Objective <p>The Notch signaling pathway, particularly Notch-1, has been implicated in various malignancies, yet its specific molecular mechanisms in breast cancer progression remain incompletely understood. This study aims to investigate the role of Notch-1 signaling in breast cancer and to elucidate a novel regulatory axis involving PI3K/CREB1/Egr1/E2F1/YAP in promoting epithelial–mesenchymal transition (EMT) and stemness.</p> Methods <p>Bioinformatics analyses were performed using TCGA-BRCA and GEO (GSE33447) datasets to identify differentially expressed genes and enriched pathways. For in vivo experiments, twenty-four BALB/c female mice were randomly divided into four groups (n = 6 per group): control, E2F1 overexpression (E2F1-OE), Notch-1 knockdown (Notch1-KD), and Notch1-KD combined with YAP overexpression (Notch1-KD + YAP-OE). MCF-7 cells were subcutaneously implanted, and tumor growth was monitored every three days. For in vitro studies, MCF-10A normal mammary epithelial cells served as the normal control, and MCF-7 breast cancer cells and MDA-MB-453 cells were used as the experimental models. Cells were treated with a PI3K agonist (PI3K/Akt/CREB activator 1), an Egr1 inhibitor (EGR-1-IN-1), and transfected with E2F1-OE, Notch1-KD, or YAP-OE constructs. Protein expression was assessed via Western blot, cell proliferation via CCK-8 and colony formation assays, and migration/invasion via wound healing and Transwell assays. All experiments were performed in triplicate, and statistical significance was determined using appropriate tests (<i>P</i> &lt; 0.05).</p> Results <p>Bioinformatics analysis revealed significant enrichment of the PI3K-Akt, Hippo, and Notch signaling pathways, with NOTCH1, PI3K, CREB1, EGR1, E2F1, and YAP forming a coordinated regulatory network. In vivo, E2F1-OE significantly promoted tumor growth compared to controls (<i>P</i> &lt; 0.01), while Notch1-KD suppressed tumor volume (<i>P</i> &lt; 0.01); this effect was partially reversed by YAP-OE (<i>P</i> &lt; 0.05). In vitro, Notch-1 upregulation enhanced the phosphorylation of PI3K and CREB1, increased Egr1 and E2F1 expression, and promoted nuclear YAP localization (<i>P</i> &lt; 0.05 vs. control). Activation of the PI3K/CREB1 axis induced EMT markers (Snail, Slug, N-cadherin) and stemness markers (SOX2, KLF4), and enhanced proliferation, migration, and invasion (<i>P</i> &lt; 0.01). Inhibition of Egr1 or knockdown of Notch-1 reversed these effects (<i>P</i> &lt; 0.05), while overexpression of E2F1 or activation of YAP restored malignant phenotypes.</p> Conclusion <p>Notch-1 signaling promotes breast cancer by upregulating the PI3K/CREB1/Egr1/E2F1/YAP pathway, inducing EMT and stemness.</p>