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.

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…Other types of modifications of ERα, which include acetylation, methylation, ubiquitination and SUMOylation (Ascenzi et al . 2006, Le Romancer et al . 2011), may also affect the sensitivity of breast cancer cells to AEs.…”

Progesterone receptor membrane component 1 promotes survival of human breast cancer cells and the growth of xenograft tumors

“…5,6 In contrast, an understanding of the actions of progestins in the development and progression of breast cancer is controversial. 7,8 In general, it is thought that progestins can both inhibit and stimulate proliferation of breast cancer cells.…”

Structural Basis for Ca2+-induced Activation and Dimerization of Estrogen Receptor α by Calmodulin

“…Approximately 70% of all breast carcinomas depend on E2 and ER-␣ for growth (52). CaM contributes to the regulation of both ER-␣ degradation and ER-␣-mediated transcriptional activation, thereby enhancing the growth-promoting effects of E2 (53).…”

“…CaM enhances the stability of ER-␣ (40) by reducing its ubiquitination (55). Several of the residues on ER-␣ with which CaM interacts are sites of post-translational modification (52). For example, Lys 302 and Lys 303 are ubiquitylated, and it is likely that bound CaM would sterically hinder ubiquitylation, preventing ER-␣ degradation.…”