ABSTRACT Background Estradiol, the key endogenous estrogen, reduces the risk of urinary obstruction by smooth muscle relaxation but also increases susceptibility to breast cancer (BC). However, whether estradiol serves as a mechanistic mediator linking urinary tract obstruction and BC remains unclear. This study aimed to determine if there is an association between urinary tract obstruction and the risk of BC and to assess the potential mediating role of systemic estradiol. Methods A case‐control study and survival analysis of Cox regression were conducted using clinical data from the United Kingdom Biobank (UKB) (502,129 participants). To explore genetic causality, we performed a two‐sample Mendelian randomization (MR) study leveraging extensive genomic data. For obstructive uropathy, we relied on female‐only summary statistics sourced from the UKB (520 cases, 193,654 controls), while BC data, categorized by estrogen receptor status, HER2 status, and triple‐negative subtypes, were sourced from the open genome‐wide association studies database. We identified single‐nucleotide polymorphisms with strong links to obstructive uropathy as instrumental variables. Inverse variance‐weighted analysis, backed by robustness checks such as Cochran's Q test and MR‐Egger regression, were used to ensure reliable results. Results The UKB research revealed a marked correlation between urinary obstruction and the risk of BC ( χ 2 = 576.25, p 0.05). Given the significant heterogeneity ( Q = 58.01, p = 1.44 × 10 −5 ) and low exposure heritability explained by single‐nucleotide polymorphisms h 2 SNP = 0.0282, standard error = 0.0015), this finding likely represents a false positive rather than a true causal effect. No pleiotropy or heterogeneity was detected in other analyses (all p > 0.05). Conclusions These observational data suggest that urinary obstruction protects against BC and that estradiol may play a mediating role. However, this association does not appear to be caused by a relationship at the genetic level, highlighting the need to explore alternative biological pathways.
Wang et al. (Wed,) studied this question.