Novel insights into UDP-glucuronosyltransferase 1A1 dysfunction and Gilbert's syndrome on estrogen metabolism and breast cancer

Breast cancer (BC) is the most commonly diagnosed malignancy in women worldwide, with over 2 million cases diagnosed each year. Almost 80% of invasive BC are estrogen receptor positive (ER+) with a large proportion of BC patients possessing elevated blood estrogen levels. Estrogen metabolism is regulated by glucuronidation, mediated by UDP-glucuronosyltransferases (UGTs), including UGT1A1. This pathway is shared between estrogen and other metabolites including unconjugated bilirubin (UCB), which has an overlapping binding site within UGT1A1. Ex vivo metabolic studies demonstrate reciprocal substrate-dependent competitive inhibition of glucuronidation between UCB and estrogens. Therefore, acutely or chronically elevated bilirubin levels could, hypothetically, reduce estrogen conjugation in vivo, increasing systemic estrogen concentrations. Similarly, elevated estrogen levels as observed in BC patients may affect UCB concentrations. Furthermore, reduced activity UGT1A1 polymorphisms (GS - Gilbert's syndrome) or mutation (CNS - Crigler-Najjar syndromes) in humans could also increase estrogen levels, increasing the risk of BC, as reported in clinical studies. This is the first review that integrates in vitro and clinical evidence demonstrating a potential interaction between estrogen and UCB metabolism. Recognition of this network could improve BC risk assessment and encourage earlier screening/surveillance strategies to prevent ER+BC.