RTN4IP1 drives breast tumorigenesis: Molecular mechanisms linking elevated expression to enhanced proliferation, suppressed apoptosis, and therapeutic resistance.

Abnormal expression of RTN4IP1 is implicated in diverse pathologies, including malignant tumors, yet its role in breast cancer (BC) remains insufficiently defined. This study integrated TCGA-based bioinformatics analysis with experimental validation to characterize RTN4IP1-related phenotypes. RTN4IP1 mRNA and protein levels were elevated in BC tissues compared to normal breast tissue, with higher expression correlating with advanced T/N stages, HER2 positivity, aggressive PAM50 subtypes, and lower PR/ER status. Clinically, increased RTN4IP1 expression was more frequent in Black/African American patients, postmenopausal women, and invasive ductal carcinoma cases. Elevated expression was also linked to poorer overall survival in both the TNBC and HER2-positive subgroups. Functional assays showed that RTN4IP1 silencing was accompanied by reduced proliferation, increased apoptosis, and inhibited xenograft growth in MCF-7 and MDA-MB-453 models, whereas overexpression exhibited the opposite pattern. RTN4IP1 expression was further linked to features of the tumor immune microenvironment and to differential responses to Tamoxifen and Paclitaxel; inhibition of RTN4IP1 was associated with greater drug sensitivity, while overexpression coincided with reduced response. Together, these findings indicate that RTN4IP1 is closely associated with BC progression, prognosis, and treatment response, supporting its potential relevance as a biomarker and a candidate target for further investigation.