bims-merabr 2025-05-18 papers

Int J Mol Sci. 2025 Apr 22. pii: 3943. [Epub ahead of print]26(9):

Targeting the Hippo Pathway in Breast Cancer: A Proteomic Analysis of Yes-Associated Protein Inhibition.

Sevinc Yanar, Merve Gulsen Bal Albayrak, Tuğcan Korak, Asuman Deveci Ozkan, Sevil Arabacı Tamer, Murat Kasap.

The dysregulation of the Hippo signaling pathway leads to the aberrant activation of oncogenic YAP and TAZ, driving tumor progression. In breast cancer, this disruption promotes proliferation and metastasis. This study investigates the effects of CA3, a selective YAP inhibitor, on the proteome of triple-negative breast cancer MDA-MB-231 and luminal-A-like MCF7 cells. Proteomic changes were analyzed via nano-LC-MS/MS, while cytotoxicity, apoptosis, and autophagy were assessed through WST-1 assays, flow cytometry, and Western blot analyses. Bioinformatics tools were employed to identify enriched pathways. MDA-MB-231 cells exhibited an increased expression of DNA repair proteins (p < 0.05), indicating a compensatory response to maintain genomic stability. In contrast, MCF7 cells showed a downregulation of DNA repair factors (p < 0.005). Additionally, metabolic reprogramming was apparent in MCF7 cells (p < 0.001). Apoptosis assays revealed a rise in cell death, while cell cycle analysis indicated pronounced G1-phase arrest in MDA-MB-231 cells (p < 0.01). Moreover, autophagic suppression was particularly evident in MCF7 cells. This study, for the first time, provides evidence that breast cancer subtypes exhibit distinct dependencies on YAP-driven pathways, revealing potential therapeutic vulnerabilities. Targeting Hippo signaling alongside DNA repair in triple-negative breast cancer or combining YAP inhibition with metabolic blockade in luminal breast cancer holds significant potential to enhance treatment efficacy.

Keywords: CA3 (CIL56); DNA repair; apoptosis; autophagy; breast cancer; hippo pathway; metabolic reprogramming; proteomics; yes-associated protein (YAP)

DOI: https://doi.org/10.3390/ijms26093943

Mol Biol Rep. 2025 May 13. 52(1): 453

Estrogenic control of matrix metalloproteinases: a perspective on breast tumor invasion and metastasis.

Ningthoujam Sonia, Snigdha Saikia, Anil Mukund Limaye.

Metastasis is the major cause of mortality in breast cancer patients, and presents an invincible therapeutic challenge. It is a complex process of dissemination of tumor epithelial cells, which is associated with disruption of tissue homeostasis, and alterations in the tumor microenvironment through extracellular matrix (ECM) remodeling, stromal alteration, and epithelial-mesenchymal transition. Matrix metalloproteinases (MMPs) constitute a group of more than 25 zinc-dependent endopeptidases. By virtue of their ability to degrade a wide variety of ECM-associated proteins, they enable ECM remodelling during development, and disease. A large body of clinical data, and experimental evidences implicate MMPs in the invasion and metastasis of breast tumors. While MMPs are aberrantly expressed in breast tumors, few appear to have a dual role in disease progression; either promoting or inhibiting metastasis. Given the role of estrogen in breast cancer development, it is natural to ask whether this steroid hormone has any role in breast cancer metastasis. This review is a round-up of the prominent literature that presents estrogenic control of MMPs, which in turn implies its influence on the tumor microenvironment and metastasis.

Keywords: Breast cancer; Estrogen; Metalloproteinase; Metastasis

DOI: https://doi.org/10.1007/s11033-025-10555-7

J Cancer Res Clin Oncol. 2025 May 13. 151(5): 162

FOXM1 boosts glycolysis by upregulating SQLE to inhibit anoikis in breast cancer cells.

Mei Xu, Guozhi Pan, Qian Zhang, Jiangming Huang, Yehua Wu, Yashengjiang Ashan.

BACKGROUND: Resisting anoikis is a prerequisite for cancer to spread and invade and a major cause of cancer-related deaths. Yet, the intricate mechanisms of how cancer cells evade anoikis remain largely unknown. There is a significant need to explore how these mechanisms play out in breast cancer (BC).
METHODS: Bioinformatics analysis revealed the expression levels of SQLE and FOXM1 in BC tissue, along with their correlation. The enrichment pathways of SQLE were also explored. qPCR detected the expression of SQLE and FOXM1 in BC cells. CCK-8 assessed cell viability, while flow cytometry measured anoikis. Western blot was employed to examine the protein expression of key genes in glycolytic metabolism and apoptosis-related proteins. Extracellular acidification rate was quantified, and corresponding kits evaluated glucose consumption, lactate production, and adenosine triphosphate levels in cells. Dual-luciferase reporter assays and chromatin immunoprecipitation tests unveiled the binding relationship between FOXM1 and SQLE.
RESULTS: SQLE was found to be highly expressed in BC and enriched in pathways associated with anoikis and glycolysis. SQLE curbed anoikis in BC via the aerobic glycolysis pathway. There was also a direct binding between FOXM1 and SQLE and a positive correlation between their expression. Recovery experiments substantiated that FOXM1 targeted SQLE to suppress anoikis in BC cells.
CONCLUSION: FOXM1 upregulates SQLE, which in turn mediates glycolysis to suppress anoikis in BC. The FOXM1/SQLE axis is a promising therapeutic target for BC treatment.

Keywords: Anoikis; Breast cancer; FOXM1; Glycolysis; SQLE

DOI: https://doi.org/10.1007/s00432-025-06174-1

Cancer Cell Int. 2025 May 15. 25(1): 177

SP1 promotes triple-negative breast cancer progression by targeting USP5.

Shi-Yi Wu, Zi-Mei Peng, Feng-Yi Deng, Jin-Yong Xiong, Pu-Ying Luo, Xiao-Jian Han, Zhen Zhang.

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by the absence of targeted therapies and a dismal prognosis, necessitating a critical exploration of the molecular mechanisms driving TNBC pathogenesis and the identification of novel therapeutic targets. While dysregulated USP5 expression has been observed in various malignancies, its specific functions and mechanisms in TNBC remain poorly understood.
METHODS: The study utilized a combination of TCGA database analysis, immunohistochemistry staining (IHC), quantitative RT-PCR, and western blotting assay to investigate the expression of USP5 and SP1 in TNBC. Furthermore, the study examined the role of the SP1-USP5 axis and the USP5 inhibitor periplocin in TNBC progression through CCK-8 assay, colony formation assay, EDU incorporation assay, and tumor xenograft experiments. Additionally, the study explored the underlying mechanisms involved in the regulation of USP5 expression in TNBC using luciferase assay, ChIP-qPCR, quantitative RT-PCR, and western blotting assay. In order to ascertain potential inhibitors of USP5 activity, a combination of the Molecular Operating Environment (MOE) multi-functional docking platform, cellular thermal shift assay, and in vitro USP5 activity assay were utilized.
RESULTS: In the current investigation, it was observed that the expression of USP5 was elevated in TNBC and was significantly correlated with decreased overall survival rates among patients. The upregulation of USP5 was found to be mediated by the transcription factor SP1 through its binding to the USP5 promoter, consequently facilitating the progression of TNBC. Notably, the natural compound periplocin was identified as a promising inhibitor of USP5, demonstrating potential efficacy in impeding the advancement of TNBC.
CONCLUSIONS: Our research findings indicate that the SP1-USP5 signaling pathway is significantly involved in the advancement of TNBC, and periplocin's ability to target USP5 presents a potential therapeutic approach for managing TNBC. These results offer valuable insights for the development of novel treatment strategies for TNBC patients.

Keywords: Cancer progression; SP1; TNBC; USP5

DOI: https://doi.org/10.1186/s12935-025-03802-1