Recurrent PIK3CA-E545K mutation promotes cervical cancer growth and invasion via AKT/mTOR signaling

ESM1-mediated DNMT3A suppresses cervical cancer metastasis through epigenetic regulation of ID3 expression

Cervical cancer remains the fourth most common malignancy among women worldwide, and patients with advanced-stage disease continue to experience poor clinical outcomes despite the availability of targeted therapies. In this study, we investigated the epigenetic role of endothelial cell-specific molecule 1 (ESM1), a soluble proteoglycan, and established an oncogene whose regulatory mechanisms in cervical cancer remain largely unexplored. The epigenetic mechanisms underlying tumor progression remain incompletely understood. Here, we identify ESM1 as a critical epigenetic regulator of cervical cancer malignancy. Integrative analyses of public datasets and clinical specimens revealed that marked ESM1 overexpression correlated with adverse patient prognosis. Functional loss- and gain-of-function studies have demonstrated that ESM1 is essential for maintaining proliferative, clonogenic, migratory, and invasive phenotypes in cervical cancer cells. Transcriptomic profiling revealed that inhibitor of DNA binding 3 (ID3) is a direct downstream tumor suppressor repressed by ESM1. Mechanistically, ESM1 selectively upregulates DNA methyltransferase 3 A (DNMT3A) to induce promoter hypermethylation and transcriptional silencing of ID3. Pharmacological demethylation reactivates ID3 expression and attenuates metastatic capacity. In vivo xenograft and experimental metastasis models validated that ESM1 depletion significantly impaired tumor growth and lung metastasis while increasing ID3 expression. These findings identify the ESM1/DNMT3A/ID3 axis as a novel epigenetic driver of cervical cancer and a potential therapeutic target.

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.

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.

The miR-338-5p/METTL3 axis regulates m6A modification to inhibit tumor progression in triple-negative breast cancer.

MXRA5 promotes the progression and metastasis of breast cancer via activation of the epithelial-to-mesenchymal transition pathway

Breast cancer remains a primary cause of cancer-associated death globally, largely due to distant metastasis and therapeutic resistance. While matrix remodeling associated 5 (MXRA5) has been implicated in inflammation and fibrosis, its specific biological function and mechanistic role in breast cancer progression remain unclear. Herein, multi-omics analysis and in vitro functional assays were employed to investigate the expression pattern, clinical significance, and biological function of MXRA5 within breast cancer. We observed that MXRA5 was considerably upregulated within breast cancer tissues in comparison with normal controls at both mRNA and protein levels. Crucially, elevated MXRA5 expression exhibited a positive correlation with advanced lymph node metastasis and impaired clinical prognosis, including overall survival, disease-specific survival, and progression-free interval, particularly within the Luminal B and HER2+ subtypes. Functional validation demonstrated that MXRA5 silencing markedly repressed the abilities of BT474 and MDA-MB-361 cells to proliferate, to migrate, and to invade in vitro, and significantly reduced lung metastasis in vivo. Mechanistically, bioinformatics analysis and pharmacological rescue experiments demonstrated that MXRA5 promotes tumor aggressiveness by activating the PI3K/AKT/mTOR signaling axis, which subsequently drives the epithelial-to-mesenchymal transition (EMT) pathway, evidenced by the positive regulation of key EMT transcription factors Snail and Twist, as well as the mesenchymal marker Vimentin. Collectively, these findings identify MXRA5 as a novel oncogenic driver in breast carcinoma and reveal its potential as a valuable prognostic biomarker and therapeutic target for managing metastatic disease.

Transcriptional modulation of the PI3K/AKT/mTOR signaling pathway mediated by HPV16 E5, E6, and E7 oncogene expression in breast cancer

Aim: Breast cancer is the most prevalent malignant tumor among women. Human papillomavirus (HPV) has been detected in breast tumors since the 1990s, and beyond its oncogenic potential, therapy resistance driven by viral immune evasion in non-anogenital tumors, such as oropharyngeal cancers, highlights the need to investigate viral activity in breast tissues. Among high-risk HPV types, HPV16 is one of the most prevalent and exhibits the highest carcinogenic potential. Therefore, this study aimed to evaluate the expression of HPV16 oncogenes E5, E6, and E7 in breast tumors, as well as the modulation of the PI3K/AKT/mTOR signaling pathway associated with viral activity. Methods: A total of 92 breast cancer patients were included after Ethics Committee approval. Clinical data were obtained from medical records. RNA was extracted from formalin-fixed, paraffin-embedded tissues and reverse-transcribed into cDNA. Transcripts of HPV oncogenes (E5, E6, and E7), components of the PI3K/AKT/mTOR pathway, and regulatory genes (EGFR and PTEN) were quantified by RT-qPCR. Gene expression levels were calculated using the ΔCt method. Results: Forty-eight samples met RNA quality criteria and were included in the expression analysis. Among these, 77.08% showed expression of at least one viral oncogene, with E5 being the most frequently expressed. The PI3K/AKT/mTOR pathway was modulated in HPV-positive samples, with increased PI3K expression and decreased mTOR expression. Notably, the high expression of E5—associated with immune evasion—combined with reduced mTOR expression suggests that HPV16 status may influence therapeutic response in breast cancer patients. Conclusions: These findings reinforce the importance of further studies investigating HPV activity in breast tumors to better understand its biological and clinical impact.