bims-merabr 2025-03-16 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–03–16
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Lipid metabolic reprogramming drives triglyceride storage and variable sensitivity to FASN inhibition in endocrine-resistant breast cancer cells.
MELK as a Mediator of Stemness and Metastasis in Aggressive Subtypes of Breast Cancer.
Diversity of ER-positive and HER2-negative breast cancer stem cells attained using selective culture techniques.
PKM2 knockout facilitates the activation of the AMPK/KLF4/ACADVL pathway, leading to increased oxidative degradation of fatty acids in TNBC.
FAT1 functions as an oncogenic driver in triple negative breast cancer through AKT pathway-driven effects on the matrisome.
Cancer-Derived Extracellular Vesicle ITGB2 Promotes the Progression of Triple-Negative Breast Cancer via the Activation of Cancer-Associated Fibroblasts.
Targeting TRAP1-dependent metabolic reprogramming to overcome doxorubicin resistance in quiescent breast cancer.
Tumor Microenvironment On-A-Chip and Single-Cell Analysis Reveal Synergistic Stromal-Immune Crosstalk on Breast Cancer Progression.

Breast Cancer Res. 2025 Mar 07. 27(1): 32

Lipid metabolic reprogramming drives triglyceride storage and variable sensitivity to FASN inhibition in endocrine-resistant breast cancer cells.

Ashley V Ward, Duncan Riley, Kirsten E Cosper, Jessica Finlay-Schultz, Heather M Brechbuhl, Andrew E Libby, Kaitlyn B Hill, Rohan R Varshney, Peter Kabos, Michael C Rudolph, Carol A Sartorius.

   BACKGROUND: Lipid metabolic reprogramming is increasingly recognized as a hallmark of endocrine resistance in estrogen receptor-positive (ER+) breast cancer. In this study, we investigated alterations in lipid metabolism in ER + breast cancer cell lines with acquired resistance to common endocrine therapies and evaluated the efficacy of a clinically relevant fatty acid synthase (FASN) inhibitor.
METHODS: ER + breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD) were derived. Global gene expression and lipidomic profiling were performed to compare parental and endocrine resistant cells. Lipid storage was assessed using Oil Red O (ORO) staining. The FASN inhibitor TVB-2640 was tested for its impact on lipid storage and cell growth. 13C2-acetate tracing was used to evaluate FASN activity and the efficacy of TVB-2640.
RESULTS: Endocrine resistant cells showed significant enrichment in lipid metabolism pathways and distinct lipidomic profiles, characterized by elevated triglyceride levels and enhanced cytoplasmic lipid droplets. 13C2-acetate tracing revealed increased FASN activity in endocrine resistant cells, which was effectively reduced by TVB-2640. While TVB-2640 reduced lipid storage in most but not all cell lines, this did not correlate with decreased cell growth. Polyunsaturated fatty acids (PUFAs) containing 6 or more double bonds were elevated in endocrine resistant cells and remained unaffected or increased with TVB-2640.
CONCLUSION: Endocrine resistant breast cancer cells undergo a metabolic shift toward increased triglyceride storage and PUFAs with high degrees of desaturation. While TVB-2640 reduced lipid storage in most conditions, it had limited effects on the growth of endocrine resistant breast cancer cells. Targeting specific lipid metabolic dependencies, particularly pathways that produce PUFAs, represents a potential therapeutic strategy in endocrine resistant breast cancer.

Keywords:  Breast cancer; Endocrine resistance, lipid metabolism; Fatty acid; Fatty acid synthase; Lipidomics

DOI:  https://doi.org/10.1186/s13058-025-01991-1
Int J Mol Sci. 2025 Mar 03. pii: 2245. [Epub ahead of print]26(5):

MELK as a Mediator of Stemness and Metastasis in Aggressive Subtypes of Breast Cancer.

Breanna McBean, Reine Abou Zeidane, Samuel Lichtman-Mikol, Benjamin Hauk, Johnathan Speers, Savannah Tidmore, Citlally Lopez Flores, Priyanka S Rana, Courtney Pisano, Meilan Liu, Alyssa Santola, Alberto Montero, Alan P Boyle, Corey W Speers.

  Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest prognosis and lacks actionable molecular targets for treatment. Maternal embryonic leucine zipper kinase (MELK) is highly expressed in TNBC and has been implicated in poor clinical outcomes, though its mechanistic role in the aggressive biology of TNBC is poorly understood. Here, we demonstrate a role of MELK in TNBC progression and metastasis. Analysis of publicly available datasets revealed that high MELK expression correlates with worse overall survival, recurrence-free survival, and distant metastasis-free survival, and MELK is co-expressed with metastasis-related genes. Functional studies demonstrated that MELK inhibition, using genomic or pharmacologic inhibition, reduces mammosphere formation, migration, and invasion in high-MELK-expressing TNBC cell lines. Conversely, MELK overexpression in low-MELK-expressing cell lines significantly increased invasive capacity in vitro and metastatic potential in vivo, as evidenced by enhanced metastasis to the liver and lungs in a chorioallantoic membrane assay. These findings highlight MELK as a key regulator of TNBC aggressiveness and support its potential as a therapeutic target to mitigate metastasis and improve patient outcomes.

Keywords:  MELK; invasion; metastasis; migration; triple-negative breast cancer (TNBC); tumor initiation

DOI:  https://doi.org/10.3390/ijms26052245
Sci Rep. 2025 Mar 10. 15(1): 8257

Diversity of ER-positive and HER2-negative breast cancer stem cells attained using selective culture techniques.

Satoshi Sueoka, Azusa Kai, Yukino Kobayashi, Masaoki Ito, Shinsuke Sasada, Akiko Emi, Noriko Gotoh, Koji Arihiro, Koh Nakayama, Morihito Okada, Takayuki Kadoya.

  Breast cancer stem cells are a promising therapeutic target in cancer. We explored breast cancer stem cell diversity and establish a methodology for selectively culturing breast cancer stem cells. We collected breast cancer tissues from surgical samples of treatment-naïve patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Following isolation, cells were subjected to spheroid culture on non-adherent plates. Of the 57 cases, successful culture was achieved in 48 cases, among which the average ratio of CD44+/CD24- breast cancer cells increased from 13.8% in primary tumors to 61.6% in spheroids. A modest number of spheroid cells successfully engrafted in mice and subsequently re-differentiated within the murine environment, confirming their stemness. ER expression in spheroid cells exhibited negative conversion in 52.1% of cases. The proportion of Twist-, Snail-, and Vimentin-positive cells increased from 43.8%, 12.9%, and 7.7-75.0%, 58.1%, and 37.7%, respectively. ER-positive, HER2-negative breast cancer stem cells were classified into two groups using DNA microarrays. Gene Ontology analysis unveiled higher expression of immune response-related genes in one group and protein binding-associated genes in the other. We demonstrated stable and selective culture of breast cancer stem cells from patient-derived breast cancer tissue using spheroid cultures.

Keywords:  Breast cancer; CD24; CD44; Epithelial–mesenchymal transition; Spheroid culture; Stem cell

DOI:  https://doi.org/10.1038/s41598-025-90689-7
Med Oncol. 2025 Mar 12. 42(4): 102

PKM2 knockout facilitates the activation of the AMPK/KLF4/ACADVL pathway, leading to increased oxidative degradation of fatty acids in TNBC.

Linghan Zhang, Li Cheng, Yingchao Ma, Junlin Li, Yue Zhong, Xiuzhi Zhu, XiaoMin Leng, Fuhua Xie.

  This study unveils PKM2 as a master metabolic coordinator in triple-negative breast cancer (TNBC), governing the glycolysis-lipolysis balance through the AMPK/KLF4/ACADVL axis. We demonstrate stage-specific PKM2 upregulation in TNBC, with CRISPR/Cas9 knockout inducing dual metabolic reprogramming-suppressed glycolysis and activated lipid catabolism. Mechanistically, PKM2 ablation triggers AMPK-dependent nuclear translocation of KLF4, which directly activates ACADVL (mitochondrial β-oxidation rate-limiting enzyme), explaining lipid droplet depletion. Therapeutically, synergistic lethality emerges from combining PKM2 knockout with ACADVL inhibition, suggesting metabolic redundancy disruption strategies. Unlike PKM2-SCAP-mediated lipogenesis reported elsewhere, our work establishes a KLF4-driven lipid catabolic pathway specific to TNBC. Crucially, this AMPK/KLF4/ACADVL network operates independently of BRCA status, proposing targeted therapy for chemoresistant non-BRCA mutant TNBC. Our findings redefine TNBC metabolic plasticity through transcriptional-metabolic crosstalk, offering combinatorial therapeutic paradigms against metabolic adaptation.

Keywords:  ACADVL; AMPK; KLF4; PKM2; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s12032-025-02671-y
Int J Biol Sci. 2025 ;21(5): 2201-2222

FAT1 functions as an oncogenic driver in triple negative breast cancer through AKT pathway-driven effects on the matrisome.

Panpan Zhao, Yuanyuan Zhang, Yang Yu, Qing Zhang, Xiaoying Liu, Xu Dong Zhang, Song Chen, Charles E de Bock, Rick F Thorne, Yujie Shi.

  FAT1 cadherin exhibits dual tumor suppressor and oncogenic roles across various cancers, but its function in breast cancer remains unclear due to conflicting reports of mutational loss and overexpression. In this study, we demonstrate that FAT1 mRNA and protein levels are reduced during mammary transformation, an effect linked to promoter methylation rather than mutational events. Subtype-specific analysis reveals that high FAT1 expression correlates with poor outcomes in basal-like/triple-negative breast cancer (TNBC), while elevated FAT1 expression in luminal A/estrogen receptor-positive breast cancers is associated with improved patient prognosis. Functional studies in TNBC models using knockdown and overexpression approaches confirm that FAT1 promotes both cell proliferation and motility. High-throughput sequencing and biochemical assessments establish strong links between FAT1 phenotypes and the activation of PI3K-AKT signaling. Additionally, FAT1 manipulation induces significant changes in matrisome-related genes, extracellular matrix components, and integrin switching. Together, these findings define an oncogenic role for FAT1 in TNBC, providing mechanistic insights into how its regulation influences AKT signaling, cell proliferation, and motility.

Keywords:  FAT1; PI3K-AKT signaling; integrin switching; matrisome; triple negative breast cancer

DOI:  https://doi.org/10.7150/ijbs.104921
Glob Chall. 2025 Mar;9(3): 2400235

Cancer-Derived Extracellular Vesicle ITGB2 Promotes the Progression of Triple-Negative Breast Cancer via the Activation of Cancer-Associated Fibroblasts.

Jingjing Fan, Tong Sha, Binlin Ma.

  Breast cancer is the most prevalent cancer and a leading cause of death among women globally, posing a significant public health challenge. Triple-negative breast cancer (TNBC), an aggressive subtype accounting for 15-20% of all breast cancers, lacks targeted therapies due to the absence of hormone receptors and HER2, resulting in poor prognosis and high recurrence rates. This study investigates the role of cancer-derived extracellular vesicle (EV) integrin beta-2 (ITGB2) in TNBC progression. These findings reveal that ITGB2 is significantly overexpressed in TNBC tissues and serum EVs, correlating with advanced tumor stages and poor patient survival. ITGB2 enhances TNBC progression by activating cancer-associated fibroblasts (CAFs) within the tumor microenvironment, promoting tumor growth, migration, and invasion. Mechanistic studies demonstrate that EV ITGB2 facilitates CAF activation, driving tumor-stroma interactions that support TNBC progression. These results highlight ITGB2 as a potential biomarker and therapeutic target in TNBC, emphasizing the need for novel interventions to combat this challenging breast cancer subtype.

Keywords:  cancer‐associated fibroblast; extracellular vesicle; integrin beta 2; triple‐negative breast cancer; tumor microenvironment

DOI:  https://doi.org/10.1002/gch2.202400235
Drug Resist Updat. 2025 Mar 03. pii: S1368-7646(25)00026-3. [Epub ahead of print]81 101226

Targeting TRAP1-dependent metabolic reprogramming to overcome doxorubicin resistance in quiescent breast cancer.

Muhammad Zubair Saleem, Ruyi Huang, Yingying Huang, Xin Guo, Yang Liu, Miao Gao, Yinjuan Fan, Zhe-Sheng Chen, Zun-Fu Ke, Shengnan Ye, Jianhua Xu.

   AIMS: TRAP1 is involved in metabolic reprogramming and promotes drug resistance. We aimed to explore whether a novel HSP90 inhibitor, C210, overcomes doxorubicin (DOX) resistance of quiescent breast cancer cells by targeting TRAP1.
METHODS: Breast cancer cells were induced to quiescence by hypoxia and low glucose. The relationship of cell metabolism with HSP90 and TRAP1 was investigated by Western blotting, ECAR, OCR, mitochondrial complex activity, and proteomic analysis. The targets of C210 and their functions were analyzed by SPR and immunoprecipitation. The antitumor effect in vivo was investigated with mouse tumor model.
RESULTS: In hypoxia and glucose deprivation, breast cancer cells exhibited elevated TRAP1 and an OXPHOS-enhanced quiescent phenotype. These cells were highly resistant to DOX but more sensitive to C210. C210 disrupted TRAP1's interaction with OXPHOS-associated client proteins, prompting proteasome-dependent degradation of these proteins, thereby reducing OCR, mitochondrial ATP production and resulting in selective elimination of the quiescent cancer cells by inducing mitochondrial apoptosis which could be reversed by exogenous ATP. Moreover, C210 targeted glycolytic, amino acid, and β-oxidation-associated proteome. C210 demonstrated promising in vivo anticancer efficacy which was particularly related to OXPHOS inhibition.
CONCLUSIONS: C210 eliminates DOX-resistant quiescent breast cancer cells by targeting TRAP1-dependent bioenergetics.

Keywords:  Apoptosis; Drug resistance; HSP90; Oxidative phosphorylation; Quiescence; TRAP1

DOI:  https://doi.org/10.1016/j.drup.2025.101226
Adv Sci (Weinh). 2025 Mar 08. e2413457

Tumor Microenvironment On-A-Chip and Single-Cell Analysis Reveal Synergistic Stromal-Immune Crosstalk on Breast Cancer Progression.

Kalpana Ravi, Yining Zhang, Lydia Sakala, Twinkle Jina Minette Manoharan, Barbara Pockaj, Joshua LaBaer, Jin G Park, Mehdi Nikkhah.

  Solid tumors develop within a complex environment called the tumor microenvironment (TME), which is sculpted by the presence of other cells, such as cancer-associated fibroblasts (CAFs) and immune cells like macrophages (Mφs). Despite the presence of immune cells, tumor cells orchestrate a tumor-supportive environment through intricate interaction with the components of the TME. However, the specific mechanism by which this intercellular dialogue is regulated is not fully understood. To that end, the development of an organotypic 3D breast TME-on-a-chip (TMEC) model, integrated with single-cell RNA sequencing analysis, is reported to mechanistically evaluate the progression of triple-negative breast cancer (TNBC) cells in the presence of patient-derived CAFs and Mφs. Extensive functional assays, including invasion and morphometric characterization, reveal the synergistic influence of CAFs and Mφs on tumor cells. Furthermore, gene expression and pathway enrichment analyses identify the involvement of the KYNU gene, suggesting a potential immune evasion mechanism through the kynurenine pathway. Lastly, the pharmacological targeting of the identified pathway is investigated.

Keywords:  cancer‐associated fibroblast (CAFs); macrophages; microfluidics; migration; scRNA sequencing; triple‐negative breast cancer (TNBC); tumor microenvironment (TME)

DOI:  https://doi.org/10.1002/advs.202413457