Purpose: Aging and metabolic syndrome (MetS) are intertwined risk factors for breast cancer (BC), but the core molecular nexus integrating these states is unknown. This study aimed to identify and validate a causal driver at this intersection. Methods: We integrated transcriptomic datasets from BC, MetS, and aging cohorts to identify common dysregulated genes. Machine learning algorithms prioritized a core diagnostic signature. We used Mendelian randomization to infer causality and characterized the lead candidate using single-cell RNA sequencing and comprehensive preclinical validation. Results: Our analysis identified a 25-gene core at the intersection of BC, MetS, and aging. Machine learning distilled this to five hub genes that formed a highly accurate diagnostic nomogram. Critically, Mendelian randomization established MCRS1 as the sole causal risk factor for BC among these candidates. Single-cell analysis revealed that Mcrs1 is predominantly expressed in proliferating cancer cells, where it drives a transcriptional program of enhanced cell cycle, senescence, and metabolic reprogramming. Accordingly, genetic knockdown of Mcrs1 profoundly suppressed BC cell proliferation and invasion in vitro , and in vivo experiments using an orthotopic BC model in C57BL/6 mice demonstrated significantly reduced tumor growth. Conclusion: This study identifies MCRS1 as a central molecular hub that causally links aging and MetS to BC pathogenesis. MCRS1 is a validated driver of tumor progression and a high-performance biomarker, representing a potential target for therapeutic development, particularly in BC patients with metabolic comorbidities.
Tao et al. (Tue,) studied this question.
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