Regulation of UDP glucuronosyltransferase 2B genes in breast cancer cells

In addition to their role in eliminating drugs and toxins, UDP glucuronosyltransferases (UGT) regulate steroid hormones levels in various tissues and organs. UGT2B family members glucuronidate androgens and some (e.g. 2B15 and 2B17) appear to influence the progression of prostate cancer. However, the roles of UGT2B enzymes in breast cancer are less well established. Androgens promote the growth of some breast cancer cell lines by binding directly to the androgen receptor (AR) or indirectly, to the estrogen receptor (ER) after their aromatization to estrogen. Hence the action of UGTs that metabolize androgens are likely to inhibit cancer cell growth, and therefore mechanisms that regulate their levels may be a target for therapeutic intervention in breast cancer initiation and progression, and in modulating drug resistance. Common hormonal therapies for breast cancer include blocking ER function with selective ER modulators and blocking conversion of androgens to estrogens with aromatase inhibitors. UGT2B15 metabolizes the most commonly used selective ER modulator, tamoxifen; whilst UGT2B17 metabolizes the commonly used aromatase inhibitor exemestane. We show here that several UGT2B enzymes are regulated by estrogens, androgens, tamoxifen and exemestane, potentially creating feedback loops that could alter the progression of cancer as well as its response to these hormonal therapies. We also provide preliminary evidence that multiple UGTs, are constitutively elevated in cancer stem cells. UGTs may play a role in the inherent resistance of cancer stem cells to anti-cancer drugs including hormonal therapies, and hence in the progression of tumours to drug resistance.