Cracking the Estrogen Receptor's Posttranslational Code in Breast Tumors

Abstract

Estrogen signaling pathways, because of their central role in regulating the growth and survival of breast tumor cells, have been identified as suitable and efficient targets for cancer therapies.Agents blocking estrogen activity are already widely used clinically, and many new molecules have entered clinical trials, but intrinsic or acquired resistance to treatment limits their efficacy.The basic molecular studies underlying estrogen signaling have defined the critical role of estrogen receptors (ER) in many aspects of breast tumorigenesis.However, important knowledge gaps remain about the role of posttranslational modifications (PTM) of ER in initiation and progression of breast carcinogenesis.Whereas major attention has been focused on the phosphorylation of ER, many other PTM (such as acetylation, ubiquitination, sumoylation, methylation, and palmitoylation) have been identified as events modifying ER expression and stability, subcellular localization, and sensitivity to hormonal response.This article will provide an overview of the current and emerging knowledge on ER PTM, with a particular focus on their deregulation in breast cancer.We also discuss their clinical relevance and the functional relationship between PTM.A thorough understanding of the complete picture of these modifications in ER carcinogenesis might not only open new avenues for identifying new markers for prognosis or prediction of response to endocrine therapy but also could promote the development of novel therapeutic strategies.(Endocrine Reviews 32: 597-622, 2011) I. Introduction II.Biology of Estrogen Receptors and Breast Cancer A. ER␣ and ER␤ subtypes B. Genomic action of ER C. Nongenomic action of ER D. Endocrine therapies in breast cancer III.Posttranslational Modifications of Estrogen Receptors A. PTM involved in ER genomic signaling B. PTM involved in ER nongenomic signaling C. Molecular events affecting ER PTM D. ER PTM deregulated in breast cancer IV. Discussion V.