Title

Estrogen Receptor Regulates E2F1 Expression to Mediate Tamoxifen Resistance

Document Type

Article

ISSN

1541-7786

Volume

8

Issue

3

First Page

343

Last Page

352

Publication Date

2010

Department

Natural Sciences and Mathematics

Abstract

Antiestrogen resistance often develops with prolonged exposure to hormone therapies, including tamoxifen, and is a major problem in the treatment of breast cancer. Understanding the mechanisms involved in the development of antiestrogen resistance is an important step in the development of new targeted therapies. Two forms of antiestrogen resistance exist: de novo resistance and acquired resistance. To mimic acquired resistance, we have established a tamoxifen-resistant breast cancer cell line (MCF-7TamR) by treating parental MCF-7 cells with tamoxifen over a period of 6 months to select for cells with the resistant phenotype. Characterization of the MCF-7TamR cells under normal, hormone-deprived, and tamoxifen-treated conditions suggests that these cells continue to grow in the presence of tamoxifen. Additionally, a greater percentage of resistant cells enter the S phase under tamoxifen conditions, compared with parental MCF-7 cells. Consistent with these growth results, molecular analysis indicates that tamoxifen-resistant cells express higher levels of cyclin E1, cdk2, ACTR, and E2F1. Faslodex or ICI 182, 780 (ICI)-mediated degradation of estrogen receptor (ER) reduced the proliferation of these cells, as well as the level of E2F1 expression in tamoxifen-resistant cells, suggesting that tamoxifen resistance and E2F1 expression are in part dependent on ER. We further showed that tamoxifen enhances the ERalpha/Sp-1 interaction and promotes the recruitment of ERalpha and Sp-1 to the proximal promoter of E2F1 in resistant cells. Collectively, our findings suggest that tamoxifen resistance is a result of increased ERalpha/Sp-1 interaction, which enhances the expression of E2F1 to promote tamoxifen resistance.

Rights

Copyright © American Association for Cancer Research. All rights reserved.

Publisher Statement

Originally published as Louie, Maggie C., McClellan, Ashley, Siewitt, Christina, Kawabata, Lauren. (2010). Estrogen receptor regulates E2F1 expression to mediate tamoxifen resistance. Molecular Cancer Research 8(3). 343 - 352.