Mechanistically, we identified the ESR1/miR-342-5p/UBE2E3 axis as a potential regulator of ITGB4 protein stability.<h4>Conclusion</h4>ITGB4 protein expression serves as a bimodal biomarker in breast cancer, predicting CDK4/6 inhibitor sensitivity in luminal subtypes while indicating immunotherapy resistance in TNBC. Here, ITGB4 is linked to breast carcinoma.