MUC16 promotes endometrial cancer progression and modulates sensitivity to lapatinib through the ESR1/PI3K/AKT axis

• High TMB is strongly associated with MUC16 mutations in endometrial cancer. • ESR1 protein stability is enhanced through inhibition of ubiquitin-mediated degradation. • Activation of the PI3K/AKT/mTOR pathway drives tumor growth and metastasis. • Lapatinib sensitivity increases when MUC16 is suppressed in cancer cells. Endometrial cancer is one of the most common gynecological malignancies, and advanced disease remains associated with poor clinical outcomes. Mucin 16 (MUC16), a transmembrane glycoprotein frequently mutated in multiple cancers, has been implicated in tumor progression. However, its functional role and molecular mechanism in endometrial cancer remain unclear. Somatic mutation data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) were analyzed to evaluate the association between MUC16 mutation and tumor mutation burden (TMB). Functional assays were performed in endometrial cancer cell lines. Protein interactions and ubiquitination were examined using co-immunoprecipitation and ubiquitination assays. Xenograft mouse models and drug sensitivity assays were used to evaluate tumor growth and response to targeted therapy. MUC16 is frequently mutated in endometrial cancer and its mutation status is associated with increased tumor mutation burden and improved overall survival in endometrial cancer patients. Functional experiments further demonstrated that MUC16 protein expression promotes tumor cell proliferation, migration, and invasion. Mechanistically, MUC16 interacted with estrogen receptor 1 (ESR1) and enhanced its stability by inhibiting ubiquitin-mediated degradation, thereby activating the PI3K/AKT signaling pathway. In addition, MUC16 knockdown significantly increased the sensitivity of endometrial cancer cells to the targeted drug lapatinib. These findings reveal that MUC16 promotes endometrial cancer progression through the ESR1/PI3K/AKT axis and highlight MUC16 as a potential prognostic biomarker and therapeutic target.