Williams syndrome transcription factor (WSTF) acts as an activator of estrogen receptor signaling in breast cancer cells and the effect can be abrogated by 1α,25-dihydroxyvitamin D3

majority of estrogen receptor positive (ER +) breast cancers are growth stimulated by estrogens. The ability to inhibit the ER signaling pathway is therefore of critical importance in the current treatment of ER + breast cancers. It has been reported that l alpha,25-dihydroxyvitamin D-3 down-regulates the expression of the CYP19A1 gene, encoding the aromatase enzyme that catalyzes the synthesis of estradiol. Furthermore, l alpha,25-dihydroxyvitamin D-3 has also been reported to down-regulate the expression of estrogen receptor alpha (ER alpha), the main mediator of ER signaling. This study reports a novel transcription factor critical to l alpha,25-dihydroxyvitamin D-3-mediated regulation of estrogenic signaling in MCF-7 breast cancer cells. We have investigated the molecular mechanisms for the la,25-dihydroxyvitamin D-3-mediated down-regulation of CYP19A1 and ERa gene expression in human MCF-7 breast cancer cells and found that Williams syndrome transcription factor (WSTF) plays a key role by binding to the promoters of CYP19A1 and ERa. Although sometimes reported as an inhibitor of gene expression, we found that WSTF acts as an activator of the promoter activity of both CYP19A1 and ER alpha. Silencing of WSTF by siRNA transfection resulted in decreased aromatase-dependent cell growth as well as decreased ER signaling in the cells. When cells were treated with l alpha,25-dihydroxyvitamin D-3, WSTF was dissociated from the promoters and the promoter activities of CYP19A1 and ERa were decreased. We have measured the expression of WSTF in ER positive tumor-samples from breast cancer patients and found that WSTF is expressed in the majority of the investigated samples and that the expression is higher in cancer tissue than in normal tissue. However, we were not able to show any significant association between the WSTF expression in the tumor and the disease free and overall survival in this patient group who have received adjuvant tarnoxifen treatment, nor between the WSTF expression and the expression of ERa, progesterone receptor or HER2. The major conclusions of this study are that WSTF acts as an activator of ER signaling in MCF-7 breast cancer cells, that this action can be inhibited by l alpha,25-dihydroxyvitamin D-3, and that the expression of WSTF is higher in breast cancer tissue than in normal tissue. WSTF may by a new target for treatment of estrogen-dependent breast cancer cell growth.