GPR19 Drives Cell Cycle Progression via ERK-Dependent FOXM1 Activation in p53-Mutant Breast Cancer.

Apoptosis-related TP53AIP1 inhibits breast cancer progression by inactivating the MAPK pathway and serves as a novel prognostic biomarker.

It is suggested that TP53AIP1 may serve as a potential prognostic biomarker and tumor-suppressive candidate in breast cancer, with its effects at least partly associated with MAPK pathway attenuation.

TPD52 promotes breast cancer cell migration, invasion and proliferation via activation of the MAPK/ERK signaling pathway

Elevated TPD52 expression was associated with longer overall survival in specific subgroups, including the basal-like subtype, invasive lobular carcinoma, and N0/N1 stages, and a random forest-based diagnostic model demonstrated high accuracy across multiple datasets.

EI24 suppresses TNBC tumorigenesis by regulating AKT signaling

Introduction Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by limited targeted therapeutic options and frequent activation of the PI3K/AKT signaling pathway. EI24, a p53-responsive tumor suppressor involved in apoptosis, autophagy, and oncogenic signaling regulation, has been implicated in multiple cancer types; however, its functional role and molecular mechanism in TNBC remain incompletely understood. This study investigated the clinical relevance of EI24 in TNBC and examined its impact on AKT signaling and tumor progression. Methods Public breast cancer datasets and breast cancer patient samples were analyzed to assess EI24 expression patterns and clinical associations. Doxycycline-inducible EI24 overexpression systems were established in TNBC cell lines to evaluate cell proliferation and AKT pathway activity. Human phospho-kinase arrays, immunoblotting, co-immunoprecipitation, domain-mapping analyses, and immunofluorescence assays were performed to investigate the molecular mechanism underlying EI24-mediated AKT regulation. In vivo functional effects were examined using the MMTV-PyMT mammary tumor mouse model combined with mammary gland-specific Ei24 overexpression. Results EI24 expression was significantly reduced in TNBC patient samples and lower EI24 expression was associated with advanced tumor progression and poorer relapse-free survival. Inducible EI24 overexpression suppressed proliferation of TNBC cell lines and reduced AKT phosphorylation at both S473 and T308. In the MMTV-PyMT model, Ei24 overexpression inhibited mammary tumor growth, reduced pulmonary metastasis, and prolonged survival. Mechanistically, EI24 interacted with the pleckstrin-homology (PH) domain of AKT and impaired growth factor-induced AKT membrane translocation, suggesting that EI24 negatively regulates AKT activation by interfering with its spatial recruitment to the plasma membrane. Discussion These findings identify EI24 as a negative regulator of AKT signaling and support its tumor-suppressive role in TNBC progression. Our study provides mechanistic and in vivo evidence linking EI24 to AKT pathway regulation and supports further investigation of EI24-based approaches as potential therapeutic strategies for AKT-driven TNBC.

Role of orphan G protein-coupled receptor GPR52 in breast cancer cell multicellular organization and collective invasion.

BACKGROUND G protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors and are emerging as targets for the effective treatment of cancer. The role of orphan GPCR GPR52 in cancer has not been characterized. Low mRNA expression of GPR52 in breast tumours correlates with reduced overall survival, leading to the hypothesis that loss of GPR52 supports breast cancer progression. METHODS CRISPR-Cas9 was used to knock out GPR52 in the human triple-negative breast cancer cell lines MDA-MB-468 and MDA-MB-231. 2D and 3D in vitro studies, electron microscopy, and a zebrafish xenograft model were used to assess the morphology and behaviour of GPR52 KO cells. RESULTS Loss of GPR52 was associated with elevated levels of cAMP, increased cell-cell interaction in 2D cultures, more spindle-like morphology on collagen, altered 3D spheroid morphology, and increased propensity to organize and invade collectively. Zebrafish injected with GPR52 KO cells developed a greater total cancer area than control. RNA sequencing and proteomic analyses of GPR52-null cells revealed an increased cAMP signalling signature. Re-expression of GPR52 and inhibition of cAMP production rescued some GPR52 KO phenotypes. CONCLUSIONS GPR52 loss is a potential mechanism by which breast cancer progression may occur and supports the investigation of GPR52 agonism as a therapeutic option for breast cancer. STATEMENT OF SIGNIFICANCE Loss of the orphan GPCR GPR52 in human breast cell lines leads to increased cell clustering, hybrid/partial EMT, and increased tumour burden in zebrafish, further expanding our understanding of mechanisms driving cancer progression and opening the door to novel therapeutic approaches.

EFO2 promotes triple-negative breast cancer progression and reduces CD8+ T cell-mediated killing by acetylating USF1 to enhance SLC2A1-mediated glycolysis.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by significant intratumoral heterogeneity and poor prognosis. Our study identified Establishment Factor-Like Protein 2 (EFO2) as a key oncogenic driver of TNBC progression. Using GEO datasets, we identified differentially expressed genes in TNBC. Functional roles of EFO2 were assessed via knockdown in human (MDA-MB-231, HCC1937) and mouse (4 T1, EMT6) TNBC cells, examining proliferation, glycolysis, and co-culture with CD8⁺ T cells. In vivo tumor growth was evaluated. Molecular mechanisms were investigated through co-immunoprecipitation, mutagenesis, luciferase reporter, and ChIP-qPCR assays. We observed that EFO2 was highly expressed in TNBC tissues, and this high expression correlated with shorter patient survival. Functional experiments showed that EFO2 knockdown suppressed tumor growth and proliferation both in vitro and in vivo. Furthermore, EFO2 knockdown inhibited glycolysis, as evidenced by decreased glucose uptake, ATP production, and lactate production. Moreover, EFO2 deficiency enhanced CD8⁺ T cell-mediated cytotoxicity against TNBC cells. Mechanistically, we demonstrated that EFO2 promoted the acetylation of Upstream Transcription Factor 1 (USF1), thereby enhancing transcriptional upregulation of the SLC2A1 promoter, a key glucose transporter. This EFO2/USF1/SLC2A1 signaling axis accelerated glycolysis in TNBC cells, which concurrently sustained tumor proliferation and impaired CD8⁺ T cell effector function, reducing TNBC cell susceptibility to T cell-mediated killing. Our findings identify a novel EFO2/USF1/SLC2A1 signaling axis that modulates glycolytic metabolism and CD8⁺T cell cytotoxicity, positioning EFO2 as a promising therapeutic target for TNBC treatment.

GATA6-mediated transcriptional activation and METTL3/IGF2BP2-dependent post-transcriptional stabilization upregulate CDC20 to promote the malignant progression of colorectal cancer and immune escape