li, Xiaoqi Ma, Jingyao Zhang, Wei Huang, Yan Wang.

Fatty acid metabolism is critical for tumor progression, supplying bioenergetic and biosynthetic substrates to rapidly proliferating cancer cells. However, the precise mechanisms by which fatty acid metabolism influences breast cancer progression remain unclear. In this study, we aimed to explore the molecular mechanism by which C-Jun activation domain-binding protein-1 (JAB1) promotes breast cancer progression through regulating fatty acid metabolism. The JAB1 is identified as an oncogene in breast cancer. JAB1 promotes cell proliferation, invasion, and stemness by stabilizing CUL4B protein. Mechanistically, JAB1 forms a transcriptional repressor complex with the Cullin 4B-Ring E3 ligase (CRL4B) complex, co-occupying the promoters of key fatty acid metabolism genes, PPARG and ACSL5, thus leading to their transcriptional repression. This activates fatty acid metabolism, increasing mitochondrial oxygen consumption and supporting the energetic demands of tumor cells. Notably, JAB1 inhibition reverses chemotherapy resistance associated with CUL4B overexpression. These findings underscore the pivotal role of JAB1 in regulating breast cancer progression and indicate that JAB1 inhibitors could serve as promising therapeutics for patients with elevated CUL4B expression.

DOI: https://doi.org/10.1038/s41418-025-01642-0
Cells. 2025 Nov 21. pii: 1839. [Epub ahead of print]14(23):

Fascin Drives Breast Cancer Cell Proliferation Partly by Modulating the Cell Cycle Checkpoint Regulators of the G1-S Phase.

Hazem Ghebeh, Huda K Al-Nasrallah, Marwa Elfoly, Alanoud Aldossry, Asma Tulbah, Taher Al-Tweigeri, Monther Al-Alwan.

  Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Despite therapeutic advances, disease relapse and metastasis remain major challenges and drivers of mortality. Fascin, an actin-bundling protein, promotes BC progression by enhancing drug resistance. However, the role of fascin in proliferation, a hallmark of cancer, and the underlying mechanism remain poorly elucidated. In this study, bioinformatics analysis of publicly available BC datasets, gene manipulation (gain and loss of function) in BC cell lines, flow cytometry, Western blots, and a real-time cell analyzer (RTCA) were employed to assess the role of fascin in proliferation. The clinical relevance of bioinformatics data and in vitro findings was assessed in BC patient samples using immunohistochemistry. FSCN1 expression exhibited a significant correlation with proliferation signature scores in BC datasets. Ectopic expression of fascin in fascin-negative SK-BR-3 and its silencing in fascin-positive MDA-MB-231 BC cell lines demonstrated its direct role in driving proliferation. In-depth bioinformatics analyses revealed a significant correlation between FSCN1 and the cell cycle signature score, particularly the G1-S signature score gene set. Indeed, fascin accelerated the cell cycle progression of synchronized cells from the G to S phase. Mechanistically, fascin upregulated nuclear SKP2 levels and reduced p27 expression-important G1-S cell cycle checkpoint regulators. Immunohistochemistry in samples from 68 patients demonstrated significant correlations between fascin and Ki-67 expression, in addition to SKP2 overexpression and p27 downregulation. Collectively, these data demonstrate the role of fascin as a driver of the G1-S-phase transition during cell cycle proliferation, thereby revealing new opportunities for targeted therapeutic intervention.

Keywords:  breast cancer; cell cycle; fascin; proliferation

DOI:  https://doi.org/10.3390/cells14231839
J Steroid Biochem Mol Biol. 2025 Dec 10. pii: S0960-0760(25)00248-1. [Epub ahead of print] 106920

17 β-Estradiol Inhibits GSDME-Mediated Pyroptosis in ERα-Positive Breast Cancer Cells by Promoting GSDME Promoter Methylation.

Yu Pan, Rui Li, Huanhuan Ma, Xiaolei Hu, Jun Zhao, Juanjuan Qiao, Xiyao Dou, Yanan Wang, Yanzhi Zhang, Xiuli Wang, Lin Wang.

  Expression of the critical pyroptosis protein gasdermin E (GSDME) has been reported to be regulated by DNA methylation and negatively correlated with expression of estrogen receptor (ER) in breast cancer tissues, suggesting that estrogen-induced target gene methylation may be involved in the regulation of GSDME expression in breast cancer cells. To test this hypothesis, we treated MCF-7 and T47D ER-positive breast cancer cells with 17-β-estradiol (E2), either alone or in combination with selective ERα antagonist AZD9496, selective ERβ antagonist PHTPP, DNA methyltransferase (DNMT) inhibitor RG108, and selective ER degrader Fulvestrant (Ful). Then, GSDME protein and mRNA expression were examined with western blot and RT-qPCR. Pyroptosis was induced by short-wave ultraviolet (UV-C) and detected with morphological observation, lactate dehydrogenase (LDH) release assay, and propidium iodide-Annexin V-FITC fluorescence staining. The methylation status of the GSDME promoter was tested with methylation-specific PCR. The results demonstrated that 100nM E2 significantly decreased GSDME protein and mRNA expression in MCF-7 and T47D cells, and significantly inhibited UV-C-induced pyroptosis. AZD9496 but not PHTPP significantly attenuated the down-regulatory effect of E2 on GSDME expression. E2 induced DNA methylation in the GSDME promoter region and up-regulated DNMT1 expression. RG108 strengthened UV-C-induced pyroptosis, and Ful reversed the inhibitory effects of E2 on UV-C-induced pyroptosis of MCF-7 and T47D cells. Taken together, our study suggests that E2 down-regulated GSDME expression in ERα-positive breast cancer by promoting GSDME promoter methylation, and inhibited UV-C-induced pyroptosis.

Keywords:  DNA methylation; Estrogen; breast cancer; gasdermin E; pyroptosis

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106920
Int J Mol Sci. 2025 Nov 30. pii: 11621. [Epub ahead of print]26(23):

SLX1 Inhibition Enhances Olaparib Sensitivity by Impairing Homologous Recombination Repair in Breast Cancer.

Jin-Young Kim, Jeeho Kim, In-Youb Chang, Sang-Gon Park, Ho Jin You, Young Jin Jeon, Jung-Hee Lee.

  While PARP inhibitors like Olaparib are effective against BRCA1-deficient breast cancers, their efficacy in BRCA1-proficient tumors depends on the functional status of homologous recombination (HR) repair. Here, we identify the structure-specific endonuclease SLX1 as a key regulator of HR and a determinant of Olaparib sensitivity in BRCA1-intact breast cancer. SLX1 is frequently upregulated in breast cancer and associated with poor prognosis. Functional studies revealed that SLX1 promotes RAD51-mediated HR repair of DNA double-strand breaks. Consequently, SLX1 depletion reduces HR efficiency, increases chromosomal instability, and sensitizes breast-proficient breast cancer cells to DNA-damaging agents, including camptothecin, ionizing radiation, and Olaparib. In contrast, SLX1 overexpression enhances DNA repair capacity and promotes Olaparib resistance. In vivo, SLX1 knockdown synergizes with Olaparib to suppress tumor growth in xenograft models. These findings establish SLX1 as a critical regulator of HR function in BRCA1-proficient breast cancer and a promising target for restoring PARP inhibitor sensitivity through induced HR deficiency.

Keywords:  PARP inhibitors; SLX1; breast cancer; homologous recombination (HR) repair

DOI:  https://doi.org/10.3390/ijms262311621
Cancers (Basel). 2025 Nov 29. pii: 3828. [Epub ahead of print]17(23):

Dual Inhibition of PARP and Akt Induces Metabolic Collapse and Apoptosis in Breast Cancer Cells.

Nasreldeen Mohamed Karshom Adam, Eszter Vámos, Hamid Ahmadi, Geofrey Ouma Maloba, Arshi Arshi, Ferenc Gallyas Junior.

   BACKGROUND: Breast cancer is the most prevalent cancer among women worldwide, and therapeutic resistance represents a major clinical challenge. Mitochondria are key regulators of cancer metabolism, redox homeostasis, and apoptosis, making them potential therapeutic targets.
AIM: This study aimed to evaluate the effects of combined Akt and PARP inhibition on mitochondrial metabolic function, energy production, and apoptosis in breast cancer cells.
METHODOLOGY: The SRB assay was used to compare the viability of MDA-MB-231 and MCF7 cells. A colony formation assay was conducted to assess the capacity of individual cells to develop colonies, and ROS production was quantified using DHR123. Flow cytometric analysis was performed to evaluate cell death, and the Seahorse Mito stress test was used to measure ATP production and essential mitochondrial parameters.
RESULTS: The combination of Akt and PARP inhibitors impaired oxidative phosphorylation without inducing a compensatory shift to glycolysis, leading to reduced ATP production, increased ROS generation, and apoptotic cell death in breast cancer cells compared to monotherapy.
CONCLUSIONS AND RECOMMENDATIONS: These findings indicate that the combination of olaparib and capivasterib is a promising therapeutic strategy for breast cancer. Furthermore, evaluation of in vivo toxicity and antitumor effectiveness is essential to validate its potential.

Keywords:  ATP production; MCF7; TNBC; apoptosis; glycolysis; mitochondrial respiration; reactive oxygen species

DOI:  https://doi.org/10.3390/cancers17233828
J Biol Chem. 2025 Dec 06. pii: S0021-9258(25)02867-4. [Epub ahead of print] 111015

Tamoxifen metabolites acting via BKCa orchestrate the dynamics of K+ and Ca2+ in breast cancer cells.

Selina Maier, Werner Schroth, Finn Mier, Lucas Matt, Helmut Bischof, Aiden Tamaddon, Darko Stojkov, Lena Birkenfeld, Melanie Cruz Santos, Dominic Gross, Johanna Dahlen, Florian A Büttner, Irina Bonzheim, Falko Fend, Hiltrud Brauch, Frank M Boeckler, Matthias Schwab, Robert Lukowski.

   THE VOLTAGE: And calcium (Ca2+)-activated potassium (K+) channel of large conductance (BKCa) is aberrantly expressed in various breast cancer (BC) subtypes including estrogen receptor (ER) positive tumors. Increased proliferation of BC cells in response to tamoxifen (TAM) and its metabolites (TAM+M) has been shown to rely on the cell's BKCa status. However, the mechanism by which TAM+M impact on BKCa activity to promote malignancy is as of yet not clear. By examining murine MMTV-PyMT tumor-derived BC cells and human BC cell lines with a genetically encoded K+ ion indicator and electrophysiological recordings, we identified BKCa-dependent intracellular K+ signals and currents provoked by treatment with clinically relevant TAM+M in an ER-independent manner. In line with this, genetical or pharmacological blockade of BKCa significantly diminished the TAM+M-induced modulation of BKCa K+ currents and consequently also the intracellular drop of intracellular K+ ions in BC cells. Changes in the K+ balance subsequently triggered intra- and extracellular Ca2+ mobilization, which was in turn stimulated by the TAM+M-BKCa axis. Our results highlight that BKCa "oncochannels" may modulate the response of BC cells to TAM+M. Activation of the TAM+M-BKCa axis causes significant changes in K+ and Ca2+ ion homeostasis, which ultimately contributes to the outcome of endocrine-based BC pharmacotherapy.

Keywords:  4-Hydroxytamoxifen; BK(Ca,) breast cancer; Endoxifen; Estrogen receptor; K(+) channels; Tamoxifen

DOI:  https://doi.org/10.1016/j.jbc.2025.111015
Int J Mol Sci. 2025 Nov 25. pii: 11389. [Epub ahead of print]26(23):

Investigating the Role of Peroxisomes in Regulating Breast Cancer Stem Cell Mechanisms.

Deniz Simsek, Ghada S Hassan, Federica Sotgia, Michael P Lisanti.

  Cancer and ageing remain major challenges for humanity, requiring innovative solutions. While the role of mitochondria in cancer and ageing has been extensively studied, peroxisomes have received comparatively little attention in this context. In our study, we investigated the impact of peroxisomes on cancer stemness. We systematically analysed the metabolic differences between MCF-7 cells with low- and high-peroxisome levels. Briefly, MCF-7 cells were stably transduced with GFP- and RFP-fluorescent reporters that were targeted to peroxisomes, by addition of a C-terminal SKL (Serine-Lysine-Leucine) peroxisomal targeting signal. To independently validate our observations, MCF-7 cells were also treated with Rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that enhances peroxisome levels. Key parameters examined included cancer stemness, levels of reactive oxygen species (ROS), cell division dynamics, autophagy activity, the DNA damage response, susceptibility to ferroptosis, mitochondrial respiration, and aerobic glycolysis in cells with low- and high-peroxisome profiles. Our results demonstrated that elevated peroxisome levels significantly decrease the capacity of breast cancer stem cells (BCSCs) to form mammospheres or colonies, thus reducing their stemness potential. In high-peroxisome cells, Mammosphere formation was reduced by approximately 50%, and colony formation by 80% compared to low-peroxisome cells. This decline in stemness was accompanied by an approximately one-and-a-half-fold increase in ROS levels and a five-fold increase in lipid peroxidation, reflecting increased mitochondrial lipid peroxidation and ferroptosis. Continued research is, however, essential to further validate these findings and to elucidate the underlying mechanisms.

Keywords:  MCF-7 cells; PPARγ; ROS; cancer; ferroptosis; peroxisomes; stemness

DOI:  https://doi.org/10.3390/ijms262311389