bims-merabr 2025-02-16 papers

Cell Death Discov. 2025 Feb 08. 11(1): 54

Anaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axis.

Ying Xu, Weiwei Meng, Yingqi Dai, Lin Xu, Ning Ding, Jinqing Zhang, Xuewei Zhuang.

Histone lactylation plays a crucial role in cancer progression, but its impact on breast cancer (BC) tumorigenesis is still unclear. We utilized chromatin immunoprecipitation sequencing with H3K18la antibodies, transcriptomics of clinical BC samples, and proteomics and ATAC-seq analyses of in vivo tumors to identify the genes regulated by H3K18la and the transcription factor PPARD. qPCR and Western blot assays were used to detect expressions of molecules. We discovered that H3K18la levels were higher in BC tissues compared to adjacent non-cancerous tissues. H3K18la promoted the expression of PPARD, which in turn influenced the transcription of AKT, but not ILK. ATAC-seq analysis revealed that glycolysis in BC cells enhanced chromatin accessibility. Additionally, we confirmed that HDAC2 and HDAC3 act as "erasers" for H3 lysine lactylation. During the proteomics analysis, AKT-phosphorylation in the aerobic respiration inhibitor group exhibited an apparent disparity and activity. Our study demonstrated that changes in H3K18la in BC and its downstream transcription factor PPARD support cell survival under anaerobic glycolysis conditions. PPARD accelerated cancer proliferation by promoting the transcription and phosphorylation of AKT. This highlights the therapeutic potential of targeting the H3K18la/PPARD/AKT axis in breast cancer, providing new insights into epigenetic regulation and cancer metabolism (Trial registration: The study was approved by the Research Ethics Committee Shandong Provincial Third Hospital (KYLL-2023057; https://www.medicalresearch.org.cn/ )).

DOI: https://doi.org/10.1038/s41420-025-02334-x

Front Oncol. 2024 ;14 1497093

RET inhibition overcomes resistance to combined CDK4/6 inhibitor and endocrine therapy in ER+ breast cancer.

Charlotte K Kindt, Sidse Ehmsen, Sofie Traynor, Benedetta Policastro, Nikoline Nissen, Mie K Jakobsen, Monique F Hundebøl, Lene E Johansen, Martin Bak, Elsa Arbajian, Johan Staaf, Henrik J Ditzel, Carla L Alves.

Background: Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improve the outcome of patients with advanced estrogen receptor-positive (ER+) breast cancer. However, resistance to this treatment and disease progression remains a major clinical challenge. High expression of the receptor tyrosine kinase REarranged during Transfection (RET) has been associated with resistance to endocrine therapy in breast cancer, but the role of RET in CDK4/6i treatment response/resistance remains unexplored.
Methods: To identify gene expression alterations associated with resistance to combined endocrine therapy and CDK4/6i, we performed RNA sequencing of two ER+ breast cancer cell models resistant to this combined therapy. The functional role of RET was assessed by siRNA-mediated RET silencing and targeted inhibition with the FDA/EMA-approved RET-selective inhibitor selpercatinib in resistant breast cancer cells and patient-derived organoids (PDOs). RET silencing was evaluated mechanistically using global gene expression and pathway analysis. The clinical relevance of RET expression in ER+ breast cancer was investigated by gene array analysis of primary tumors treated with endocrine therapy and by immunohistochemical scoring of metastatic lesions from patients who received combined CDK4/6i and endocrine therapy.
Results: We show that RET is upregulated in ER+ breast cancer cell lines resistant to combined CDK4/6i and fulvestrant compared to isogenic cells resistant to fulvestrant alone. siRNA-mediated silence of RET in high RET-expressing, combined CDK4/6i- and fulvestrant-resistant cells reduced their growth partially by affecting cell cycle regulators of the G2-M phase and E2F targets. Notably, targeting RET with selpercatinib in combination with CDK4/6i inhibited the growth of CDK4/6i-resistant cell lines and resensitized ER+ breast cancer patient-derived organoids resistant to CDK4/6i. Finally, analysis of RET expression in ER+ breast cancer patients treated with endocrine therapy showed that high RET expression correlated with poor clinical outcomes. We further observed a shorter median survival to combined CDK4/6i and endocrine therapy in patients with RET-positive compared to RET-negative tumors, but this difference did not reach statistical significance.
Conclusions: Our findings show that RET is overexpressed in ER+ metastatic breast cancer resistant to combined CDK4/6i and endocrine therapy, rendering RET inhibition a promising therapeutic approach for patients who experience disease progression on combined CDK4/6i and endocrine therapy.

Keywords: CDK4/6 inhibitor; RET; drug resistance; estrogen receptor-positive breast cancer; selpercatinib

DOI: https://doi.org/10.3389/fonc.2024.1497093

Discov Oncol. 2025 Feb 11. 16(1): 161

PGAM1: a potential therapeutic target mediating Wnt/β-catenin signaling drives breast cancer progression.

Yongxuan Wang, Wei Liu, Xudong Lai, Haixiong Miao, Xifeng Xiong.

Phosphoglycerate mutase 1 (PGAM1) has been identified as a key player in the progression and metastasis of various human cancer types, including breast cancer (BC); however, its precise oncogenic mechanism remains unclear. The present study aimed to investigate the oncogenic mechanisms of PGAM1 and establish its potential as a therapeutic target. Comprehensive analyses from the Tumor Immune Estimation Resource 2.0 and The Cancer Genome Atlas databases revealed a significant upregulation of PGAM1 in BC, correlating with poor clinical outcomes. Additionally, elevated expression of PGAM1 was confirmed in clinical BC samples. Silencing PGAM1 with specific small hairpin RNA in BC cells resulted in a marked reduction in cell proliferation, invasiveness and migration, alongside increased apoptosis and cell cycle arrest. In vivo experiments using tumor-bearing nude mice demonstrated that PGAM1 knockdown significantly reduced tumor volume and weight, effectively inhibiting tumor growth. Mechanistic investigations suggested that PGAM1 promoted BC tumorigenesis through the activation of the Wnt/β-catenin signaling pathway, both in vitro and in vivo. Therefore, the upregulation of PGAM1 in BC enhances malignancy via the Wnt/β-catenin signaling pathway, highlighting PGAM1 as a promising therapeutic target for BC treatment.

Keywords: Breast cancer; Cell migration; Cell proliferation; PGAM1; Wnt/β-catenin signaling

DOI: https://doi.org/10.1007/s12672-025-01939-z

Front Endocrinol (Lausanne). 2025 ;16 1494411

Interaction of GPER-1 with the endocrine signaling axis in breast cancer.

Luis Molina Calistro, Yennyfer Arancibia, Marcela Alejandra Olivera, Sigrid Domke, Rodrigo Flavio Torres.

G Protein-Coupled Estrogen Receptor 1 (GPER-1) is a membrane estrogen receptor that has emerged as a key player in breast cancer development and progression. In addition to its direct influence on estrogen signaling, a crucial interaction between GPER-1 and the hypothalamic-pituitary-gonadal (HPG) axis has been evidenced. The novel and complex relationship between GPER-1 and HPG implies a hormonal regulation with important homeostatic effects on general organ development and reproductive tissues, but also on the pathophysiology of cancer, especially breast cancer. Recent research points to a great versatility of GPER-1, interacting with classical estrogen receptors and with signaling pathways related to inflammation. Importantly, through its activation by environmental and synthetic estrogens, GPER-1 is associated with hormone therapy resistance in breast cancer. These findings open new perspectives in the understanding of breast tumor development and raise the possibility of future applications in the design of more personalized and effective therapeutic approaches.

Keywords: GPER-1; breast cancer; endocrine resistance; estrogen; hypothalamic-pituitary-gonadal axis; personalized medicine

DOI: https://doi.org/10.3389/fendo.2025.1494411

Mol Biol Rep. 2025 Feb 10. 52(1): 216

Decoding gene expression profiles of Hippo signaling pathway components in breast cancer.

Hunayna M Bhavnagari, Franky D Shah.

INTRODUCTION: The Hippo signaling pathway is an evolutionarily conserved, tumor suppressor, stem cell pathway. This is the very less explored pathway in Breast Cancer. It is a crucial regulator of several biological processes, such as organ size, differentiation, tissue homeostasis, cellular proliferation, and stemness. Interestingly, deregulation of this pathway leads to tumorigenesis. Hence, the present study aims to identify the role of the Hippo signaling pathway in Breast Cancer.
MATERIALS AND METHODS: The mRNA expression of the Hippo signaling pathway molecules was evaluated in 120 pre-therapeutic patients by quantitative real-time PCR. Statistical analysis was carried out using SPSS 23. The association between the gene expression and clinicopathological parameters was analyzed by the paired sample t-test, and Pearson chi-square test. ROC curve analysis was carried out using Med Cal. A p-value of ≤ 0.05 was considered statistically significant.
RESULTS: The hippo signaling pathway contains 10 core components i.e.SAV1, MOB1A, MOB1B, MST1, MST2, LATS1, LATS2, YAP, TAZ, and TEAD1 which were downregulated in malignant tissues as compared to adjacent normal tissue in breast cancer. In the correlation of hippo signaling pathway molecules with clinico pathological parameters, only LATS1, MST1, and SAV1 were found to be significantly negatively associated with stages of Breast Cancer. MOB1B was found to be significantly positively correlated with stages of Breast Cancer. ROC curve analysis of YAP, TAZ, LATS2, and TEAD showed significant discrimination between adjacent normal and malignant tissue.
CONCLUSION: In the current study, all the molecules of the hippo signaling pathway i.e. YAP, TAZ, LATS1, LATS2, MST1, MST2, SAV1, MOB1, MOB1B, TEAD1 were downregulated in BC suggesting the activation of hippo pathway which played a significant role in tumor suppression.

Keywords: Breast cancer; Clinico pathological parameter; Hippo signaling pathway; Real-Time PCR; TAZ; YAP

DOI: https://doi.org/10.1007/s11033-025-10299-4

FASEB J. 2025 Feb 15. 39(3): e70315

Novel role of the SOX4/CSNK2A1 axis in regulating TOP2A phosphorylation in breast cancer progression.

Jiaqiong Zou, Ruiman Geng, Zhengkun Zhang, Xuxu Ji, Zhaoru Yin, Dingxue Wang, Rong Guo, Lihong Chen, Ji Liu.

This study examines the critical role of DNA topoisomerase II alpha (TOP2A) phosphorylation in breast cancer progression, regulated by the SRY-box transcription factor 4 (SOX4)/Casein kinase II subunit alpha 1 (CSNK2A1) axis. Using integrated transcriptomic and proteomic analyses, data were sourced from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) databases. To explore the dataset, differential analysis, kinase-substrate enrichment analysis (KSEA), and weighted gene co-expression network analysis (WGCNA) were performed. Immune profiling, combined with survival analysis, revealed the prognosis linked to different immune profiles in breast cancer patients. In vitro experiments assessed the effect of SOX4 on CSNK2A1 promoter activity through real-time quantitative polymerase chain reaction (RT-qPCR), Western blot, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP). The phosphorylation level of TOP2A was also measured. Cell proliferation, migration, and invasion were evaluated using cell counting kit-8 (CCK-8), colony formation, and Transwell assays. In vivo studies extended to mouse models, where the effect of SOX4 on CSNK2A1-TOP2A phosphorylation was analyzed about tumor growth and metastasis. The results showed that upregulation of SOX4 increases CSNK2A1 transcription, which in turn promotes TOP2A phosphorylation and accelerates breast cancer progression. The clinical analysis identified three immune profiles, with the intermediate profile associated with a poorer prognosis, possibly due to enhanced TOP2A phosphorylation mediated by SOX4/CSNK2A1. Silencing SOX4 significantly reduced cell proliferation, migration, invasion, and tumor growth in vivo by lowering CSNK2A1-TOP2A phosphorylation. These findings highlight the therapeutic potential of targeting the SOX4/CSNK2A1 axis in breast cancer and provide insight into its mechanism through TOP2A phosphorylation.

Keywords: CSNK2A1 kinase; SOX4; TOP2A phosphorylation; breast cancer; proteomics; transcriptomics; tumor growth and metastasis

DOI: https://doi.org/10.1096/fj.202401907RR