bims-merabr 2025-02-23 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–02–23
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Hypoxia‑induced SREBP1‑mediated lipogenesis and autophagy promote cell survival via fatty acid oxidation in breast cancer cells.
GABPα inhibits tumor progression and angiogenesis via a novel 18-bp indel within VEGF promoter in breast cancer.
AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple-Negative Breast Cancer.
Metastasis and chemoresistance in breast cancer: Crucial function of ZEB1/2 proteins.
Amino acid metabolism in breast cancer: Pathogenic drivers and therapeutic opportunities.
LATS1/2 inactivation in the mammary epithelium drives the evolution of a tumor-associated niche.
Cannabinoid Receptor Type 2 Agonist, GW405833, Reduced the Impacts of MDA-MB-231 Breast Cancer Cells on Bone Cells.
Stemness-related gene signatures as a predictive tool for breast cancer radiosensitivity.

Oncol Lett. 2025 Apr;29(4): 175

Hypoxia‑induced SREBP1‑mediated lipogenesis and autophagy promote cell survival via fatty acid oxidation in breast cancer cells.

Jae-Ha Jung, Yeseul Yang, Yongbaek Kim.

  In the hypoxic tumor microenvironment, cancer cells undergo metabolic reprogramming to survive. The present study aimed to assess the effects of hypoxic conditions on the lipid metabolism of breast cancer cells to elucidate the mechanisms by which cancer cells survive in an unfavorable environment. Cell viability was assessed by trypan blue staining, MTT and Annexin V-PI assays. Intracellular lipid levels were quantified using Nile red stain with immunofluorescence (IF). Autophagy was detected using LC3 antibody, Cyto-ID stain, IF, Western blotting, and flow cytometry. Fatty acid oxidation (FAO) and ATP production were analyzed using specific assays, while gene expression was assessed by reverse transcription-polymerase chain reaction. siRNA transfection was used for gene knockdown, and Kaplan-Meier analysis was performed for survival analysis. Fatostatin and rapamycin served as an inhibitor of sterol regulatory element-binding protein 1 (SREBP1) and an autophagy inducer, respectively. Under hypoxic conditions, triple-negative breast cancer (TNBC) MDA-MB-231 cells showed markedly increased survival and proliferation rates compared with normal cells (MCF-10A) and estrogen receptor-positive cells (MCF-7), with no change in apoptosis. Under hypoxic conditions, MDA-MB-231 cells showed increased expression of lipogenesis, autophagy and FAO-related enzymes and activation of SREBP1, a key transcription factor for lipogenic genes, whereas these changes were not observed in MCF-7 cells. When SREBP1 was inhibited with chemical inhibitors and siRNA, the expression of lipogenic, autophagic and FAO-related enzymes decreased, resulting in reduced ATP production and viability in hypoxic MDA-MB-231 cells; however, this effect was restored when an autophagy inducer was added. Kaplan-Meier analysis demonstrated that higher SREBP1 expression in patients with TNBC was associated with a worse prognosis, suggesting that SREBP1-mediated reprogramming of lipid metabolism and autophagy under hypoxia is essential for TNBC cell survival. The results of the present study indicate that strategies targeting SREBP1 could be exploited to treat TNBC and improve prognosis.

Keywords:  FAO; SREBP1; TNBC; autophagy; hypoxia; lipid

DOI:  https://doi.org/10.3892/ol.2025.14921
Cancer Biomark. 2024 Dec;41(3): CBM230541

GABPα inhibits tumor progression and angiogenesis via a novel 18-bp indel within VEGF promoter in breast cancer.

Hui Guo, Yue Han, Qiaoyi Zhou, Jihua Chen, Mengyi Wang, Xiaotong Deng, Zhenrong Wang, Fan Li, Yao Xu.

   BACKGROUND: Pathological angiogenesis is crucial for tumor progression, thus targeting neovascularization is regarded as an effective strategy for cancer therapy. Vascular endothelial growth factor (VEGF), a specific pro-vascular endothelial regulator, contributes to aberrant tumor angiogenesis.
OBJECTIVE: To identify sequence polymorphisms of VEGF gene and the effects on breast cancer.
METHODS: Protein-DNA binding was validated by EMSA and ChIP assay. Gene expression levels were detected by qPCR and western blot. The CCK-8, wound healing and transwell assays were used to assess proliferation, migration, and invasion. Tube formation, CAM, ELISA and IHC assays were performed to evaluate tumor angiogenesis.
RESULTS: A novel 18-bp indel mutation of the VEGF promoter was detected in breast cancer cases, and the deletion allele (DD) presented dominant distribution in patients comparing to the insert type (II). Further analysis revealed that the 18-bp deletion eliminated the recognition sites of GA binding protein alpha (GABPα), which was confirmed by binding experiments. Functionally, the GABPα expression is decreased in breast cancer tissues, and acts as a tumor suppressor to inhibit proliferation, migration, invasion and angiogenesis of breast cancer cells, accompanied by accelerated tumor cell apoptosis. In addition, consistent regulatory roles were investigated in mouse models in response to GABPα overexpression or knockdown as well. Mechanistically, we revealed that GABPα inhibited breast cancer progression and angiogenesis by downregulating VEGF transcription via the 18-bp promoter sequences.
CONCLUSIONS: Our findings provide insights into angiogenic targeted strategy aiming at GABPα-VEGF axis in clinical diagnosis and therapy of breast cancer.

Keywords:  GABPα; VEGF; breast cancer; indel polymorphism; promoter; tumor angiogenesis

DOI:  https://doi.org/10.3233/CBM-230541
Adv Sci (Weinh). 2025 Feb 20. e2408106

AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple-Negative Breast Cancer.

Zicheng Sun, Huazhen Xu, Guanming Lu, Ciqiu Yang, Xinya Gao, Jing Zhang, Xin Liu, Yongcheng Chen, Kun Wang, Jianping Guo, Jie Li.

  Cuproptosis, a recently defined copper-dependent cell death pathway, remains largely unexplored in tumor therapies, particularly in breast cancer. This study demonstrates that triple-negative breast cancer (TNBC) bears a relatively elevated copper levels and exhibits resistance to cuproptosis. Mechanistically, copper activates the AKT signaling pathway, which inhibits ferredoxin-1 (FDX1), a key regulator of cuproptosis. AKT1-mediated FDX1 phosphorylation not only abrogates FDX1-induced cuproptosis and aerobic respiration but also promotes glycolysis. Consequently, the combination of AKT1 inhibitors and the copper ionophores synergistically alleviate TNBC tumorigenesis both in vitro and in vivo. In summary, the findings reveal a crucial mechanism underlying TNBC resistance to cuproptosis and suggest a potential therapeutic approach for TNBC.

Keywords:  AKT1; FDX1; breast cancer; cuproptosis; metabolic reprogramming

DOI:  https://doi.org/10.1002/advs.202408106
Pathol Res Pract. 2025 Feb 11. pii: S0344-0338(25)00030-5. [Epub ahead of print]267 155838

Metastasis and chemoresistance in breast cancer: Crucial function of ZEB1/2 proteins.

Seyed Mohammad Doodmani, Mohamad Hosein Safari, Mohammadarian Akbari, Najma Farahani, Mina Alimohammadi, Amir Reza Aref, Fatemeh Tajik, Amin Maghsoodlou, Salman Daneshi, Teimour Tabari, Afshin Taheriazam, Maliheh Entezari, Noushin Nabavi, Mehrdad Hashemi.

  Breast cancer remains one of the leading causes of mortality worldwide. While advancements in chemotherapy, immunotherapy, radiotherapy, and targeted therapies have significantly improved breast cancer treatment, many patients are diagnosed at advanced stages, where tumor cells exhibit aggressive behavior and therapy resistance. Understanding the mechanisms driving breast cancer progression is therefore critical. Metastasis is a major factor that drastically reduces patient prognosis and survival, accounting for most breast cancer-related deaths. ZEB proteins have emerged as key regulators of cancer metastasis. Beyond their role in metastasis, ZEB proteins also influence drug resistance. This review focuses on the role of ZEB1 and ZEB2 in regulating breast cancer metastasis. These proteins interact with components of the tumor microenvironment (TME) to drive cancer progression and metastasis. Additionally, ZEB proteins regulate angiogenesis through interactions with VEGF. Targeting ZEB proteins offers potential therapeutic benefits, particularly for aggressive breast cancer subtypes such as triple-negative breast cancer (TNBC), which often show poor therapeutic response. ZEB proteins also influence the sensitivity of breast cancer cells to chemotherapy, making them promising targets for enhancing treatment efficacy. Given their upregulation in breast cancer, ZEB proteins can serve as valuable diagnostic and prognostic markers.

Keywords:  Breast cancer; Cancer chemoresistance; EMT; Metastasis; ZEB

DOI:  https://doi.org/10.1016/j.prp.2025.155838
Protein Cell. 2025 Feb 20. pii: pwaf011. [Epub ahead of print]

Amino acid metabolism in breast cancer: Pathogenic drivers and therapeutic opportunities.

Yawen Liu, Xiangyun Zong, Patricia Altea-Manzano, Jie Fu.

  Amino acid metabolism plays a critical role in the progression and development of breast cancer. Cancer cells, including those in breast cancer, reprogram amino acid metabolism to meet the demands of rapid proliferation, survival, and immune evasion. This includes alterations in the uptake and utilization of amino acids such as glutamine, serine, glycine, and arginine, which provide essential building blocks for biosynthesis, energy production, and redox homeostasis. Notably, the metabolic phenotypes of breast cancer cells vary across molecular subtypes and disease stages, emphasizing the need for patient stratification and personalized therapeutic strategies. Advances in multi-level diagnostics, including phenotyping and predictive tools such as AI-based analysis and body fluid profiling, have highlighted the potential for tailoring treatments to individual metabolic profiles. Enzymes such as glutaminase and serine hydroxymethyltransferase, often upregulated in breast cancer, represent promising therapeutic targets. Understanding the interplay between amino acid metabolism and breast cancer biology, alongside the integration of personalized medicine approaches, can uncover novel insights into tumor progression and guide the development of precision therapies. This review explores the metabolic pathways of amino acids in breast cancer, with a focus on their implications for personalized treatment strategies.

Keywords:  amino acid metabolism; breast cancer; cancer therapy; metabolic reprogramming; personalized medicine

DOI:  https://doi.org/10.1093/procel/pwaf011
EMBO Rep. 2025 Feb 14.

LATS1/2 inactivation in the mammary epithelium drives the evolution of a tumor-associated niche.

Joseph G Kern, Lina Kroehling, Anthony J Spinella, Stefano Monti, Xaralabos Varelas.

  Basal-like breast cancers exhibit distinct cellular heterogeneity that contributes to disease pathology. In this study we used a genetic mouse model of basal-like breast cancer driven by epithelial-specific inactivation of the Hippo pathway-regulating LATS1 and LATS2 kinases to elucidate epithelial-stromal interactions. We demonstrate that basal-like carcinoma initiation in this model is accompanied by the accumulation of distinct cancer-associated fibroblasts and macrophages and dramatic extracellular matrix remodeling, phenocopying the stromal diversity observed in human triple-negative breast tumors. Dysregulated epithelial-stromal signals were observed, including those mediated by TGF-β, PDGF, and CSF. Autonomous activation of the transcriptional effector TAZ was observed in LATS1/2-deleted cells along with non-autonomous activation within the evolving tumor niche. We further show that inhibition of the YAP/TAZ-associated TEAD family of transcription factors blocks the development of the carcinomas and associated microenvironment. These observations demonstrate that carcinomas resulting from Hippo pathway dysregulation in the mammary epithelium are sufficient to drive cellular events that promote a basal-like tumor-associated niche and suggest that targeting dysregulated YAP/TAZ-TEAD activity may offer a therapeutic opportunity for basal-like mammary tumors.

Keywords:  Hippo Signaling; LATS1/2; TEAD; Tumor Microenvironment; YAP/TAZ

DOI:  https://doi.org/10.1038/s44319-025-00370-3
Cancer Med. 2025 Feb;14(4): e70709

Cannabinoid Receptor Type 2 Agonist, GW405833, Reduced the Impacts of MDA-MB-231 Breast Cancer Cells on Bone Cells.

Ingon Inson, Chartinun Chutoe, Janjira Kanjanapipak, Kornkamon Lertsuwan.

   AIM: Breast cancer frequently metastasizes to bones. The interaction between breast cancer cells and bone cells results in osteolytic lesions by disrupting the balance between osteoblast-mediated bone production and osteoclast-mediated bone resorption. This study aims to investigate the effects of the cannabinoid receptor type 2 (CB2) agonist, GW405833, on interactions between breast cancer cells and osteoblasts as well as its impact on breast cancer-induced osteoclastogenesis.
MATERIALS & METHODS: MDA-MB-231, UMR-106, RAW 264.7 cells were used to represent breast cancer cells, osteoblast-like cells and macrophage-osteoclast precursor cells, respectively. Cell viability was evaluated by MTT assay, and breast cancer cell invasion was assessed by Transwell invasion assay. Tartrate-resistant acid phosphatase (TRAP) staining was utilized to evaluate osteoclastogenesis.
RESULTS: Our results demonstrated that GW405833 disrupted MDA-MB-231-induced UMR-106 cell death and promoted UMR-106 cell viability. The underlying mechanism of these effects was determined in this study. GW405833 reduced AKT phosphorylation in MDA-MB-231 cells without affecting mTOR protein expression or its phosphorylation. Conversely, in UMR-106 cells, GW405833 induced AKT and mTOR phosphorylated protein. Furthermore, the mTOR inhibitor reversed the GW405833-induced recovery of UMR-106 cell viability under MDA-MB-231-derived conditioned media (CM) exposure. These findings underscore the critical role of the AKT/mTOR pathway in mediating GW405833's inhibitory effects on cancer-bone interactions. Additionally, GW405833 suppressed osteoblast-enhanced breast cancer cell invasion and the expression of invasion-related proteins in both cell types, along with reducing osteoclastogenic factors induced by MDA-MB-231 CM in UMR-106 cells and suppressing MDA-MB-231 CM-enhanced osteoclastogenesis in RAW 264.7 cells.
CONCLUSION: This study highlights the therapeutic potential of cannabinoid receptor agonist for treating breast cancer bone metastasis and bone-related complications.

Keywords:  CB2 agonist; bone interaction; breast cancer; metastasis; osteoblast; osteoclast

DOI:  https://doi.org/10.1002/cam4.70709
Front Immunol. 2025 ;16 1536284

Stemness-related gene signatures as a predictive tool for breast cancer radiosensitivity.

Jinzhi Lai, Rongfu Huang, Jingshan Huang.

   Background: Understanding the role of cancer stemness in predicting breast cancer (BRCA) response to radiotherapy is crucial for optimizing treatment outcomes. This study developed a stemness-based signature to identify BRCA patients who are likely to benefit from radiotherapy.
Methods: Gene expression data for BRCA patients were obtained from the TCGA and METABRIC databases, including 920 TCGA-BRCA and 1980 METABRIC-BRCA patients. Univariate and multivariate Cox regression analyses were used to construct a radiosensitivity signature. Immune cell infiltration and pathway enrichment analyses were conducted using ESTIMATE and GSVA methods. The TIDE algorithm and the pRRophetic platform were employed to predict responses to radiotherapy. Radioresistant BRCA cells were examined using a colony formation assay. Key genes identified in the radiosensitivity signature were validated in vitro by qRT-PCR.
Results: By analyzing gene expression data from 920 BRCA samples, we identified a set of 267 stemness-related genes between high and low mRNAsi groups. Based on these genes, a radiosensitivity signature comprising two stemness-related genes (EMILIN1 and CYP4Z1) was constructed, stratifying patients into radiosensitive (RS) and radioresistant (RR) groups. Radiotherapy within the RS group significantly improved prognosis compared to non-radiotherapy patients. This signature was further validated in the METABRIC dataset. Notably, patients in the RS group also exhibited a significantly better response to immunotherapy compared to the RR group. We established a radioresistant BRCA cell line using the MCF-7 breast cancer cell line. A radioresistant breast cancer cell line (MCF-7/IR) was established by progressive exposure to increasing radiation doses. Comparative clonogenic and CCK8 assays demonstrated a radioresistant phenotype in the MCF-7/IR compared to MCF-7. In vitro studies utilizing both the MCF-7/IR and MCF-7 cell lines validated the expression of two radiosensitivity genes.
Conclusion: This study identified a stemness-related gene signature predictive of radiosensitivity in breast cancer. This signature may guide personalized treatment strategies and inform the development of novel radiosensitizing agents.

Keywords:  PD-L1; breast cancer; cancer stemness; radiosensitivity; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1536284