Abstract

The enzyme aromatase, encoded by the CYP19A1 gene, catalyzes the production of estrogens and inhibition of aromatase has therefore become one of the key strategies in breast cancer treatment We have studied the effects of the vitamin D analog EB1089 on aromatase gene expression and enzyme activity in breast cancer cells. We found that EB1089 was able to decrease the gene expression and enzyme activity as well as inhibit aromatase-dependent cell growth. Furthermore, a low dose of EB1089 combined with low doses of clinically used aromatase inhibitors such as anastrozole, letrozole and exemestane were able to effectively inhibit aromatase-dependent growth of breast cancer cells. The molecular mechanism for this effect of EB1089 on the aromatase gene expression was investigated and we found that it is mediated by the vitamin D receptor (VDR), vitamin D receptor interacting repressor (VDIR) and Williams syndrome transcription factor (WSTF). ChIP and Re-ChIP assays revealed that EB1089 mediates dissociation of WSTF from the CYP19A1 promoter and thereby decreases the gene expression. Regulation of aromatase via WSTF has not been reported previously. Furthermore, gene silencing of WSTF results in decreased gene expression of CYP19A1 and aromatase activity, showing that WSTF is an interesting drug target for development of new anti-cancer drugs. In summary, we report that the vitamin D analog EB1089 is able to decrease the gene expression and enzyme activity of aromatase via a novel regulatory pathway for aromatase and suggest that EB1089 may be a new treatment option for estrogen dependent breast cancer. (c) 2012 Elsevier B.V. All rights reserved.

Keywords

Breast cancer; Aromatase; Vitamin D; Selective aromatase modulator; CYP19 regulation

Published in

Biochimica et biophysica acta. Molecular cell research
2013, Volume: 1833, number: 1, pages: 40-47

UKÄ Subject classification

Pharmacology and Toxicology


Publication identifier

DOI: https://doi.org/10.1016/j.bbamcr.2012.10.012

Permanent link to this page (URI)

https://res.slu.se/id/publ/88784