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. showing the proposed interplay between UDP-glucuronosyltransferases ( UGTs) conjugation of bilirubin (UCB) and estrogens (ESTs: E1, E2, E3) in breast cancer (BC). Substrate dependent competition for conjugation between UCB and estrogens, suggests overlapping binding sites on UGT1A1. UGT1A1, an enzyme for UCB conjugation, also glucuronidates estrogens. Accumulation of estrogen due to reduced UGT1A1 activity and/or UCB competition could also increase estrogen metabolites. Estrogens activate estrogen receptors (ER) that can increase the risk of BC. Furthermore, reduced UGT1A1 activity can also increase serum UCB concentrations reducing the risk of metabolic syndrome and associated CVDs. CB; conjugated BR, RET; reticuloendothelial system, E1; estrone, E2; estradiol, E3; estradiol. • Gilbert’s syndrome (GS; reduced UGT1A1 expression) is considered a benign condition • UGT1A1 enzyme is responsible for bilirubin (BR) and estrogens (ESTs) conjugation/elimination • In vitro/ex vivo studies indicate competition for conjugation between ESTs and BR, hindering EST metabolism • Human trials on UGT1A1 polymorphism in BC are inconsistent and retrospective • Prospective trials will determine whether UGT1A1 dysfunction perturbs EST metabolism and increases BC risk