bims-merabr 2025-02-09 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–02–09
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

SLC31A1 promotes chemoresistance through inducing CPT1A-mediated fatty acid oxidation in ER-positive breast cancer.
Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism.
Tumor-derived exosomal lncRNA-MIR193BHG promotes bone metastasis of breast cancer by targeting the miR-489-3p/DNMT3A signaling axis in osteoclasts.
CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells.
Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer.
MiR-301b-3p targets and regulates EBF3 to impact the stem-like phenotype of breast cancer cells through glycolysis.
GPER agonist G-1 activates YAP to induce apoptosis in breast cancer cells.
MiR-5586-5p Suppresses Hypoxia-induced Angiogenesis Through Multiple Targeting of HIF-1α, HBEGF and ADAM17 in Breast Cancer.

Neoplasia. 2025 Feb 03. pii: S1476-5586(25)00004-1. [Epub ahead of print]61 101125

SLC31A1 promotes chemoresistance through inducing CPT1A-mediated fatty acid oxidation in ER-positive breast cancer.

Xudong Li, Jingjing Ge, Mengdi Wan, Tongtong Feng, Xiaoqian Li, Haibo Zhang, Zhangyan Wang, Yongsheng Gao, Meiting Chen, Fei Pan.

  Over 60% of breast cancer cases are diagnosed with estrogen-receptor (ER) positive. Tamoxifen (TAM), a commonly employed medication for ER-positive breast cancer, often yields suboptimal therapeutic outcomes due to the emergence of TAM resistance, leading to the recurrence and a poor prognosis. The copper transporter, solute carrier family 31 member 1 (SLC31A1), has been associated with tumor aggressiveness and unfavorable outcomes in various types of tumors. In our current study, we found high expression of SLC31A1 that predicted poor survival in patients with breast cancer. Significantly, ER-positive breast cancer tissues in patients with recurrence post-TAM treatment exhibited considerably stronger SLC31A1 expression levels. In vitro experiments verified that TAM-resistant ER-positive breast cancer cell lines expressed notably higher SLC31A1 levels compared to the parental cell lines. Of great significance, SLC31A1 depletion notably rescued TAM sensitivity in chemoresistant ER-positive breast cancer cells, as demonstrated by the attenuated cell proliferative and invasive capabilities. Conversely, promoting SLC31A1 significantly facilitated the proliferation and invasion of wild-type breast cancer cells. Subsequently, we detected reduced copper levels in TAM-resistant breast cancer cells with SLC31A1 depletion. Mechanistically, we observed that in chemoresistant breast cancer cell lines, SLC31A1 knockdown resulted in a substantial decrease in the expression of carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of fatty acid oxidation (FAO). RNA-Seq analysis indicated that FAO might be implicated in SLC31A1-mediated breast cancer progression. CPT1A was also overexpressed in TAM-resistant breast cancer cells, accompanied by enhanced FAO rates and ATP levels. Suppressing CPT1A significantly enhanced the chemosensitivity of TAM-resistant breast cancer cells in response to TAM treatments. Intriguingly, copper exposure dose-dependently increased CPT1A expression in chemoresistant breast cancer cells, but this could be abolished upon SLC31A1 knockdown, along with enhanced apoptosis, which elucidated that copper uptake contributed to CPT1A expression. Furthermore, SLC31A1 overexpression significantly augmented CPT1A expression in parental breast cancer cells, accompanied by facilitated copper levels, FAO rates, and ATP levels, while being notably diminished upon CPT1A suppression. Finally, our in vivo studies confirmed that SLC31A1 deficiency re-sensitized TAM-resistant breast cancer cells to TAM treatment and abolished tumor growth. Collectively, all our studies demonstrated that SLC31A1/copper suppression could enhance TAM responses for chemoresistant ER-positive breast cancer cells through constraining the CPT1A-mediated FAO process.

Keywords:  CPT1A; ER-positive breast cancer; FAO; SLC31A1; Tamoxifen resistance

DOI:  https://doi.org/10.1016/j.neo.2025.101125
Nat Commun. 2025 Feb 01. 16(1): 1241

Copy number amplification of FLAD1 promotes the progression of triple-negative breast cancer through lipid metabolism.

Xiao-Qing Song, Tian-Jian Yu, Yang Ou-Yang, Jia-Han Ding, Yi-Zhou Jiang, Zhi-Ming Shao, Yi Xiao.

Triple-negative breast cancer (TNBC) is known for frequent copy number alterations (CNAs) and metabolic reprogramming. However, the mechanism by which CNAs of metabolic genes drive distinct metabolic reprogramming and affect disease progression remains unclear. Through an integrated analysis of our TNBC multiomic dataset (n = 465) and subsequent experimental validation, we identify copy number amplification of the metabolic gene flavin-adenine dinucleotide synthetase 1 (FLAD1) as a crucial genetic event that drives TNBC progression. Mechanistically, FLAD1, but not its enzymatically inactive mutant, upregulates the enzymatic activity of FAD-dependent lysine-specific demethylase 1 (LSD1). LSD1 subsequently promotes the expression of sterol regulatory element-binding protein 1 (SREBP1) by demethylating dimethyl histone H3 lysine 9 (H3K9me2). The upregulation of SREBP1 enhances the expression of lipid biosynthesis genes, ultimately facilitating the progression of TNBC. Clinically, pharmacological inhibition of the FLAD1/LSD1/SREBP1 axis effectively suppresses FLAD1-induced tumor progression. Moreover, LSD1 inhibitor enhances the therapeutic effect of doxorubicin and sacituzumab govitecan (SG). In conclusion, our findings reveal the CNA-derived oncogenic signalling axis of FLAD1/LSD1/SREBP1 and present a promising treatment strategy for TNBC.

DOI: https://doi.org/10.1038/s41467-025-56458-w
J Transl Med. 2025 Jan 31. 23(1): 142

Tumor-derived exosomal lncRNA-MIR193BHG promotes bone metastasis of breast cancer by targeting the miR-489-3p/DNMT3A signaling axis in osteoclasts.

Xiaoya Liu, Rui Ma, Feng Wei, Maihuan Wang, Yiwei Jiang, Peng Zheng, Zhen Cao.

   BACKGROUND: Breast cancer exhibits high incidence and mortality among women, with distant metastasis, especially bone metastasis, being the leading cause of death. Despite advances in adjuvant therapies, bone metastasis remains a challenge for patient survival and quality of life. Exosomes, small vesicles capable of mediating intercellular communication, play a crucial role in tumor metastasis.
RESULTS: This study investigated the role of tumor-derived exosomal long noncoding RNA (lncRNA)-MIR193BHG in breast cancer bone metastasis. LncRNA-MIR193BHG was delivered to osteoclasts via exosomes and promoted osteoclast formation and activity by targeting the miR-489-3p/DNA methyltransferase 3A (DNMT3A) signaling axis, thereby accelerating breast cancer-induced osteolysis. Knockdown experiments demonstrated that reducing the levels of exosomal lncRNA-MIR193BHG significantly inhibited osteoclast differentiation and bone resorption, which was confirmed both in vitro and in vivo. Additionally, mechanistic studies revealed that lncRNA-MIR193BHG acted as a competitive endogenous RNA (ceRNA) interacting with miR-489-3p, regulating DNMT3A expression and subsequently affecting osteoclast differentiation.
CONCLUSIONS: These findings suggest that lncRNA-MIR193BHG plays a critical regulatory role in breast cancer bone metastasis, and the lncRNA-MIR193BHG/miR-489-3p/DNMT3A signaling axis could be a potential target for the treatment of breast cancer bone metastasis. Future studies should further explore the broader applicability of this mechanism and its clinical feasibility.

Keywords:  Breast cancer bone metastasis; Exosomes; LncRNA

DOI:  https://doi.org/10.1186/s12967-025-06156-4
Cancer Metab. 2025 Feb 07. 13(1): 6

CD36 inhibition enhances the anti-proliferative effects of PI3K inhibitors in PTEN-loss anti-HER2 resistant breast cancer cells.

You-Yu Liu, Wei-Lun Huang, Sin-Tian Wang, Hui-Ping Hsu, Tzu-Ching Kao, Wei-Pang Chung, Kung-Chia Young.

   BACKGROUND: HER2-positive patients comprise approximately 20% of breast cancer cases, with HER2-targeted therapy significantly improving progression-free and overall survival. However, subsequent reprogramed tumor progression due to PI3K signaling pathway activation by PIK3CA mutations and/or PTEN-loss cause anti-HER2 resistance. Previously, alpha isoform-specific PI3K inhibitors were shown to potentiate HER2-targeted therapy in breast cancer cells carrying PI3K pathway alterations with less potent effects on PTEN-loss than PIK3CA-mutant cells. Therefore, seeking for alternative combination therapy needs urgent attentions in PTEN-loss anti-HER2 resistant breast cancer.
METHODS: Since remodeling of fatty acid (FA) metabolism might contribute to HER-positive breast cancer and is triggered by the PI3K signal pathway, herein, we examined the effects of the inhibition of endogenous FA conversion, SCD-1 or exogenous FA transport, CD36, in combination with PI3K inhibitors (alpelisib and inavolisib) in anti-HER2 resistant PTEN-loss breast cancer cells.
RESULTS: The activated HER2/PI3K/AKT/mTOR signaling pathway positively correlated with SCD-1 and CD36 expression in PTEN-loss breast cancer cells. PI3K inhibition downregulated SCD-1, and accordingly, the addition of the SCD-1 inhibitor did not augment the antiproliferative effects of the PI3K inhibitors. CD36 was upregulated by blocking the PI3K signal pathway or limited serum supplementation, indicating that suppressing CD36 may decrease the excess transport of exogenous FA. The addition of the CD36 inhibitor synergistically enhanced the anti-proliferative effects of the PI3K inhibitors.
CONCLUSION: Simultaneously targeting the PI3K signaling pathway and exogenous FA uptake could potentially be advantageous for patients with PTEN-loss anti-HER2 resistant breast cancer.

Keywords:  CD36 fatty acids transporter; Fatty acids metabolism; PI3K inhibitors; PTEN-loss; anti-HER2 resistant breast cancer

DOI:  https://doi.org/10.1186/s40170-025-00375-5
Cell Rep. 2025 Feb 04. pii: S2211-1247(25)00038-5. [Epub ahead of print]44(2): 115267

Hypoxia-induced CTCF mediates alternative splicing via coupling chromatin looping and RNA Pol II pause to promote EMT in breast cancer.

Parik Kakani, Shruti Ganesh Dhamdhere, Deepak Pant, Rushikesh Joshi, Sachin Mishra, Anchala Pandey, Dimple Notani, Sanjeev Shukla.

  Hypoxia influences the epithelial-mesenchymal transition (EMT) through the remodeling of the chromatin structure, epigenetics, and alternative splicing. Hypoxia drives CCCTC-binding factor (CTCF) induction through hypoxia-inducible factor 1-alpha (HIF1α), which promotes EMT, although the underlying mechanisms remain unclear. We find that hypoxia significantly increases CTCF occupancy at various EMT-related genes. We present a CTCF-mediated intricate mechanism promoting EMT wherein CTCF binding at the collagen type V alpha 1 chain (COL5A1) promoter is crucial for COL5A1 upregulation under hypoxia. Additionally, hypoxia drives exon64A inclusion in a mutually exclusive alternative splicing event of COL5A1exon64 (exon64A/64B). Notably, CTCF mediates COL5A1 promoter-alternatively spliced exon upstream looping that regulates DNA demethylation at distal exon64A. This further regulates the CTCF-mediated RNA polymerase II pause at COL5A1exon64A, leading to its inclusion in promoting the EMT under hypoxia. Genome-wide study indicates the association of gained CTCF occupancy with the alternative splicing of many cancer-related genes, similar to the proposed model. Specifically, disrupting the HIF1α-CTCF-COL5A1exon64A axis through the dCas9-DNMT3A system alleviates the EMT in hypoxic cancer cells and may represent a novel therapeutic target in breast cancer.

Keywords:  COL5A1; CP: Cancer; CP: Molecular biology; CRISPR-dCas9-mediated editing; CTCF; EMT; alternative splicing; breast cancer; epigenetics; hypoxia; promoter-exon upstream looping

DOI:  https://doi.org/10.1016/j.celrep.2025.115267
J Clin Biochem Nutr. 2025 Jan;76(1): 25-34

MiR-301b-3p targets and regulates EBF3 to impact the stem-like phenotype of breast cancer cells through glycolysis.

Jiankang Huang, Weidong Zhen, Xiaokai Ma, Suxia Ge, Ling Ma.

   BACKGROUND: Cancer stem cells are essential for the development of tumors, their recurrence, metastasis, and resistance to treatment. Previous studies have shown that the silencing of EBF3 promotes the progression of malignant tumors, but its impact on the stem-like phenotype of tumor cells remains unexplored. Therefore, this work aims to investigate the influence of EBF3 on the stem-like phenotype of breast cancer (BC) cells and its underlying molecular mechanisms.
METHODS: Bioinformatics analysis was utilized to predict EBF3 and miR-301b-3p expression and their binding sites in BC tissues. qRT-PCR was conducted to assess EBF3 and miR-301b-3p expression in BC cells. Cell viability was assessed using CCK-8 assay, while sphere-forming ability was assayed by sphere formation experiments. Western blot analysis was employed to assess the expression of stem cell-related markers and proteins associated with the glycolysis metabolic pathway. ECAR experiments and analysis of glycolysis metabolite production were performed to evaluate cellular glycolysis capacity. Dual-luciferase reporter assays and RIP were utilized to validate the binding relationship between EBF3 and miR-301b-3p.
RESULTS: EBF3 was downregulated in BC tissues and cells, and overexpression of EBF3 repressed the glycolysis capacity of BC cells, thereby suppressing stem-like phenotype. Furthermore, miR-301b-3p was identified as a direct target of EBF3, and its expression was increased in BC. Cell experiments revealed that miR-301b-3p suppressed EBF3 expression, thereby promoting the glycolysis capacity and stem-like phenotype of BC cells.
CONCLUSION: miR-301b-3p enhanced glycolysis and promoted the stem-like phenotype of BC cells by targeting EBF3. These findings can offer new therapeutic approaches for BC.

Keywords:  EBF3; breast cancer; glycolysis; miR-301b-3p; stem-like phenotype

DOI:  https://doi.org/10.3164/jcbn.23-131
J Steroid Biochem Mol Biol. 2025 Feb 04. pii: S0960-0760(25)00021-4. [Epub ahead of print] 106693

GPER agonist G-1 activates YAP to induce apoptosis in breast cancer cells.

Ze Fu, Xin Xin, Yongtong Zhan, Xuhong Fan, Xin Li, Tongsheng Chen, Xiaoping Wang.

  G-1, a G protein-coupled estrogen receptor (GPER)-specific agonist, exhibits anticancer potential in breast cancer cells. This study aims to explore the molecular basis of apoptosis induced by G-1 in MCF-7 and MDA-MB-231 breast cancer cells. Here, we found that G-1 induced cytotoxicity and GPER-dependent apoptosis with PARP cleavage and mitochondrial membrane potential (MMP) loss, as well as nuclear condensation. Fluorescence resonance energy transfer (FRET) analysis in living cells indicated that G-1 effectively disrupted the interaction between large tumor suppressor 1/2 (LATS1/2) and Yes-associated protein (YAP). Furthermore, G-1 reduced YAP phosphorylation levels and promoted its nuclear accumulation. Notably, knockdown of YAP attenuated G-1-induced apoptosis, highlighting the crucial role of YAP in this process. Additionally, FRET analysis revealed that G-1 enhanced the binding of YAP to p73, leading to an increase in Bcl-2-associated X protein (Bax) expression and an induction of apoptosis. In summary, our findings demonstrate that G-1 induces apoptosis through the GPER/YAP/p73-mediated pathway.

Keywords:  Apoptosis; Breast cancer; G-1; GPER; YAP

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106693
Anticancer Res. 2025 Feb;45(2): 473-489

MiR-5586-5p Suppresses Hypoxia-induced Angiogenesis Through Multiple Targeting of HIF-1α, HBEGF and ADAM17 in Breast Cancer.

Dongjo Shin, Je-Ok Yoo, Jae-Hoon Jeong, Young-Hoon Han.

   BACKGROUND/AIM: Hypoxia-inducible factor-1 alpha (HIF-1α) plays a key role in the cellular response to hypoxia, which plays a crucial role in the induction of abnormal angiogenesis and metastasis. Understanding the mechanism for the regulation of angiogenesis by HIF-1α-regulating miRNA will contribute to developing the strategy to prevent metastasis.
MATERIALS AND METHODS: We conducted a functional screening for HIF-1α-inhibiting miRNAs by evaluating the effects of miRNA mimics on HIF-1α expression and identified miR-5586-5p as an angiogenesis inhibitor through a mechanistic study. Angiogenic activity was assessed by tube formation assays using HUVEC cells exposed to conditioned media from miRNA-transfected breast cancer cells. In vivo activity of miR-5586-5p was examined through intratumoral injection of miRNA in orthotopic xenograft mice established by injecting MDA-MB-231 cells into the mammary fat pads of BALB/c nu/nu mice.
RESULTS: The expression of the critical proangiogenic factors vascular endothelial growth factor A (VEGFA) and angiopoietin-like protein 4 (ANGPTL4) was inhibited by miR-5586-5p. Migration and tube formation of human umbilical vein endothelial cells were reduced in the conditioned medium prepared from miR-5586-5p-transfected cells. miR-5586-5p also suppressed the expression of heparin-binding EGF-like growth factor (HBEGF) and a disintegrin and metalloprotease 17 (ADAM17), which play a role in hypoxic signaling to induce the expression of VEGFA and ANGPTL4. HIF-1α, HBEGF, and ADAM17 were verified as the direct targets of miR-5586-5p responsible for the angiogenesis-suppressing function of miR-5586-5p. Expression levels of miR-5586-5p were lower in tumor tissues than in neighboring normal tissues of breast cancer patients. The expression of miR-5586-5p was inversely correlated to those of HIF-1α, HBEGF, ADAM17, VEGFA, and ANGPTL4. Angiogenesis and subsequent tumor growth were suppressed by intratumoral injection of miR-5586-5p in orthotopic MDA-MB-231 xenografts in mice.
CONCLUSION: A potent tumor-suppressive function of miR-5586-5p applicable for the development of a novel cancer treatment strategy is herein described.

Keywords:  ADAM17; ANGPTL4; HBEGF; HIF-1α; VEGFA; angiogenesis; miR-5586-5p

DOI:  https://doi.org/10.21873/anticanres.17437