Integrin Beta 4 Protein Expression Bimodally Predicts Sensitivity to CDK4/6 Inhibition and Resistance to Immunotherapy in Breast Cancer.

BACKGROUND

Integrin beta 4 (ITGB4) has been implicated in breast cancer progression, yet its clinical utility as a biomarker remains unclear due to inconsistent findings across studies. This discrepancy may stem from the failure to distinguish between RNA and protein levels.

METHODS

We performed an integrated multiomics analysis of ITGB4 across breast cancer subtypes using data from TCGA, CPTAC, METABRIC, and GEO cohorts. Key findings were functionally validated using CDK4/6 inhibition in luminal cells and via immunohistochemistry on triple-negative breast cancer (TNBC) tissue microarrays.

RESULTS

ITGB4 exhibited significant RNA-protein discordance across breast cancer subtypes. High ITGB4 protein expression predicted a favorable prognosis in ER-positive breast cancer (HR = 0.58, 95% CI: 0.39-0.86, p = 0.007) and enhanced sensitivity to CDK4/6 inhibitors. Conversely, high ITGB4 expression in TNBC correlated with immunotherapy resistance, characterized by elevated PD-L1/PD-L2 expression and reduced cytotoxic lymphocyte infiltration. Mechanistically, we identified the ESR1/miR-342-5p/UBE2E3 axis as a potential regulator of ITGB4 protein stability.

CONCLUSION

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. ITGB4 protein thus represents a critical biomarker for guiding personalized therapy in precision oncology.