Genotype-Dependent Dysregulation of the MDM2-p53 Axis and Breast Cancer Susceptibility in Bangladeshi Women: A Cas-Control Study

Abstract

BackgroundThe MDM2-p53 signaling pathway plays a central role in tumor suppression, and genetic variants that disrupt this pathway may influence breast cancer (BC) susceptibility. However, data from South Asian populations, particularly Bangladesh, remain limited. MethodsA case-control study was conducted in Bangladeshi women, including BC patients and healthy controls (HCs). Genotyping of MDM2 polymorphisms was performed using PCR-based methods. Circulating MDM2 and p53 protein levels were measured using enzyme-linked immunosorbent assays (ELISA). Associations between genotype, protein levels, BC status, and clinicopathological features were evaluated using appropriate statistical models. ResultsA strong and genotype-specific association was observed for MDM2 rs2279744. Women carrying the heterozygous TG genotype had a markedly increased risk of BC across additive, dominant, and over-dominant models, whereas the GG genotype showed a protective effect under the recessive model. In contrast, rs937282 did not show a significant association with BC risk. Circulating MDM2 levels were significantly elevated in patients compared with controls and varied by rs2279744 genotype, while circulating p53 levels showed an opposite trend. A strong inverse correlation was observed between serum MDM2 and p53 levels, supporting dysregulation of the MDM2-p53 feedback loop. Elevated MDM2 levels were also noted in HER2-positive and triple-positive BC subtypes. ConclusionTogether, these findings indicate that the MDM2 rs2279744 polymorphism contributes to BC susceptibility in a genotype-specific manner, likely through disruption of the MDM2-p53 regulatory balance. However, the absence of functional validation limits direct causal inference.