Estrogen regulation of the glucuronidation enzyme UGT2B15 in estrogen receptor-positive breast cancer cells.

Estrogens and androgens influence many properties of breast cancer cells; hence, regulation of local estrogen and androgen levels by enzymes involved in steroid hormone biosynthesis and metabolism would impact signaling by these hormones in breast cancer cells. In this study, we show that the UDP-glucuronosyltransferase (UGT) enzyme UGT2B15, a member of the UGT family of phase II enzymes involved in the glucuronidation of steroids and xenobiotics, is a novel, estrogen-regulated gene in estrogen receptor (ER)-positive human breast cancer cells (MCF-7, BT474, T47D, and ZR-75). UGT2B15 is the only UGT2B enzyme up-regulated by estrogen, and marked estradiol stimulation of UGT2B15 mRNA levels is observed, in a time- and dose-dependent manner.

Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action.

Estrogenic hormones are classically thought to exert their effects by binding to nuclear estrogen receptors and altering target gene transcription, but estrogens can also have nongenomic effects through rapid activation of membrane-initiated kinase cascades. The development of ligands that selectively activate only the nongenomic pathways would provide useful tools to investigate the significance of these pathways. We have prepared large, abiotic, nondegradable poly(amido)amine dendrimer macromolecules that are conjugated to multiple estrogen molecules through chemically robust linkages.

Activities of estrogen receptor alpha- and beta-selective ligands at diverse estrogen responsive gene sites mediating transactivation or transrepression.

Estrogens exert their regulatory transcriptional effects, which can be stimulatory or repressive, at diverse gene sites via two estrogen receptors, ERalpha and ERbeta. Since these two ERs have different tissue distributions, ligands that have the capacity to selectively activate or inhibit these two ERs would be useful in elucidating the biology of these two receptors and might assist in the development of estrogen pharmaceuticals with improved tissue selectivity. We have developed several ligands that showed ERalpha or ERbeta selectivity at promoter-gene sites containing consensus estrogen response elements (EREs): ERalpha-selective agonist (propyl-pyrazole-triol (PPT)), ERalpha-selective antagonist (methyl-piperidino-pyrazole (MPP)), ERbeta-potency selective agonist (diarylpropionitrile (DPN)) and ERbeta-selective antagonist/ERalpha-agonist (R,R-tetrahydrochrysene (R,R-THC)).

Antagonists selective for estrogen receptor alpha.

To develop compounds that are antagonists on ER(alpha), but not ER(beta), we have added basic side-chains typically found in nonsteroidal antiestrogens to pyrazole compounds that bind with much higher affinity to ER(alpha) than to ER(beta). In this way we have developed basic side-chain pyrazoles (BSC-pyrazoles) that are high affinity, potent, selective antagonists on ER(alpha). These BSC-pyrazoles are themselves inactive on ER(alpha) and ER(beta), and they antagonize E2 stimulation by ER(alpha) only.