bims-merabr 2025-06-29 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–06–29
ten papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Targeting lipid metabolism to overcome tamoxifen resistance in breast cancer: Evaluating the synergistic therapeutic potential of quercetin.
Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance.
Leptin-Upregulated Metastasis-Associated Protein 1 Promotes Vasculogenic Mimicry in Breast Cancer Cells.
Ivermectin inhibits epithelial-to-mesenchymal transition via Wnt signaling in endocrine-resistant breast cancer cells.
ZBTB12 promotes breast cancer progression through transcriptional activation of the DNMT3B/ALDH1A2 axis.
TRIM34 inhibits triple-negative breast cancer progression by attenuating fatty acid synthesis via facilitating FASN ubiquitination.
AP1S3 affects lipid metabolism in breast cancer cells by regulating the PI3K/AKT/mTOR pathway.
MYC/TET3-Regulated TMEM65 Activates OXPHOS-SERPINB3 Pathway to Promote Progression and Cisplatin Resistance in Triple-Negative Breast Cancer.
The Impact and Safety of GLP-1 Agents and Breast Cancer.
DCTPP1 is Transcriptionally Activated by FOXA1 to Affect Cisplatin Sensitivity in Triple-Negative Breast Cancer via Suppression of Ferroptosis.

Cancer Treat Res Commun. 2025 Jun 10. pii: S2468-2942(25)00089-9. [Epub ahead of print]44 100953

Targeting lipid metabolism to overcome tamoxifen resistance in breast cancer: Evaluating the synergistic therapeutic potential of quercetin.

Radwa M Rifaat, Marwa W Kamel, Marwa Sharaky, Yasmin M Attia, Samia A Shouman.

  Breast cancer remains the most prevalent malignancy among women globally, with hormone receptor-positive subtypes representing the majority of cases. Despite significant advances in treatment, resistance to Tamoxifen, a cornerstone therapy for estrogen receptor-positive (ER+) breast cancer, poses a critical challenge, affecting up to 50 % of patients. Emerging evidence suggests that dysregulated lipid metabolism plays a pivotal role in breast cancer progression and therapy resistance. This systematic review aims to explore the intricate relationship between lipid metabolism and Tamoxifen resistance, with a particular focus on the potential therapeutic synergy of combining Tamoxifen with lipid metabolism modulators, such as Quercetin. We systematically searched PubMed, Scopus, Web of Science, and the Cochrane Library for studies published between 2000 and 2023, examining the role of lipid metabolic pathways in breast cancer and the impact of Quercetin on enhancing Tamoxifen efficacy. The findings suggest that targeting key enzymes involved in lipid metabolism, including fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC), may impair cancer cell survival mechanisms and sensitize tumors to Tamoxifen. The combination of Tamoxifen and Quercetin appears to exhibit synergistic effects, enhancing apoptosis and reducing cell proliferation more effectively than either agent alone. This review highlights the potential of combining Tamoxifen with Quercetin as a therapeutic strategy to overcome Tamoxifen resistance, providing a rationale for further clinical trials to investigate this combination therapy.

Keywords:  Acetyl-CoA Carboxylase (ACC); Breast cancer; Fatty acid synthase (FASN); Lipid metabolism; Quercetin; Tamoxifen resistance

DOI:  https://doi.org/10.1016/j.ctarc.2025.100953
Front Cell Dev Biol. 2025 ;13 1548724

Intercellular communication between extracellular vesicles from conditioned macrophages and breast cancer cells drives endocrine therapy resistance.

María C Rodriguez-Baili, Miguel Palma-Cobo, César G Prucca, María Yáñez-Mó, German A Gil.

   Introduction: Breast cancer is a leading cause of cancer-related mortality among women, with nearly 70% of cases being estrogen receptor-positive (ER+). While endocrine therapies, such as tamoxifen, have significantly improved patient outcomes, resistance-whether intrinsic or acquired-remains a major clinical challenge that limits treatment efficacy. Emerging evidence suggests that endocrine resistance is often driven by the presence and expansion of cancer stem cells (CSCs), which contribute to recurrence, metastasis, and therapeutic failure. The tumor microenvironment (TME), including immune cells like macrophages, soluble factors, and extracellular vesicles (EVs), plays a crucial role in promoting tumor progression and therapy resistance. EVs are small lipid bilayer-bound particles that facilitate intercellular communication by transferring bioactive cargo capable of reprogramming recipient cells.
Methods: To investigate the role of macrophage-derived EVs in endocrine resistance, we isolated EVs from TNF-α-conditioned macrophages (TNF EVs) and treated MCF-7 ER+ breast cancer cells with these vesicles. We assessed changes in proliferation, migration, epithelial-mesenchymal transition (EMT), CSC-like properties, and tamoxifen resistance. Additionally, we evaluated whether tumor-derived EVs modulate macrophage polarization by analyzing the expression of PD-1 and other immunomodulatory markers.
Results: TNF EV-treated MCF-7 cells showed significantly increased proliferation, enhanced migratory behavior, and morphological changes associated with EMT. Importantly, treated cells developed a stem-like phenotype, characterized by a larger CD44High/CD24Low subpopulation and improved spheroid-forming ability. These features correlated with sustained proliferation even in the presence of tamoxifen, supporting the development of endocrine resistance. Furthermore, EVs derived from tumor cells triggered macrophage polarization toward a tumor-associated macrophage (TAM) profile, with increased PD-1 expression, indicating a role in immune suppression and tumor immune evasion.
Discussion: These findings emphasize the dual role of TNF-α-conditioned macrophage-derived EVs in driving both endocrine resistance and immune modulation in ER+ breast cancer. By promoting stemness, EMT, and tamoxifen resistance, as well as inducing immunosuppressive macrophage polarization, these EVs emerge as key contributors to tumor progression. Our study highlights the therapeutic potential of targeting EV-mediated communication to overcome endocrine resistance and enhance clinical outcomes for ER+ breast cancer patients. This work establishes a critical framework for future studies aimed at harnessing EVs as therapeutic targets or biomarkers in breast cancer management.

Keywords:  breast cancer; cancer stem cells (CSS); endocrine resistance; epithelial-mesenchymal transition (EMT); estrogen receptor-positive (ER+); extracellular vesicles (EVs); tumor microenvironment (TME); tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3389/fcell.2025.1548724
Int J Mol Sci. 2025 Jun 15. pii: 5726. [Epub ahead of print]26(12):

Leptin-Upregulated Metastasis-Associated Protein 1 Promotes Vasculogenic Mimicry in Breast Cancer Cells.

Deok-Soo Han, Seung-Il Wang, Seung-Hyeon Lee, Eun-Ok Lee.

  Leptin, a hormone primarily produced by adipose tissue, regulates energy balance and appetite, while contributing significantly to obesity and cancer progression. Vasculogenic mimicry (VM) refers to the process by which aggressive tumor cells form blood vessel-like structures, enabling blood supply independent of endothelial angiogenesis. Metastasis-associated protein 1 (MTA1) facilitates tumor progression and metastasis. This study investigated the role of MTA1 in the relationship between leptin and VM in human breast cancer cells. Leptin upregulated the mRNA and protein expression of MTA1, as revealed by a quantitative real-time PCR and Western blot analysis, respectively. However, the Western blot revealed that leptin-induced MTA1 upregulation was inhibited by the leptin receptor (Ob-R) blocker, Ob-R BP, and the signal transducer and activator of the transcription 3 (STAT3) inhibitor, AG490. The overexpression of MTA1 was observed to induce VM in a three-dimensional culture assay and to upregulate the expression of VM-related proteins, as confirmed by the Western blot. Conversely, silencing MTA1 suppressed leptin-induced VM and the expression of VM-related proteins. These findings indicate that leptin regulates MTA1 expression through the Ob-R/STAT3 signaling pathway and that MTA1 serves as a crucial mediator of leptin-induced VM.

Keywords:  Ob-R; STAT3; breast cancer cells; leptin; metastasis-associated protein 1; vasculogenic mimicry

DOI:  https://doi.org/10.3390/ijms26125726
PLoS One. 2025 ;20(6): e0326742

Ivermectin inhibits epithelial-to-mesenchymal transition via Wnt signaling in endocrine-resistant breast cancer cells.

Kitiya Rujimongkon, Patthamapon Adchariyasakulchai, Phum Meeprasertskul, Wannarasmi Ketchart.

Ivermectin (IVM), an antiparasitic drug, has been explored for its anticancer properties in various cancer types, including breast cancer. Endocrine therapy resistance poses a significant challenge in breast cancer treatment, often leading to metastasis prevention failure. This study aimed to investigate the effects of IVM on endocrine-resistant breast cancer cells, focusing on mechanisms associated with epithelial-to-mesenchymal transition (EMT). IVM was administered to endocrine-resistant breast cancer cell lines, MCF-7/LCC2 (tamoxifen resistant) and MCF-7/LCC9 (fulvestrant resistant), to evaluate its influence on cell proliferation, invasion, and EMT-related mechanisms. The findings indicated that IVM's half-maximum inhibitory concentration (IC50) inhibited MCF-7/LCC2 and MCF-7/LCC9 at 9.35 and 9.06 µM, respectively, within 24 h of treatment. Moreover, IC50 concentration treatment for 24 h led to over a 50% reduction in cell motility and a 62% and 35% decrease in cell invasion in MCF-7/LCC2 and MCF-7/LCC9 cells, respectively. Metastasis biomarkers demonstrated that IVM treatment reduced the expression of vimentin and snail. The study also discovered that IVM diminished the expression of Wnt5a/b and lipoprotein receptor-related protein 6 (LRP6), associated with the metastasis-related Wnt signaling pathway. In conclusion, IVM inhibits the Wnt signaling pathway associated with EMT in the metastasis of endocrine-resistant breast cancer cells. These insights underscore the potential of repurposing IVM for endocrine-resistant breast cancer patients.

DOI: https://doi.org/10.1371/journal.pone.0326742
Biochem Biophys Res Commun. 2025 Jun 16. pii: S0006-291X(25)00929-5. [Epub ahead of print]776 152214

ZBTB12 promotes breast cancer progression through transcriptional activation of the DNMT3B/ALDH1A2 axis.

Wenshan Zhang, Yinghui Zhi, Zhenyu Wu, Yan Chen, Liang Feng, Jing He, Feng Wang, Liang Chen, Huan Liu.

  Breast cancer (BC) is a prevalent malignant neoplasm. Utilizing the GEPIA database for analysis and subsequent validation via reverse transcription quantitative polymerase chain reaction (RT-qPCR), we identified that aldehyde dehydrogenase 1 family member A2 (ALDH1A2) exhibits reduced expression and heightened methylation in BC, which is associated with an unfavorable prognosis. In vitro cellular assays demonstrated that the overexpression of ALDH1A2 attenuates the proliferative, invasive, and migratory capacities of breast cancer cell lines, concurrently reducing apoptotic rates. Subsequent investigations employing Methylation-Specific PCR and Western blot analysis in breast cancer cells uncovered that DNA methyltransferase 3B (DNMT3B) is implicated in the DNA methylation of ALDH1A2, with the suppression of DNMT3B leading to an elevation in ALDH1A2 protein levels, thereby establishing an inverse relationship between DNMT3B and ALDH1A2. Furthermore, through the prediction of transcription factors binding to the promoter region of DNMT3B, we discerned that zinc fingers and BTB domain containing 12 (ZBTB12) transcriptionally activates DNMT3B, thereby repressing ALDH1A2 expression. Cellular assays revealed that the knockdown of ZBTB12 or the overexpression of DNMT3B correspondingly inhibits or enhances the proliferative, invasive, and migratory capabilities of breast cancer cells, with DNMT3B abrogating the suppressive effects of si-ZBTB12. Our findings elucidate a novel mechanism involving ALDH1A2 in the progression of breast cancer, where ZBTB12 transcriptionally activates DNMT3B, and the ZBTB12-DNMT3B axis orchestrates the methylation and consequent silencing of ALDH1A2.

Keywords:  ALDH1A2; Breast cancer; DNMT3B; Methylation; Transcription factor; ZBTB12

DOI:  https://doi.org/10.1016/j.bbrc.2025.152214
Biochim Biophys Acta Mol Basis Dis. 2025 Jun 19. pii: S0925-4439(25)00306-0. [Epub ahead of print]1871(7): 167958

TRIM34 inhibits triple-negative breast cancer progression by attenuating fatty acid synthesis via facilitating FASN ubiquitination.

Yong Li, Jijun Shan, Shanqing Liu, Yan Shen, Lianjie Niu, Qixin Mao, Xiaobing Chen.

  TRIM34, an E3 ubiquitin ligase, plays a pivotal role in regulating protein degradation, the cell cycle, and tumor progression. So far, the precise mechanisms and function of TRIM34 in triple-negative breast cancer (TNBC) remain unclear. In this study, we investigated the effect of TRIM34 in TNBC through in vitro and in vivo experiments. We identified TRIM34 as a significant regulator of Fatty Acid Synthase (FASN). TRIM34 was found to be downregulated in TNBC tissues, and its overexpression inhibited cell proliferation and migration by reducing fatty acid synthesis. Mechanistically, TRIM34 directly interacts with FASN, promoting its K48-linked ubiquitination and degradation. Clinical analysis revealed a negative correlation between TRIM34 and FASN expression, and low TRIM34 levels associated with poor patient prognosis. TRIM34 is a tumor suppressor and impedes TNBC progression by targeting FASN, offering a promising avenue for therapeutic intervention.

Keywords:  FASN; Fatty acid synthesis; TNBC; TRIM34; Ubiquitination

DOI:  https://doi.org/10.1016/j.bbadis.2025.167958
Biochem Biophys Res Commun. 2025 Jun 12. pii: S0006-291X(25)00915-5. [Epub ahead of print]776 152200

AP1S3 affects lipid metabolism in breast cancer cells by regulating the PI3K/AKT/mTOR pathway.

Zankai Wu, Shanshan Wang, Qingfeng Yang, Yiping Gong, Jin Hu.

   OBJECTIVE: This study aims to investigate the role of adaptor protein complex 1 sigma 3 (AP1S3) in breast cancer (BRCA) progression, focusing on its regulatory effects on lipid metabolism and the PI3K/AKT/mTOR signaling pathway.
METHODS: AP1S3 expression levels in BRCA cells were analyzed using the TCGA transcriptome database, with associated pathways identified through GO and KEGG analyses. The effects of AP1S3 on BRCA cell (MDA-MB-231 and MDA-MB-436) proliferation and migration were detected using CCK-8, colony formation, wound healing, and Transwell migration assays. Additionally, the regulatory effect of AP1S3 on lipid metabolism in BRCA cells was evaluated by measuring lipid droplet accumulation, free fatty acid (FFA) levels and total cholesterol (TC) content.
RESULTS: AP1S3 was significantly upregulated in BRCA cells and correlated with poor patient prognosis. Functional studies demonstrated that AP1S3 knockdown substantially inhibited BRCA cell proliferation and migration. Mechanistically, AP1S3 facilitated lipid metabolism and tumor progression by activating the PI3K/AKT/mTOR pathway. AP1S3 silencing resulted in decreased lipid accumulation and downregulation of lipid metabolism-related genes.
CONCLUSION: This study highlights the crucial involvement of AP1S3 in BRCA progression through its modulation of lipid metabolism and the PI3K/AKT/mTOR pathway. These findings suggest that targeting AP1S3 could provide novel insights and therapeutic avenues for treating metastatic BRCA.

Keywords:  AP1S3; Breast cancer; Lipid metabolism; PI3K/AKT/mTOR pathway

DOI:  https://doi.org/10.1016/j.bbrc.2025.152200
Adv Sci (Weinh). 2025 Jun 23. e00421

MYC/TET3-Regulated TMEM65 Activates OXPHOS-SERPINB3 Pathway to Promote Progression and Cisplatin Resistance in Triple-Negative Breast Cancer.

Yin-Ling Zhang, Min-Ying Huang, Shao-Ying Yang, Jia-Yang Cai, Qian Zhao, Fang-Lin Zhang, Xin Hu, Zhi-Min Shao, Li Liao, A-Yong Cao, Da-Qiang Li.

  Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its aggressive clinical features and the lack of effective targeted therapeutics. Mitochondrial metabolism is intimately linked to TNBC progression and therapeutic resistance and is an attractive therapeutic target for TNBC. Here, it is first reported that human transmembrane protein 65 (TMEM65), a poorly characterized mitochondrial inner-membrane protein-encoding gene in human cancer, acts as a novel oncogene in TNBC to promote tumor growth, metastasis, and cisplatin resistance both in vivo and in vitro. Transcription factor MYC and DNA demethylase ten-eleven translocation 3 (TET3) coordinately upregulate TMEM65 in TNBC, and its upregulation is associated with poor patient survival. Moreover, pharmacological inhibition or knockdown of MYC and TET3 attenuates TMEM65-driven TNBC progression. Mechanistic investigations reveal that TMEM65 enhances mitochondrial oxidative phosphorylation and its byproduct reactive oxygen species (ROS) production. Increased ROS induces the expression of hypoxia-inducible factor 1α (HIF1α), which in turn transcriptionally activates serpin family B member 3 (SERPINB3) to enhance TNBC stemness, thus leading to TNBC progression and cisplatin resistance. Collectively, these findings identify TMEM65 as a vital oncogene of TNBC, unveil its regulatory mechanisms, and shed light on its potential role in TNBC therapy.

Keywords:  cancer stemness; chemoresistance; mitochondrial metabolism; transmembrane protein; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/advs.202500421
Cancer Med. 2025 Jun;14(12): e70932

The Impact and Safety of GLP-1 Agents and Breast Cancer.

Kayla Parsons, Mateo Montalvo, Neal Fischbach, Melissa Taylor, Salome Alfaro, Maryam Lustberg.

   INTRODUCTION: Obesity and breast cancer rates are increasing globally, with obesity prevalence more than doubling since 1990. By 2022, 44% of women were overweight, and 18% were obese. Breast cancer remains the most common malignancy among women, with 2.2 million new cases in 2020. A significant proportion of breast cancer patients are overweight or obese at diagnosis, which is associated with higher recurrence and mortality rates. Recently, GLP-1 receptor agonists (GLP-1 RAs) have emerged as remarkably effective weight loss drugs. Understanding the relationship between obesity, breast cancer, and weight loss is crucial for improving patient outcomes.
METHODOLOGY: A comprehensive review of literature from 1996 to 2024 was conducted using databases such as PubMed, Medline, and Web of Science. Studies included epidemiological data on obesity and breast cancer incidence, systematic reviews, meta-analyses, and clinical trials on weight management interventions (behavioral modification, bariatric surgery, and pharmacological treatments) for breast cancer patients. Preclinical studies examining the biological mechanisms linking obesity and breast cancer progression were also reviewed.
RESULTS: Epidemiological studies consistently show that overweight and obese post-menopausal women have an increased risk of developing breast cancer. Obesity at diagnosis is linked to worse outcomes, including higher disease recurrence, breast cancer-specific mortality, and all-cause mortality. Weight gain during treatment, particularly with chemotherapy, is common and often leads to sarcopenic obesity. Behavioral interventions have shown modest weight loss but are difficult to maintain. Bariatric surgery reduces the risk of developing breast cancer but lacks data on its impact on tumor characteristics and recurrence. GLP-1 receptor agonists like semaglutide and tirzepatide have demonstrated significant weight loss in non-cancer populations, but their safety and efficacy in breast cancer patients are not well established.
DISCUSSION: The biology underlying obesity's role in breast cancer progression involves complex interactions between adipocytokines, hormones, and inflammatory cytokines. Weight loss interventions have potential benefits, but sustaining weight reduction in breast cancer patients is challenging. The emerging pharmacological treatments, particularly GLP-1 receptor agonists, show promise for effective weight management but require further investigation to confirm their safety and impact on breast cancer outcomes.
CONCLUSION: Addressing obesity in breast cancer patients is critical for improving prognosis and quality of life. While current data do not suggest adverse safety signals with GLP-1 receptor agonists, more research is needed to fully understand their effects. Effective, safe, and sustainable weight management strategies are urgently needed to support breast cancer patients.

Keywords:  GLP‐1 receptor agonists; bariatric surgery; behavioral modification; breast cancer; obesity; pharmacological intervention; sarcopenic obesity; weight management

DOI:  https://doi.org/10.1002/cam4.70932
Cell Biochem Biophys. 2025 Jun 23.

DCTPP1 is Transcriptionally Activated by FOXA1 to Affect Cisplatin Sensitivity in Triple-Negative Breast Cancer via Suppression of Ferroptosis.

Ying He, Guangxin Li, Xianwei Shi, Jun Bie, Guocheng Du, Xuqin Feng, Feng Yu, Yongpeng He.

  Triple negative breast cancer (TNBC) leads to significant global death due to the therapeutic failure such as the development of chemoresistance. The objective of this study was to discover the potential targets inhibiting cancer progression and enhancing cisplatin sensitivity in TNBC. Forkhead Box Protein A1 (FOXA1) and deoxycytidine triphosphate pyrophosphatase 1 (DCTPP1) expression was detected via real-time quantification PCR and western blotting. Cell proliferation and death were examined using EdU and flow cytometry. Transwell migration/invasion assays were performed to assess cell metastasis. Associated indicators were determined to evaluate ferroptosis. Half inhibitory concentration of cisplatin was tested via cell counting kit-8 assay. In vivo assays were implemented using xenograft models in mice. FOXA1 and DCTPP1 binding was validated through chromatin immunoprecipitation and dual-luciferase reporter assays. DCTPP1 was highly expressed in TNBC tissues and cells, and DCTPP1 was related to poor prognosis. Silencing DCTPP1 impeded TNBC cell malignant phenotypes (reduced proliferation, inhibited migration/invasion, and enhanced cell death) in vitro and tumor growth in vivo. DCTPP1 knockdown increased cisplatin sensitivity of TNBC cells via inducing ferroptosis. FOXA1 activated transcription of DCTPP1 and then promoted DCTPP1 expression. FOXA1 overexpression contributed to TNBC cell development, while inhibited ferroptosis and cisplatin sensitivity. FOXA1 knockdown facilitated ferroptosis and cisplatin sensitivity by targeting DCTPP1 in TNBC cells. Animal model also showed that FOXA1/DCTPP1 mediated cisplatin sensitivity through ferroptosis in vivo. The above evidence elucidated the role of FOXA1-mediated DCTPP1 in regulating TNBC development and cisplatin sensitivity by mediating ferroptosis.

Keywords:  Cisplatin sensitivity; DCTPP1; FOXA1; Ferroptosis; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s12013-025-01801-7