Germline TWAS Convergence Between NMN- Responsive Aging Pathways and Triple-Negative Breast Cancer Susceptibility: Autophagy and MAP2K2 as Translational Leads

Background Triple-negative breast cancer remains difficult to prevent and treat because it lacks the receptor-defined targets available for other breast cancer subtypes and encompasses considerable biological heterogeneity. Autophagy, NAD-positive metabolism, and intracellular trafficking help cells adapt to metabolic stress and age-related damage. Long-term nicotinamide mononucleotide treatment in mice has also been linked to transcriptional changes involving RAB11A-mediated trafficking, CPT2-dependent fatty-acid oxidation, MAP2K2 signaling, and autophagy-related processes. Whether these pathways overlap with inherited susceptibility to triple-negative breast cancer is unknown. Methods A multi-gene-set transcriptome-wide association study pipeline was applied to overall breast cancer and triple-negative breast cancer summary statistics derived from Zhang et al. (2020). Ten full KEGG pathways nominated through 35 NMN-responsive genes were evaluated using tissue-combined S-PrediXcan scores, Stouffer enrichment, random-gene permutation, bootstrap confidence intervals, differential tests, cross-phenotype profile correlations, leave-one-out influence analysis, and sensitivity analyses. Results Autophagy produced the strongest supported result in triple-negative breast cancer, with a Stouffer Z of −8.98, a bootstrap 95% confidence interval of −14.78 to −3.09, a permutation p value of .0022, and a pathway false discovery rate of .022. The overall breast cancer–triple-negative breast cancer difference was consistent across 11 tissues, with a mean gap of +2.83 and the same gap direction in 82% of tissues. The signal remained stable under the prespecified influence rule. MAP2K2 was recurrent across autophagy, Ras/MAPK, and cytoskeletal pathways and had oppositely signed associations in the two phenotypes. Endocytosis was suggestive but did not survive pathway correction. Fatty-acid degradation was not enriched but showed marked cross-phenotype anticorrelation. Conclusions The results identify an autophagy-related germline expression pattern associated with triple-negative breast cancer susceptibility and nominate MAP2K2 for focused follow-up. They support cross-context convergence between NMN-responsive aging biology and breast cancer genetics, but they do not show that NMN prevents or treats breast cancer. Gene-level colocalization, case-case analyses, and functional validation are required.