Sp1 Is Necessary for Gene Activation of Adamts17 by Estrogen

Adamts17 is a member of a family of secreted metalloproteinases. In this report, we show that knockdown of Adamts17 expression induces apoptosis and inhibits breast cancer cell growth. Adamts17 expression can rapidly be induced by estrogens. siRNA knockdown of Sp 1 or Myc demonstrated that Sp 1 is required to induce Adamts17 gene expression in response to estrogen. Moreover, reporter assays showed that the proximal promoter and the upstream sequences were not capable of conferring estrogen responsiveness, suggesting that Sp 1 elements may be located in the downstream intronic region. We further demonstrated that Sp 1 and Myc binding in the proximal promoter region contributed to the Adamts17 basal expression. Furthermore, histone deacetylase (HDAC) and methylase inhibitors also induced Adamts17 expression, indicating that epigenetic alterations, such as aberrant HDAC and/or methylation are associated with dysregulated Adamts17 expression. By meta-analysis using Oncomine microarray data, we found that higher Adamts17 expression is found in several human cancer cell subtypes, especially in breast ductal carcinoma. Moreover, we found that there is an inverse correlation between higher Adamts17 expression and patients' survival. Our study suggests that Adamts17 may support breast cancer cell growth and survival. (C) 2014 Wiley Periodicals, Inc.