EVALUATION OF CLINICAL AND ENVIRONMENTAL ANTIESTROGENS WITH HUMAN ESTROGEN-RECEPTOR EXPRESSED IN SACCHAROMYCES-CEREVISIAE - A NOVEL ROLE FOR ABC-CASSETTE TRANSPORTERS IN MEDIATING ANTIESTROGENIC ACTIVITY

The effectiveness of anti-estrogens in treating estrogen-dependent dis eases is limited by the acquired resistance of some diseases to anti-e strogens. This effect could occur by the export of anti-estrogens by c ell membrane transport proteins. To study this phenomenon we have expr essed human estrogen receptor (hER) and an estrogen-sensitive reporter in wild-type yeast and two transport-defective strains. In the wild-t ype strain, the most effective anti-estrogen was nafoxidine. 4-Hydroxy tamoxifen and clomiphene were inactive whereas tamoxifen had signific ant inhibitory activity in the wild-type strain. Using a strain missin g the ABC-cassette transporter Snq2, clomiphene had anti-estrogenic ac tivity. 4-Hydroxy tamoxifen had anti-estrogenic activity only in yeast lacking the transporter Pdr5. Whole cell binding assays indicated tha t 4-hydroxy tamoxifen is exported by Pdr5. Environmental chemicals suc h as polychlorinated biphenyls function as partial estrogens and anti- estrogens in yeast. In the absence of Pdr5 or Snq2, the estrogenic act ivity of 4-hydroxy, 2',4',6'-trichloro biphenyl (3-PCB) was substantia lly reduced in comparison to its activity in the wild-type strain. Int erestingly, the antiestrogenic activity of 3-PCB was equivalent in the wild-type and transporter-defective strains. Our results suggest a no vel role for ABC-cassette transporters in regulating the activity of c linical and environmental anti-estrogens. (C) 1997 Academic Press.