Potential Novel Role of UDP Glucuronosyltransferases 2B11 and 2B28 in Crosstalk Between Androgen and Lipid Signalling

Androgens play critical roles in both prostate and breast cancer progression. Recent work has revealed extensive crosstalk between androgen and lipid signalling, including the ability of the androgen receptor to control lipid synthesis and uptake to fuel prostate cancer growth [1, 2]. Members of the UDP-glucuronosyltransferase (UGT) enzyme family can metabolically inactivate multiple lipophilic small molecules including steroids such as androgens, which modulates both prostate and breast cancer progression [3, 4]. Moreover, transcriptional induction of UGTs by steroid-liganded nuclear receptors (e.g. AR and ER) can create a feedback loop to control steroid signalling [3].

The UGT2B11 and UGT2B28 enzymes are dramatically induced by androgens in prostate and breast cancer cells (up to 200-fold); however, unlike some other UGTs they have little or no activity towards androgens and hence their functions have been enigmatic. We now have evidence that UGT2B11 and UGT2B28 function via two novel mechanisms that together indirectly drive cancer cell growth downstream of androgen signals. First, UGT2B11 and UGT2B28 control the activity of the SREBP lipid-sensing and signalling pathway leading to increased expression of target genes involved in lipid synthesis/metabolism. They also appear to influence feedback regulation of nuclear SREBP via proteolytic turnover. Second, UGT2B11 and UGT2B28 heterodimerize with and inhibit known androgen-metabolizing UGT enzymes, thus preventing androgen inactivation and clearance. These findings suggest a new mechanism for crosstalk between androgen and lipid signalling pathways in breast and prostate cancer cells, and prompt further investigation of UGTs as therapeutic targets.