Differential regulation of native estrogen receptor-regulatory elements by estradiol, tamoxifen, and raloxifene

Levy, N; Tatomer, D; Herber, CB; Zhao, XY; Tang, H; Sargeant, T; Ball, LJ; Summers, J; Speed, TP; Leitman, DC

Author(s): Levy, N; Tatomer, D; Herber, CB; Zhao, XY; Tang, H; Sargeant, T; Ball, LJ; Summers, J; Speed, TP; Leitman, DC;
Details: Publication Year 2008-02,Volume 22,Issue #2,Page 287-303
Journal Title: MOLECULAR ENDOCRINOLOGY
Publication Type: Journal Article
Abstract: Estrogen receptors (ERs) regulate gene transcription by interacting with regulatory elements. Most information regarding how ER activates genes has come from studies using a small set of target genes or simple consensus sequences such as estrogen response element, activator protein 1, and Sp1 elements. However, these elements cannot explain the differences in gene regulation patterns and clinical effects observed with estradiol (E-2) and selective estrogen receptor modulators. To obtain a greater understanding of how E-2 and selective estrogen receptor modulators differentially regulate genes, it is necessary to investigate their action on a more comprehensive set of native regulatory elements derived from ER target genes. Here we used chromatin immunoprecipitation-cloning and sequencing to isolate 173 regulatory elements associated with ER alpha. Most elements were found in the introns (38%) and regions greater than 10 kb upstream of the transcription initiation site (38%); 24% of the elements were found in the proximal promoter region (< 10 kb). Only 11% of the elements contained a classical estrogen response element; 23% of the elements did not have any known response elements, including one derived from the naked cuticle homolog gene, which was associated with the recruitment of p160 coactivators. Transfection studies found that 80% of the 173 elements were regulated by E 2, raloxifene, or tamoxifen with ER alpha or ER beta. Tamoxifen was more effective than raloxifene at activating the elements with ER alpha, whereas raloxifene was superior with ER beta. Our findings demonstrate that E-2, tamoxifen, and raloxifene differentially regulate native ER-regulatory elements isolated by chromatin immunoprecipitation with ER alpha and ER beta.
Publisher: ENDOCRINE SOC
Keywords: BREAST-CANCER CELLS; GENE-EXPRESSION; TARGET GENES; POSTMENOPAUSAL WOMEN; BINDING-SITES; ER-ALPHA; TRANSCRIPTIONAL REGULATION; OSTEOSARCOMA CELLS; TISSUE-SPECIFICITY; RESPONSE ELEMENTS
Publisher's Version: https://doi.org/10.1210/me.2007-0340
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2008-02-01 12:00:00