%0 Journal Article
%T The Estrogen Receptor Joins Other Cancer Biomarkers as a Predictor of Outcome
%A Kimberly K. Leslie
%A Kristina W. Thiel
%A Henry D. Reyes
%A Shujie Yang
%A Yuping Zhang
%A Matthew J. Carlson
%A Nirmala S. Kumar
%A Donghai D. Dai
%J Obstetrics and Gynecology International
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/479541
%X Endometrial cancer, the most common gynecologic malignancy in the United States, is on the rise, and survival is worse today than 40 years ago. In order to improve the outcomes, better biomarkers that direct the choice of therapy are urgently needed. In this review, we explore the estrogen receptor as the most studied biomarker and the best predictor for response for endometrial cancer reported to date. 1. Endometrial Cancer as a Hormonally Regulated Disease Endometrial cancer is the most common gynecologic malignancy in the United States, with an estimated 47,130 cases and over 8,500 deaths expected in 2013. The disease is on the rise and, unlike cancers arising in most other sites, five-year survival is worse today than in 1975 (87% in 1975¨C77; 83% in 2003¨C08) [1]. Biomarkers that can be used to guide treatment selection are urgently needed in order to address this alarming trend of decreasing survival. The purpose of this paper is to review the most consistently studied marker for response to therapy on clinical trials in endometrial cancer, the estrogen receptor (ER), and to highlight new information linking its expression to the outcomes. Estrogen binds to at least three major classes of receptors, ER- , ER- , and GPR30 (Figure 1). ER- predominates in the endometrium and is the best studied of the three. 17 -OH-estradiol is the most active ligand and, upon binding to ER- , causes the transactivation of numerous growth-promoting genes, including growth factors such as epidermal growth factor (EGF) and its receptor (EGFR), insulin-like growth factor-1 (IGF-1), and growth-enhancing protooncogenes such as c-fos and c-myc [2¨C13]. Most relevant for this discussion are growth factors such as EGF, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and IGF. These ligands, in turn, activate cognate growth factor receptors, leading to multiple signaling cascades which drive cellular proliferation. Figure 1: Hormone receptors in endometrial tumors. In ER- dependent tumors (left side), estrogen induces growth factors and PR through ER- . This creates a positive feedback loop between ER- and growth factor signaling. However, progesterone (P4), when bound to PR, downregulates ER and PR. In addition, MAPK activation downstream of growth factor signaling results in phosphorylation of ER and PR and the ligand-dependent loss of PR and ER proteins by ubiquitination-mediated proteasomal degradation. ER- and PR levels are increased again at the level of transcription by estrogen stimulation. Hence, the growth of these tumors is dependent upon
%U http://www.hindawi.com/journals/ogi/2013/479541/