bims-merabr 2025-06-22 papers

Front Oncol. 2025 ;15 1577114

PLCH1 overexpression promotes breast cancer progression and predicts poor prognosis through the ERK1/2-EGR1 axis.

Jing Li, Fenge Jiang, Congcong Wang, Ping Sun, Lei Song, Jiannan Liu.

Background: Phospholipase C η1 (PLCH1), a member of the phospholipase C superfamily, has been implicated in the development of multiple cancers. However, its specific role in breast cancer progression, its association with clinicopathological features, and its prognostic significance remain unclear.
Methods: PLCH1 expression was analyzed across multiple tumor types using the TNMplot database, which integrates RNA-seq, microarray, and normalized data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO), encompassing 40,442 tumor and 15,648 normal samples. Differential expression analysis was performed using boxplots and statistical tests to assess significance. DNA methylation and survival analyses were conducted using TCGA data, with Kaplan-Meier curves and Cox regression to evaluate prognostic value. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, were performed on differentially expressed genes using the clusterProfiler package. Mutation analyses were conducted using mutation annotation format (MAF) files, and pathway activities were correlated with PLCH1 expression via single-sample GSEA (ssGSEA). Experimental validation included immunohistochemistry (IHC) on 100 breast invasive ductal carcinoma samples, real-time quantitative PCR (RT-qPCR), and Western blotting. PLCH1 knockdown functional studies assessed cell proliferation and signaling pathways.
Results: PLCH1 was significantly overexpressed in various cancers, including breast cancer, compared to normal tissues. PLCH1 expression was strongly correlated with the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer tissues, further linking PLCH1 to poor prognosis and adverse patient outcomes. Functional studies revealed that PLCH1 was highly expressed in breast cancer cell lines, and PLCH1 knockdown significantly inhibited cell proliferation, induced cell cycle arrest, and reduced cyclin-dependent kinase 1 (CDK1) expression in BT-474 cells. Mechanistically, PLCH1 silencing downregulated early growth response 1 (EGR1) expression by suppressing the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway, impairing tumor cell proliferation.
Conclusions: PLCH1 was overexpressed in breast cancer and was associated with worse patient outcomes. Its role in promoting cell proliferation via the ERK1/2-EGR1 axis highlighted PLCH1 as a potential therapeutic target for breast cancer. These findings offer new insights into the molecular mechanisms underlying breast cancer progression and suggest promising avenues for targeted therapy development.

Keywords: ERK1/2; PLCH1; apoptosis; breast cancer; cell cycle

DOI: https://doi.org/10.3389/fonc.2025.1577114

J Exp Clin Cancer Res. 2025 Jun 16. 44(1): 175

PARP-1 as a novel target in endocrine-resistant breast cancer.

Azzurra Zicarelli, Marianna Talia, Muriel Lainé, Rosamaria Lappano, Marcello Maggiolini, Geoffrey L Greene.

BACKGROUND: Several mechanisms are involved in the resistance to endocrine therapy (ET) in estrogen receptor (ERα)-positive breast cancer (BC), including acquired mutations of ERα gene (ESR1). For example, the frequent mutation, Y537S, was shown to trigger a constitutively active receptor leading to reduced affinity for both agonist and antagonist ligands. The development of more comprehensive therapies remains a challenge in BC patients exhibiting activating mutations in ERα. Here, we show that Poly (ADP-ribose) polymerase-1 (PARP-1) may be considered as a novel therapeutic target in ERα-positive BC.
METHODS: ERα wild type or Y537S mutated MCF7 and T47D BC cell lines were used as model systems. Immunoblotting, immunofluorescence, gene silencing, real-time PCR, promoter assays, chromatin immunoprecipitation sequencing (ChIP-seq) as well as cell viability, colony and cell cycle assays served to investigate the involvement of PARP-1 in BC progression. The growth of MCF7 ERα Y537S cells injected into the mammary ducts of NSG mice and treated with the ERα antagonist lasofoxifene or the PARP-1 inhibitor niraparib was monitored by luminescence imaging, weight measurement, and histological analysis. RNA sequencing studies were performed on the above-described xenograft tumors. METABRIC dataset was used to evaluate the clinical significance of PARP-1 and the biological role of the PARP-1-associated genes in ERα-positive BC patients.
RESULTS: We first demonstrated that the up-regulation of PARP-1 expression induced by estrogens is abrogated either by inhibiting or silencing ERα in MCF7 and T47D BC cells expressing ERα wild type or Y537S mutation. We then showed that PARP-1 is involved in the binding of ERα and its co-activator FoxA1 to the promoters of several target genes, as determined by ChIP-sequencing studies. Of note, the inhibition of PARP-1 prevented the proliferative effects mediated by ERα in BC cells expressing either wild type or Y537S ERα. In accordance with these findings, the growth of xenograft tumors derived from MCF7 ERα Y537S BC cells was significantly reduced using niraparib and lasofoxifene. Finally, RNA-sequencing analyses showed that ERα signaling is downregulated by niraparib compared to vehicle-treated tumors.
CONCLUSIONS: Overall, our results suggest that PARP-1 should be explored as a potential target in comprehensive therapeutic approaches in ET-resistant BC.

Keywords: Breast cancer; Endocrine therapy; Niraparib; PARP-1

DOI: https://doi.org/10.1186/s13046-025-03441-4

Discov Oncol. 2025 Jun 14. 16(1): 1103

LMNB1 regulates breast cancer cell senescence and migration through PPAR signaling pathway.

Shaoda Meng, Sicheng Liu, Chunsheng Liu, Kunxian Yang, Minghua Lai.

Breast cancer is the malignant tumor with the highest incidence in the world. LMNB1 is an important component of the nuclear backbone. LMNB1 is abnormally highly expressed in breast cancer, but its role in tumors still needs to be comprehensively studied. In this study, we overexpress and knockdown LMNB1 in breast cancer cells and explore the effects of LMNB1 on cell proliferation, senescence, migration, and underlying mechanisms. We analyzed the expression level of LMNB1 in breast cancer and its clinical relevance utilizing bioinformatics methods, qRT-PCR, and western blot. To elucidate the effects and mechanisms of LMNB1 on breast cancer cells, we performed SA-β-gal staining, CCK-8, colony formation, wound healing, and Transwell assays in breast cancer cells with LMNB1 overexpression and knockdown, and then examined the expression of relevant genes and proteins. In addition, we also analyzed the signaling pathways regulated by LMNB1 with the help of bioinformatics tools. Overexpression of LMNB1 significantly inhibited the senescence of cancer cells and promoted cell proliferation, migration, and invasion. The opposite results were obtained in LMNB1 knockdown cells. LMNB1 inhibited the PPAR signaling pathway in breast cancer. Our study suggests that LMNB1 is a novel therapeutic target in breast cancer.

Keywords: Breast cancer; Migration; PPAR signaling pathway; Proliferation; Senescence

DOI: https://doi.org/10.1007/s12672-025-02709-7

Biol Direct. 2025 Jun 13. 20(1): 70

Estrogen receptor alpha dynamics and plasticity during endocrine resistance.

Aswathy Sivasailam, Kiran S Kumar, Aparna Geetha Jayaprasad, Shine Varghese Jancy, Ashwathi Harikumar, P S Unnikrishnan, K C Sivakumar, P J Jain Tiffee, Aman Munirpasha Halikar, S S Nithin, Prakash R Pillai, Shivanshu Kumar Tiwari, Vishnu S Sanjeev, A V Surabhi, T R Santhoshkumar.

BACKGROUND: Breast cancer is subdivided into four distinct subtypes based on the status of hormone receptors (HR) and human epidermal growth factor receptor 2 (HER2) as HER2-/HR+, HER2+/HR+, HER2+/HR- and HER2-/HR-. Among this, ERα positive breast cancer, even though they respond to endocrine treatment, half of the patients acquire resistance and progress with metastasis despite ERα status. Spatio-temporal changes in ERα and their loss under treatment pressure have been reported in a subset of patients, which is a serious problem.
RESULTS: We have demonstrated that in vitro-generated resistance is correlated with the down regulation of ERα. To study the ERα status transition in live cells, triple-negative breast cancer cells were engineered to express EGFP-ERα, which further supported the existence of complex intracellular signaling that regulates ERα plasticity even in unperturbed conditions. Single-cell clones generate heterogeneity and loss of expression depending on proliferative cues. However, the initial response of cells to 4 μM of 4-hydroxytamoxifen and 1 μM of endoxifen involves up-regulation of ERα, likely due to its early effect on the proteasome or autophagy pathway. Supporting this, inhibition of autophagy and the proteasome further enhanced the expression of ERα. Systematic analysis of RNA sequencing of ERα stable cells further confirmed that ERα regulates diverse intracellular signaling networks such as ubiquitin, proteasome pathways, cell proliferation and Unfolded Protein Responses (UPR), implicating its direct role in post-translational protein modifications. Cell cycle indicator probe expressing receptor-positive breast cancer cells confirmed the ERα expression heterogeneity both in 2D and 3D culture in a cell cycle phase-independent manner.
CONCLUSIONS: Overall, the study confirms the cell's intrinsic post-transcriptional mechanisms of ERα plasticity that could play a role in receptor heterogeneity and tumor progression under endocrine treatment, which warrants further investigation.

Keywords: Breast cancer; Endocrine resistance; Estrogen receptor alpha (ERα); Real-time imaging; Receptor heterogeneity; TNBC; Tamoxifen; Unfolded protein response

DOI: https://doi.org/10.1186/s13062-025-00653-8

Discov Oncol. 2025 Jun 17. 16(1): 1135

PARP14-mediated glycolysis enhances Tamoxifen resistance in estrogen receptor + breast cancer cells.

Wenju Mo, Fanrong Zhang, Chen Wang, Xiaowen Ding, Lili Ren.

BACKGROUND: Resistance to Tamoxifen is a major challenge in the therapeutic management of estrogen receptor (ER) + breast cancer (BC). Glycolysis, as reported, exerts a crucial influence on the regulation of Tamoxifen resistance in BC, highlighting the need for further investigation into the mechanisms by which it contributes to Tamoxifen resistance in ER + BC.
METHOD: Bioinformatics was employed to analyze the differential expression of PARP14 between Tamoxifen-responsive and -resistant ER + BC tissues. Poly (ADP-ribose) polymerase family member 14 (PARP14) expression in Tamoxifen-resistant cell lines (T47D/TAMR) was quantified through quantitative real time polymerase chain reaction (qRT-PCR). A subsequent Gene Set Enrichment Analysis (GSEA) was conducted to determine the relationship between PARP14 and glycolysis-related genes. The assessment of glycolytic activity included measurements of hexokinase II (HK2) expression, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose uptake, lactate secretion, and adenosine Triphosphate (ATP) synthesis. Cellular proliferation was evaluated using a colony formation assay, cell viability was assessed with the Cell Counting Kit-8 (CCK-8) assay to establish the half maximal inhibitory concentration (IC50) value, and apoptosis was measured by flow cytometry.
RESULTS: PARP14 exhibited elevated expression in Tamoxifen-resistant tissues and cells such as T47D/TAMR, where its knockdown increased responsiveness to Tamoxifen. PARP14 was also notably associated with the glycolysis pathway, showing a positive correlation with genes that enhance glycolysis, and its suppression led to decreased glycolysis in T47D/TAMR cells. Overexpression of PARP14 in vitro induced Tamoxifen resistance in these cells, but co-administration of the glycolytic inhibitor 2-DG could recover their sensitivity to Tamoxifen.
CONCLUSION: PARP14 facilitates Tamoxifen resistance in ER + BC cells via the activation of the glycolysis pathway. We suspect that targeting PARP14 or the glycolytic pathway could be a viable therapeutic option for ER + BC that has developed resistance to Tamoxifen.

Keywords: Drug resistance; ER + BC; Glycolysis; PARP14; Tamoxifen

DOI: https://doi.org/10.1007/s12672-025-02404-7

Sci Adv. 2025 Jun 20. 11(25): eadt3075

FAM50A drives breast cancer brain metastasis through interaction with C9ORF78 to enhance ʟ-asparagine production.

Weilong Chen, Yuanyuan Qin, Libo Qiao, Xue Liu, Chenyun Gao, Tian-Ran Li, Yanrui Luo, Dongxue Li, Hong Yan, Linhong Han, Long Hai, Fang Nie, Hai-Bo Wu, Cong Chen, Yi-Fang Ping, Xiu-Wu Bian.

Elevated levels of asparagine, catalyzed by asparagine synthetase (ASNS), have been identified as a prerequisite for lung metastasis in breast cancer. However, the roles and regulatory mechanisms of ASNS in breast cancer brain metastasis (BCBM) are not well understood. Our study revealed that the family with sequence similarity 50 member A (FAM50A) gene substantially modulates the brain metastatic potential of breast cancer by up-regulating ASNS and promoting asparagine biosynthesis. We demonstrated that FAM50A forms a complex with chromosome 9 open reading frame 78 (C9ORF78), specifically at the S121 residue, to enhance ASNS transcription. This interaction accelerates the rate of ASNS-mediated asparagine synthesis, which is essential in facilitating metastatic cascades to the brain. From a therapeutic perspective, both the genetic suppression of FAM50A and pharmacological inhibition of asparagine synthesis effectively counteract BCBM. Our results highlight the importance of the FAM50A-ASNS signaling pathway in BCBM therapy.

DOI: https://doi.org/10.1126/sciadv.adt3075