ASCL2 contributes to clinical assessments of breast cancer and mediates tumor progression via the interaction with CLDN3.

Breast carcinoma (BC) is the most common malignant neoplasm occurring in women, posing a serious threat to public health. Metastasis is its leading cause of death, nevertheless there is still a lack of effective treatment. Epithelial-mesenchymal transition (EMT) is a critical process involved in cancer malignant progression, which is expected to provide new insights into BC treatment. Through lasso regression SVM-RFE algorithms, ASCL2 was identified as a potential regulator for BC progression. Multi-omics bioinformatics investigation confirmed its great value in clinical assessments. ASLC2 can elevate the decision-making benefit of TNM and AJCC-stage prognostic models and distinguish the prognostic differences of patients with different molecular subtypes. A survival meta-analysis confirmed its prognostic value in five public cohorts. High expression of ASCL2 was associated with unfavorable anti-tumor immune response as determined by CIBERSORT algorithm and immunofluorescence staining. Meanwhile, ASCL2 was also indicative of metabolic status and therapeutic efficacy through GSEA, GDSC, TIDE and TMB analyses. As for its biofunctions, overexpression of ASCL2 promoted proliferation, migration and invasion of MCF-7 and MDA-MB-231 cells. Silencing ASCL2 can significantly inhibit the growth of xenograft tumors in mice. Mechanistically, CLDN3 was predicted to have a close functional link with ASCL2 through module and spearman analyses. Co-IP assay confirmed the interaction of ASCL2 and CLDN3. Rescue experiments demonstrated that overexpression of CLDN3 could partly reverse the inhibitory effects of ASCL2 deletion on the malignant capacities of BC cells, suggesting their synergistic effects. Collectively, ASCL2 is a pivotal biomarker for successful individualized cancer therapy, targeting ASCL2 has enormous therapeutic potential.