Identification and cloning of a novel androgen-responsive gene, uridine diphosphoglucose dehydrogenase, in human breast cancer cells.

Abstract

Androgens inhibit the growth of breast cancer cells, but the mechanism of androgen-induced growth inhibition has not yet been elucidated, and few androgen-responsive genes have been identified. We, therefore, used differential display PCR to identify novel androgen-responsive genes in ZR-75-1 human breast cancer cells. The human UDP-glucose dehydrogenase gene (UDPGDH), which was not known to be androgen regulated, was detected and cloned by complementary DNA library screening. The UDPGDH open reading frame codes for a protein of 494 amino acids that migrates at an apparent molecular mass of approximately 54 kDa. Northern blot analysis revealed the existence of two messenger RNA species of approximately 3.5 and 2.7 kb in all of the human breast cancer cell lines examined. The major UDPGDH transcript was induced rapidly (within 6 h) by dihydrotestosterone in ZR-75-1 cells, and a maximal 13-fold induction was observed after 24 h of treatment. The increase in UDPGDH messenger RNA was completely prevented by coincubation with the pure antiandrogen hydroxyflutamide, but not by cycloheximide, indicating that UDPGDH is directly regulated by the androgen receptor. As UDPGDH is required for the production of uridine 5'-diphosphoglucuronic acid, a substrate for the steroid-conjugating uridine diphospho-glucuronosyltransferase enzymes, up-regulation of UDPGDH expression by androgens might play an important role in the control of sex steroid inactivation via glucuronidation in breast cancer cells.